Applying an Agent-based Model to Simulate Just-In-Time Support for Keeping Users of eLearning Courses Motivated.
Persuasive technology can support users of self-paced eLearning courses during critical moments of low motivation. Agent-based models (ABMs) - a relatively unfamiliar phenomenon within the persuasive technology and eLearning domains- offers a potentially relevant methodology to understand when the support should be delivered. Using ABMs, the dynamics of motivational user states can be simulated. Subsequently, emerging user patterns can be traced that can potentially provide insight in the ebb and flow of motivation. For the purpose of this study, we designed an exploratory ABM on motivation based on the mental energy notion of which the foundations can be found both within the literature of motivational psychology and agent-based modeling. During the simulations we succeeded in generating moments of critically low user motivation. In addition, we were able to simulate the positive impact of external user support at those critical moments. These results suggest that it is plausible to put further energy in developing ABM models with the ultimate goal of feeding persuasive technology with the ability to deliver just-in-time user support during eLearning.


Standardised mindfulness-based interventions in healthcare: an overview of systematic reviews and meta-analyses of RCTs.
Mindfulness-based therapies are being used in a wide range of common chronic conditions in both treatment and prevention despite lack of consensus about their effectiveness in different patient categories. To systematically review the evidence of effectiveness MBSR and MBCT in different patient categories. A systematic review and meta-analysis of systematic reviews of RCTs, using the standardized MBSR or MBCT programs. We used PRISMA guidelines to assess the quality of the included reviews and performed a random effects meta-analysis with main outcome measure Cohen's d. All types of participants were considered. The search produced 187 reviews: 23 were included, covering 115 unique RCTs and 8,683 unique individuals with various conditions. Compared to wait list control and compared to treatment as usual, MBSR and MBCT significantly improved depressive symptoms (d=0.37; 95%CI 0.28 to 0.45, based on 5 reviews, N=2814), anxiety (d=0.49; 95%CI 0.37 to 0.61, based on 4 reviews, N=2525), stress (d=0.51; 95%CI 0.36 to 0.67, based on 2 reviews, N=1570), quality of life (d=0.39; 95%CI 0.08 to 0.70, based on 2 reviews, N=511) and physical functioning (d=0.27; 95%CI 0.12 to 0.42, based on 3 reviews, N=1015). Limitations include heterogeneity within patient categories, risk of publication bias and limited long-term follow-up in several studies. The evidence supports the use of MBSR and MBCT to alleviate symptoms, both mental and physical, in the adjunct treatment of cancer, cardiovascular disease, chronic pain, depression, anxiety disorders and in prevention in healthy adults and children.


Effect of diets with goat milk fat supplemented with exercise on anxiety and oxidative stress in the brains of adult rats.
The objective of this study is to evaluate the effects of a diet with goat milk fat supplemented with physical training on markers of oxidative stress in the brain and anxiety behavior in rats. Adult male rats were randomly divided into six groups (n = 10 per group): control sedentary (CON) and exercised (CON-EX) groups, goat milk fat sedentary (GM) and exercised (GM-EX) groups, goat milk fat enriched with CLA sedentary (GM-CLA) and exercised (GM-CLA-EX) groups. The exercised groups were submitted to treadmill running during four weeks. Anxiety parameters were evaluated with the open field (OF) and elevated plus maze (EPM) tests. Malondialdehyde (MDA) and glutathione (GSH) levels were measured in the brain. Compared to the CON and GM groups, the GM-CLA group (p < 0.05), in which the animals were treated with goat milk fat with an increased CLA content, showed higher rearing. All exercised animals presented an increase in grooming when compared to sedentary animals. The number of entries in the open arms and time spent in the open arms was higher in sedentary groups (p < 0.05). MDA levels in the brain were lower in the GM group when compared to those in the CON group (p < 0.05). MDA increased in exercised animals (p < 0.05). GM and GM-CLA groups showed a significant elevation in the GSH levels in the brain. Goat milk fat, however, showed a potential effect on the reduction of oxidative stress, which was associated with a reduction in anxiety behavior. However, this beneficial effect was reversed when exercise was involved.


The role of monocyte subsets in myocutaneous revascularization.
The controlled recruitment of monocytes from the circulation to the site of injury and their differentiation into tissue macrophages are critical events in the reconstitution of tissue integrity. Subsets of monocytes/macrophages have been implicated in the pathogenesis of atherosclerosis and tumor vascularity; however, the significance of monocyte heterogeneity in physiologic neovascularization is just emerging. A cranial-based, peninsular-shaped myocutaneous flap was surgically created on the dorsum of wild-type mice (C57BL6) and populations of mice with genetic deletion of subset-specific chemokine ligand-receptor axes important in monocyte trafficking and function (CCL2(-/-) and CX3CR1(-/-)) (n=36 total; 12 mice per group, nine with flap and three unoperated controls). Planimetric analysis of digital photographic images was utilized to determine flap surface viability in wild-type and knockout mice. Real-time myocutaneous flap perfusion and functional revascularization was determined by laser speckle contrast imaging. Image analysis of CD-31 immunostained sections confirmed flap microvascular density and anatomy. Macrophage quantification and localization in flap tissues was determined by F4/80 gene and protein expression. Quantitative reverse transcription-polymerase chain reaction was performed on nonoperative back skin and postoperative flap tissue specimens to determine local gene expression. Myocutaneous flaps created on wild type and CX3CR1(-/-) mice were engrafted to the recipient site, resulting in viability. In contrast, distal full thickness cutaneous necrosis and resultant flap dehiscence was evident by d 10 in CCL2(-/-) mice. Over 10 d, laser speckle contrast imaging documented immediate graded flap ischemia in all three groups of mice, functional flap revascularization in wild type and CX3CR1(-/-) mice, and lack of distal flap reperfusion in CCL2(-/-) mice. Immunostaining of serial histologic specimens confirmed marked increases in microvascular density and number of macrophages in wild type mice, intermediate increases in CX3CR1(-/-) mice, and no significant change in vessel count or macrophage quantity in CCL2(-/-) mice over the study interval. Finally, quantitative reverse transcriptase polymerase chain reaction demonstrated that the loss of function of chemokine ligand and receptor genes influenced the transcription of local genes involved in monocyte chemotaxis and wound angiogenesis. In a graded-ischemia wound healing model, monocyte recruitment was severely impaired in CCL2(-/-) mice, resulting in failure of flap revascularization and concomitant cutaneous necrosis. Analysis of CX3CR1-deficient mice revealed adequate monocyte recruitment and revascularization for flap survival; however, the myeloid cell response and magnitude of neovascularization were dampened compared with wild type mice.


Effect of plant lectins on murine myeloma cells.
The mitogenic response (determined by uptake of [3H]-thymidine) of two different BALB/c myeloma lines, normal BALB/c spleen cells and spleen cells from tumour-bearing mice in primary culture to PHA, Con A, PWM and Robinia pseudoaccacia (RPA) extract was determined by measuring the uptake of [3H]-thymidine over 96 h. The pattern of the response of tumour and tumour-spleen cells to the 4 different lectins was similar, and different from that of normal spleen cells. The unstimulated cultures of tumour and tumour-spleen cells displayed an initial increased uptake of [3H]-thymidine, whereas stimulated cultures displayed a low initial uptake of label. After an initial phase of inhibition, ADJ-PC5 myeloma cells were stimulated by PHA and PWM to a greater extent than were normal spleen cells. On the other hand, normal spleen cells gave a markedly better response to Con A and RPA. The mitogenic response of tumour-spleen cells to all 4 lectins was intermediate between those observed for tumour and normal spleen cells; they responded better to Con A and RPA than did tumour cells but were not as responsive as spleen cells, whereas the converse was true for their response to PWM and PHA. In agreement with other reports, the data suggest that the responsiveness of tumour-spleen cells was due to the presence of tumour cells in this tissue. These results indicate that there is no definite evidence of an impaired lectin-responsiveness in lymphoid cells of mice bearing a myeloma.


In memory of Giovanni Berlinguer. The Man, the Scientist, the Politician.
On this occasion I am very grateful to the Academic Authorities for having asked me to illustrate the life of Giovanni Berlinguer as a Researcher, a Professor and a Doctor of Public Health. I will try to fulfill this duty, perhaps with some reservations, because I find it almost impossible to think of Giovanni as a researcher and a professor separately from his complex personality and his role as a politician and a brilliant and prolific writer. This is because Giovanni was an inextricable combination of all these roles, which cannot be described separately.


Zirconium ions up-regulate the BMP/SMAD signaling pathway and promote the proliferation and differentiation of human osteoblasts.
Zirconium (Zr) is an element commonly used in dental and orthopedic implants either as zirconia (ZrO2) or in metal alloys. It can also be incorporated into calcium silicate-based ceramics. However, the effects of in vitro culture of human osteoblasts (HOBs) with soluble ionic forms of Zr have not been determined. In this study, primary culture of human osteoblasts was conducted in the presence of medium containing either ZrCl4 or Zirconium (IV) oxynitrate (ZrO(NO3)2) at concentrations of 0, 5, 50 and 500 µM, and osteoblast proliferation, differentiation and calcium deposition were assessed. Incubation of human osteoblast cultures with Zr ions increased the proliferation of human osteoblasts and also gene expression of genetic markers of osteoblast differentiation. In 21 and 28 day cultures, Zr ions at concentrations of 50 and 500 µM increased the deposition of calcium phosphate. In addition, the gene expression of BMP2 and BMP receptors was increased in response to culture with Zr ions and this was associated with increased phosphorylation of SMAD1/5. Moreover, Noggin suppressed osteogenic gene expression in HOBs co-treated with Zr ions. In conclusion, Zr ions appear able to induce both the proliferation and the differentiation of primary human osteoblasts. This is associated with up-regulation of BMP2 expression and activation of BMP signaling suggesting this action is, at least in part, mediated by BMP signaling.


Nonstationary evolution and compositional heterogeneity in beetle mitochondrial phylogenomics.
Many published phylogenies are based on methods that assume equal nucleotide composition among taxa. Studies have shown, however, that this assumption is often not accurate, particularly in divergent lineages. Nonstationary sequence evolution, when taxa in different lineages evolve in different ways, can lead to unequal nucleotide composition. This can cause inference methods to fail and phylogenies to be inaccurate. Recent advancements in phylogenetic theory have proposed new models of nonstationary sequence evolution; these models often outperform equivalent stationary models. A variety of new phylogenetic software implementing such models has been developed, but the studies employing the new methodology are still few. We discovered convergence of nucleotide composition within mitochondrial genomes of the insect order Coleoptera (beetles). We found variation in base content both among species and among genes in the genome. To this data set, we have applied a broad range of phylogenetic methods, including some traditional stationary models of evolution and all the more recent nonstationary models. We compare 8 inference methods applied to the same data set. Although the more commonly used methods universally fail to recover established clades, we find that some of the newer software packages are more appropriate for data of this nature. The software packages p4, PHASE, and nhPhyML were able to overcome the systematic bias in our data set, but parsimony, MrBayes, NJ, LogDet, and PhyloBayes were not.


Calmodulin inhibition of human RyR2 channels requires phosphorylation of RyR2-S2808 or RyR2-S2814.
Calmodulin (CaM) is a Ca-binding protein that binds to, and can directly inhibit cardiac ryanodine receptor calcium release channels (RyR2). Animal studies have shown that RyR2 hyperphosphorylation reduces CaM binding to RyR2 in failing hearts, but data are lacking on how CaM regulates human RyR2 and how this regulation is affected by RyR2 phosphorylation. Physiological concentrations of CaM (100 nM) inhibited the diastolic activity of RyR2 isolated from failing human hearts by ~50% but had no effect on RyR2 from healthy human hearts. Using FRET between donor-FKBP12.6 and acceptor-CaM bound to RyR2, we determined that CaM binds to RyR2 from healthy human heart with a Kd = 121 ± 14 nM. Ex-vivo phosphorylation/dephosphorylation experiments suggested that the divergent CaM regulation of healthy and failing human RyR2 was caused by differences in RyR2 phosphorylation by protein kinase A and Ca-CaM-dependent kinase II. Ca2+-spark measurements in murine cardiomyocytes harbouring RyR2 phosphomimetic or phosphoablated mutants at S2814 and S2808 suggest that phosphorylation of residues corresponding to either human RyR2-S2808 or S2814 is both necessary and sufficient for RyR2 regulation by CaM. Our results challenge the current concept that CaM universally functions as a canonical inhibitor of RyR2 across species. Rather, CaM's biological action on human RyR2 appears to be more nuanced, with inhibitory activity only on phosphorylated RyR2 channels, which occurs during exercise or in patients with heart failure.


13C-n.m.r. study of citrate metabolism in rabbit renal proximal-tubule cells.
The metabolism of a 13C-labelled substrate, [3-13C]citrate, was monitored in rabbit renal proximal-tubule cells by 13C n.m.r. The relative enrichments of label in glutamate, glutamine and alpha beta-glucose allowed a calculation of the rate of the glutamate dehydrogenase flux relative to the flux via phosphoenolpyruvate carboxykinase. A ratio of 1.2 +/- 0.05 was found. Under steady-state conditions of active gluconeogenesis, the ratio of flux through pyruvate kinase to the gluconeogenic rate was 0.97 +/- 0.03.


Gallstones and ethnicity in the Americas.
Information on ethnicity as related to gallstones has been limited by insufficient or inaccurate characterization of ethnicity. Nevertheless, in recent years, ultrasonography has allowed limited examination of ethnic differences in the risk of gallbladder disease, defined by a history of cholecystectomy or ultrasonographic detection of gallstones. Among women, the risk of gallbladder disease is highest among American Indians, followed by Hispanics, non-Hispanic whites, and non-Hispanic blacks. Men differ from women by having lower risk in all ethnic groups and by having a similar prevalence between Hispanics and non-Hispanic whites. It does not appear that the type of stone differs much according to ethnic group in the United States. Well-known risks for gallbladder disease, such as obesity, weight loss, pregnancy, and low alcohol use do not explain differences in ethnic risk. As yet, genetic markers have not been identified that would explain differences in risk among ethnic groups. Higher case fatality rates among non-Hispanic blacks than non-Hispanic whites suggest that blacks may have inadequate access to medical care for gallbladder disease.


CYP2C9 and CYP2C19 polymorphic forms are related to increased indisulam exposure and higher risk of severe hematologic toxicity.
The anticancer agent indisulam is metabolized by the cytochrome P450 of enzymes CYP2C9 and CYP2C19. Polymorphisms of these enzymes may affect the elimination rate of indisulam. Consequently, variant genotypes may be clinically relevant predictors for the risk of developing severe hematologic toxicity. The purposes of this study were to evaluate the effect of genetic variants of CYP2C9 and CYP2C19 on the pharmacokinetics of indisulam and on clinical outcome and to assess the need for pharmacogenetically guided dose adaptation. Pharmacogenetic screening of CYP2C polymorphisms was done in 67 patients treated with indisulam. Pharmacokinetic data were analyzed with a population pharmacokinetic model, in which drug elimination was described by a linear and a Michaelis-Menten pathway. The relationships between allelic variants and the elimination pharmacokinetic parameters (CL, V(max), K(m)) were tested using nonlinear mixed-effects modeling. Polymorphisms causing a high risk of dose-limiting neutropenia were identified in a simulation study. The Michaelis-Menten elimination rate (V(max)) was decreased by 27% (P<0.0001) for heterozygous CYP2C9*3 mutants. Heterozygous CYP2C19*2 and CYP2C19*3 mutations reduced the linear elimination rate (CL) by 38% (P < 0.0001). The risk of severe neutropenia was significantly increased by these mutations and dose reductions of 50 to 100 mg/m(2) per mutated allele may be required to normalize this risk. CYP2C9*3, CYP2C19*2, and CYP2C19*3 polymorphisms resulted in a reduced elimination rate of indisulam. Screening for these CYP2C polymorphisms and subsequent pharmacogenetically guided dose adaptation may assist in the selection of an optimized initial indisulam dosage.


Rényi Generalization of the Accessible Entanglement Entropy.
Operationally accessible entanglement in bipartite systems of indistinguishable particles could be reduced due to restrictions on the allowed local operations as a result of particle number conservation. In order to quantify this effect, Wiseman and Vaccaro [Phys. Rev. Lett. 91, 097902 (2003)PRLTAO0031-900710.1103/PhysRevLett.91.097902] introduced an operational measure of the von Neumann entanglement entropy. Motivated by advances in measuring Rényi entropies in quantum many-body systems subject to conservation laws, we derive a generalization of the operationally accessible entanglement that is both computationally and experimentally measurable. Using the Widom theorem, we investigate its scaling with the size of a spatial subregion for free fermions and find a logarithmically violated area law scaling, similar to the spatial entanglement entropy, with at most a double-log leading-order correction. A modification of the correlation matrix method confirms our findings in systems of up to 10^{5} particles.


[Mucosal immunity in children with HIV infection and the possibility of correcting this immunity].
The influence of bacterial lysate [see text]PC-19 on the mucosal immunity of children with HIV infection was evaluated. The action of this topical immunomodulator was found to increase the synthesis of sIgA, which was indirectly reflected in a rise of the local immunity of the upper respiratory ways, preventing the aggravation of the chronic focal infection and the main disease. It should be pointed out that in a group of HIV-infected children and adolescents with an initially high level of salivary IgG the prescription of preparation [see text]PC-19 led to its considerable decrease. A decrease in the level of IgG and a rise in the content of sIgA in saliva under the action of the preparation correlated with a decrease in inflammatory changes in the nasopharyngeal mucosa. On the basis of results obtained in this study additions to the algorithm of the prophylactic medical observation of children and adolescents with HIV infection have been developed.


A case-control study of physical activity patterns and risk of non-fatal myocardial infarction.
The interactive effects of different types of physical activity on cardiovascular disease (CVD) risk have not been fully considered in previous studies. We aimed to identify physical activity patterns that take into account combinations of physical activities and examine the association between derived physical activity patterns and risk of acute myocardial infarction (AMI). We examined the relationship between physical activity patterns, identified by principal component analysis (PCA), and AMI risk in a case-control study of myocardial infarction in Costa Rica (N=4172), 1994-2004. The component scores derived from PCA and total METS were used in natural cubic spline models to assess the association between physical activity and AMI risk. Four physical activity patterns were retained from PCA that were characterized as the rest/sleep, agricultural job, light indoor activity, and manual labor job patterns. The light indoor activity and rest/sleep patterns showed an inverse linear relation (P for linearity=0.001) and a U-shaped association (P for non-linearity=0.03) with AMI risk, respectively. There was an inverse association between total activity-related energy expenditure and AMI risk but it reached a plateau at high levels of physical activity (P for non-linearity=0.01). These data suggest that a light indoor activity pattern is associated with reduced AMI risk. PCA provides a new approach to investigate the relationship between physical activity and CVD risk.


People systematically update moral judgments of blame.
Six experiments examine people's updating of blame judgments and test predictions developed from a socially regulated blame perspective. According to this perspective, blame emerged in human history as a socially costly tool for regulating other's behavior. Because it is costly for both blamers and violators, blame is typically constrained by requirements for "warrant"-evidence that one's moral judgment is justified. This requirement motivates people to systematically process available causal and mental information surrounding a violation. That is, people are relatively calibrated and evenhanded in utilizing evidence that either amplifies or mitigates blame. Such systematic processing should be particularly visible when people update their moral judgments. Using a novel experimental paradigm, we test 2 sets of predictions derived from the socially regulated blame perspective and compare them with predictions from a motivated-blame perspective. Studies 1-4 demonstrate (across student, Internet, and community samples) that moral perceivers systematically grade updated blame judgments in response to the strength of new causal and mental information, without anchoring on initial evaluations. Further, these studies reveal that perceivers update blame judgments symmetrically in response to exacerbating and mitigating information, inconsistent with motivated-blame predictions. Study 5 shows that graded and symmetric blame updating is robust under cognitive load. Lastly, Study 6 demonstrates that biases can emerge once the social requirement for warrant is relaxed-as in the case of judging outgroup members. We conclude that social constraints on blame judgments render the normal process of blame well calibrated to causal and mental information, and biases may appear when such constraints are absent. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Mepolizumab for difficult-to-control asthma with persistent sputum eosinophilia.
In asthma, anti-inflammatory therapy can usually reduce airway eosinophilic inflammation; but in certain subgroups this persists despite maximal therapy, and disease control is suboptimal. Mepolizumab is an anti IL-5. antibody that might reduce airway inflammation in such subgroups. Evaluation of the efficacy and safety data on mepolizumab in two studies performed in patients with refractory and corticosteroid-dependent asthma with persistent sputum eosinophilia. Mepolizumab given intravenously once a month was able to reduce sputum/blood eosinophilia and asthma exacerbations and to improve quality of life. Mepolizumab may be a promising anti-inflammatory therapy in asthma subgroups with heavy eosinophilic load in which conventional anti-inflammatory therapy is only partially effective.


Inhibition of nitrate reduction by chromium (VI) in anaerobic soil microcosms.
Chromium is often found as a cocontaminant at sites polluted with organic compounds. For nitrate-respiring microbes, Cr(VI) may be not only directly toxic but may also specifically interfere with N reduction. In soil microcosms amended with organic electron donors, Cr(VI), and nitrate, bacteria oxidized added carbon, but relatively low doses of Cr(VI) caused a lag and then lower rates of CO(2) accumulation. Cr(VI) strongly inhibited nitrate reduction; it occurred only after soluble Cr(VI) could not be detected. However, Cr(VI) additions did not eliminate Cr-sensitive populations; after a second dose of Cr(VI), bacterial activity was strongly inhibited. Differences in microbial community composition (assayed by PCR-denaturing gradient gel electrophoresis) driven by different organic substrates (glucose and protein) were smaller than when other electron acceptors had been used. However, the selection of bacterial phylotypes was modified by Cr(VI). Nine isolated clades of facultatively anaerobic Cr(VI)-resistant bacteria were closely related to cultivated members of the phylum Actinobacteria or Firmicutes. In Bacillus cereus GNCR-4, the nature of the electron donor (fermentable or nonfermentable) affected Cr(VI) resistance level and anaerobic nitrate metabolism. Our results indicate that carbon utilization and nitrate reduction in these soils were contingent upon the reduction of added Cr(VI). The amount of Cr(VI) required to inhibit nitrate reduction was 10-fold less than for aerobic catabolism of the same organic substrate. We speculate that the resistance level of a microbial process is directly related to the diversity of microbes capable of conducting it.


Development of PROTACs to address clinical limitations associated with BTK-targeted kinase inhibitors.
Chronic lymphocytic leukemia is a common form of leukemia and is dependent on growth-promoting signaling via the B-cell receptor. The Bruton tyrosine kinase (BTK) is an important mediator of B-cell receptor signaling and the irreversible BTK inhibitor ibrutinib can trigger dramatic clinical responses in treated patients. However, emergence of resistance and toxicity are major limitations which lead to treatment discontinuation. There remains, therefore, a clear need for new therapeutic options. In this review, we discuss recent progress in the development of BTK-targeted proteolysis targeting chimeras (PROTACs) describing how such agents may provide advantages over ibrutinib and highlighting features of PROTACs that are important for the development of effective BTK degrading agents. Overall, PROTACs appear to be an exciting new approach to target BTK. However, development is at a very early stage and considerable progress is required to refine these agents and optimize their drug-like properties before progression to clinical testing.


Unconventional natural gas development and public health: toward a community-informed research agenda.
Unconventional natural gas development (UNGD) using high-volume horizontal hydraulic fracturing ("fracking") has vastly increased the potential for domestic natural gas production in recent years. However, the rapid expansion of UNGD has also raised concerns about its potential impacts on public health. Academics and government agencies are developing research programs to explore these concerns. Community involvement in activities such as planning, conducting, and communicating research is widely recognized as having an important role in promoting environmental health. Historically, however, communities most often engage in research after environmental health concerns have emerged. This community information needs assessment took a prospective approach to integrating community leaders' knowledge, perceptions, and concerns into the research agenda prior to initiation of local UNGD. We interviewed community leaders about their views on environmental health information needs in three states (New York, North Carolina, and Ohio) prior to widespread UNGD. Interviewees emphasized the cumulative, long-term, and indirect determinants of health, as opposed to specific disease outcomes. Responses focused not only on information needs, but also on communication and transparency with respect to research processes and funding. Interviewees also prioritized investigation of policy approaches to effectively protect human health over the long term. Although universities were most often cited as a credible source of information, interviewees emphasized the need for multiple strategies for disseminating information. By including community leaders' concerns, insights, and questions from the outset, the research agenda on UNGD is more likely to effectively inform decision making that ultimately protects public health.


Cardiometabolic risk variables in overweight and obese children: a worldwide comparison.
The growing prevalence rate of pediatric obesity, which is frequently accompanied by several cardiometabolic risk factors, has become a serious global health issue. To date, little is known regarding differences for cardiometabolic risk factors (prevalence and means) in children from different countries. In the present review, we aimed to provide a review for the available evidence regarding cardiometabolic risk factors in overweight pediatric populations. We therefore provided information with respect to the prevalence of impaired fasting glucose/impaired glucose tolerance, high triglycerides, low HDL-cholesterol and hypertension (components of the metabolic syndrome) among cohorts from different countries. Moreover, we aimed to compare the means of glucose and lipid levels (triglycerides and HDL-cholesterol) and systolic/diastolic blood pressure values. After careful selection of articles describing cohorts with comparable age and sex, it was shown that both prevalence rates and mean values of cardiometabolic risk factors varied largely among cohorts of overweight children. After ranking for high/low means for each cardiometabolic risk parameter, Dutch-Turkish children and children from Turkey, Hungary, Greece, Germany and Poland were in the tertile with the most unfavorable risk factor profile overall. In contrast, cohorts from Norway, Japan, Belgium, France and the Dominican Republic were in the tertile with most favorable risk profile. These results should be taken with caution, given the heterogeneity of the relatively small, mostly clinical cohorts and the lack of information concerning the influence of the values of risk parameters on true cardiometabolic outcome measures in comparable cohorts. The results of our review present a fair estimation of the true differences between cardiometabolic risk profiles among pediatric cohorts worldwide, based on available literature.


Pavarotti/MKLP1 regulates microtubule sliding and neurite outgrowth in Drosophila neurons.
Recently, we demonstrated that kinesin-1 can slide microtubules against each other, providing the mechanical force required for initial neurite extension in Drosophila neurons. This sliding is only observed in young neurons actively forming neurites and is dramatically downregulated in older neurons. The downregulation is not caused by the global shutdown of kinesin-1, as the ability of kinesin-1 to transport membrane organelles is not diminished in mature neurons, suggesting that microtubule sliding is regulated by a dedicated mechanism. Here, we have identified the "mitotic" kinesin-6 Pavarotti (Pav-KLP) as an inhibitor of kinesin-1-driven microtubule sliding. Depletion of Pav-KLP in neurons strongly stimulated the sliding of long microtubules and neurite outgrowth, while its ectopic overexpression in the cytoplasm blocked both of these processes. Furthermore, postmitotic depletion of Pav-KLP in Drosophila neurons in vivo reduced embryonic and larval viability, with only a few animals surviving to the third instar larval stage. A detailed examination of motor neurons in the surviving larvae revealed the overextension of axons and mistargeting of neuromuscular junctions, resulting in uncoordinated locomotion. Taken together, our results identify a new role for Pav-KLP as a negative regulator of kinesin-1-driven neurite formation. These data suggest an important parallel between long microtubule-microtubule sliding in anaphase B and sliding of interphase microtubules during neurite formation.


Minimal tooth preparation techniques for restorations with adhesive materials.
Dramatic progress over the past ten years in adhesive composite and glass ionomer materials has made possible innovative, minimal cavity designs. These designs, by conserving tooth tissue, maximize the strength of the remaining structure and facilitate the aesthetic preservation of the patient's own dentition. The author gives a critical review of some of the new techniques that have been proposed.


Proteomic analysis of the nucleus accumbens in rhesus monkeys of morphine dependence and withdrawal intervention.
It has been known that the reinforcing effects and long-term consequences of morphine are closely associated with nucleus accumbens (NAc) in the brain, a key region of the mesolimbic dopamine pathway. However, the proteins involved in neuroadaptive processes and withdrawal symptom in primates of morphine dependence have not been well explored. In the present study, we performed proteomes in the NAc of rhesus monkeys of morphine dependence and withdrawal intervention with clonidine or methadone. Two-dimensional electrophoresis was used to compare changes in cytosolic protein abundance in the NAc. We found a total of 46 proteins differentially expressed, which were further identified by mass spectrometry analysis. The identified proteins can be classified into 6 classes: metabolism and mitochondrial function, synaptic transmission, cytoskeletal proteins, oxidative stress, signal transduction and protein synthesis and degradation. Importantly, we discovered 14 proteins were significantly but similarly altered after withdrawal therapy with clonidine or methadone, revealing potential pharmacological strategies or targets for the treatment of morphine addiction. Our study provides a comprehensive understanding of the neuropathophysiology associated with morphine addiction and withdrawal therapy in primate, which is helpful for the development of opiate withdrawal pharmacotherapies.


Hepatozoon canis in three imported dogs: a new tickborne disease reaching the United Kingdom.
An increasing number of non-endemic vectorborne pathogens have been described in dogs imported to the UK in the past two decades. Recently, an outbreak of canine babesiosis in south-east England has raised veterinary awareness with regard to the impact of such diseases on the UK canine population. Canine hepatozoonosis, caused by Hepatozoon canis and transmitted by the ingestion of Rhipicephalus sanguineus ticks, is widespread in the Mediterranean basin. Herein we describe the first three molecularly confirmed clinical cases of canine hepatozoonosis in dogs imported into the UK. Veterinarians in the UK should be aware of H canis as a potential infection in imported dogs, especially in the face of the expanding distribution of R sanguineus ticks in Europe.


Assessing guilt toward the former spouse.
Divorce is often accompanied by feelings of guilt toward the former spouse. So far, no scale has been available to measure such feelings. For this purpose, the authors developed the Guilt in Separation Scale (GiSS). Content validity was assured by using experts and lay experts to generate and select items. Exploratory analyses were run on samples of 214 divorced individuals and confirmatory analyses on 458 individuals who were in the process of divorcing. Evidence was provided for the reliability and construct validity of the GiSS. The internal consistency was high (α = .91), as were the 6-month and 12-month test-retest reliabilities (r = .72 and r = .76, respectively). The GiSS was related to shame, regret, compassion, locus of cause of the separation, unfaithfulness, and psychological functioning.


The Influence of Group Versus Individual Prenatal Care on Phase of Labor at Hospital Admission.
Group prenatal care, an alternate model of prenatal care delivery, has been associated with various improved perinatal outcomes in comparison to standard, individual prenatal care. One important maternity care process measure that has not been explored among women who receive group prenatal care versus standard prenatal care is the phase of labor (latent vs active) at hospital admission. A retrospective case-control study was conducted comparing 150 women who selected group prenatal care with certified nurse-midwives (CNMs) versus 225 women who chose standard prenatal care with CNMs. Analyses performed included descriptive statistics to compare groups and multivariate regression to evaluate the contribution of key covariates potentially influencing outcomes. Propensity scores were calculated and included in regression models. Women within this sample who received group prenatal care were more likely to be in active labor (≥ 4 cm of cervical dilatation) at hospital admission (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.03-2.99; P = .049) and were admitted to the hospital with significantly greater cervical dilatation (mean [standard deviation, SD] 5.7 [2.5] cm vs. 5.1 [2.3] cm, P = .005) compared with women who received standard prenatal care, controlling for potential confounding variables and propensity for group versus individual care selection. Group prenatal care may be an effective and safe intervention for decreasing latent labor hospital admission among low-risk women. Neither group prenatal care nor active labor hospital admission was associated with increased morbidity.


The High Osmolarity Glycerol (HOG) Pathway Functions in Osmosensing, Trap Morphogenesis and Conidiation of the Nematode-Trapping Fungus Arthrobotrys oligospora.
Hog1, a mitogen-activated protein kinase (MAPK), has been identified in diverse fungal species, and it regulates various cellular processes, such as osmoadaptation, nutrient-sensing, and pathogenesis. However, the roles that Hog1 plays in nematode-trapping fungi were previously unclear. Here, we characterized orthologs of Saccharomyces cerevisiae Hog1 and membrane mucin Msb2 in the nematode-trapping fungus Arthrobotrys oligospora. We generated gene deletion mutants of HOG1 and MSB2 in A. oligospora, and characterized their roles in osmosensing, growth, and trap morphogenesis. We found that both hog1 and msb2 mutants were highly sensitive to high osmolarity. Predation analyses further revealed that hog1 and msb2 deletion caused a reduction in trap formation and predation efficiency. Furthermore, HOG1 is required for conidiation in A. oligospora, demonstrating its critical role in this developmental pathway. In summary, this study demonstrated that the conserved Hog1 and Msb2 govern physiology, growth and development in the nematode-trapping fungus A. oligospora.


Telepresence interface with applications to microsurgery and surgical simulation.
To address the needs for performing microsurgical procedures, the SRI telepresence surgery workstation has been combined with a pair of micromanipulator arms. The prototype microsurgery system has been tested with ex-vivo tasks similar to those required for surgical procedures, such as cutting, grasping, suturing, and knot tying. Initial animal testing has been done on a rat model in which end-to-end anastomosis of the femoral artery (approximately 1 millimeter in diameter) was completed with ten rats, and 100% patency was obtained. To address the needs of surgical training, SRI has begun to develop a system that uses a 6-DOF telepresence workstation. A computer-generated stereo image is reflected in a mirror and appears to be superimposed on the surgeon's hands, creating an immersive and realistic environment. Tools held in the surgeon's hands are connected to left- and right-hand manipulators that both continuously measure tool position/orientation and apply force/torque to the tools. Furthermore, the visual image and tool locations are registered, so that the user perceives that he or she is looking at and moving the simulated tools in the visual image.


Patients' perceptions of depression and coronary heart disease: a qualitative UPBEAT-UK study.
The prevalence of depression in people with coronary heart disease (CHD) is high but little is known about patients' own perceptions and experiences of this. This study aimed to explore (i) primary care (PC) patients' perceptions of links between their physical condition and mental health, (ii) their experiences of living with depression and CHD and (iii) their own self-help strategies and attitudes to current PC interventions for depression. Qualitative study using consecutive sampling, in-depth interviews and thematic analysis using a process of constant comparison. 30 participants from the UPBEAT-UK cohort study, with CHD and symptoms of depression. All participants were registered on the General Practitioner (GP) primary care, coronary register. A personal and social story of loss underpinned participants' accounts of their lives, both before and after their experience of having CHD. This theme included two interrelated domains: interpersonal loss and loss centred upon health/control issues. Strong links were made between CHD and depression by men who felt emasculated by CHD. Weaker links were made by participants who had experienced distressing life events such as divorce and bereavement or were living with additional chronic health conditions (i.e. multimorbidity). Participants also felt 'depressed' by the 'medicalisation' of their lives, loneliness and the experience of ageing and ill health. Just under half the sample had consulted their GP about their low mood and participants were somewhat ambivalent about accessing primary care interventions for depression believing the GP would not be able to help them with complex health and social issues. Talking therapies and interventions providing the opportunity for social interaction, support and exercise, such as Cardiac Rehabilitation, were thought to be helpful whereas anti-depressants were not favoured. The experiences and needs of patients with CHD and depression are diverse and include psycho-social issues involving interpersonal and health/control losses. In view of the varying social and health needs of patients with CHD and depression the adoption of a holistic, case management approach to care is recommended together with personalised support providing the opportunity for patients to develop and achieve life and health goals, where appropriate.


Effects of mutations on the molecular dynamics of oxygen escape from the dimeric hemoglobin of Scapharca inaequivalvis.
Like many hemoglobins, the structure of the dimeric hemoglobin from the clam Scapharca inaequivalvis is a "closed bottle" since there is no direct tunnel from the oxygen binding site on the heme to the solvent. The proximal histidine faces the dimer interface, which consists of the E and F helicies. This is significantly different from tetrameric vertebrate hemoglobins and brings the heme groups near the subunit interface. The subunit interface is also characterized by an immobile, hydrogen-bonded network of water molecules. Although there is data which is consistent with the histidine gate pathway for ligand escape, these aspects of the structure would seem to make that pathway less likely. Locally enhanced sampling molecular dynamics are used here to suggest alternative pathways in the wild-type and six mutant proteins. In most cases the point mutations change the selection of exit routes observed in the simulations. Exit via the histidine gate is rarely seem although oxygen molecules do occasionally cross over the interface from one subunit to the other. The results suggest that changes in flexibility and, in some cases, creation of new cavities can explain the effects of the mutations on ligand exit paths.


Established and candidate transthyretin amyloidosis variants identified in the Saudi population by data mining.
Familial transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease with significant phenotypic heterogeneity. Its prevalence in Saudi Arabia has not previously been investigated. An existing exome variant database of Saudi individuals, sequenced to globally investigate rare diseases in the population, was mined for TTR variants and filtered for missense mutations resulting in single amino acid changes. A total of 13,906 Saudi exomes from unrelated individuals were analyzed blindly. Three TTR variants known to be associated with ATTR amyloidosis were identified. Additionally, three novel TTR mutations were identified. Structural analysis of the three novel variants suggests that at least two could be amyloidogenic. The most common variant associated with amyloidosis was p.Val142Ile (allele frequency 0.001). Further investigation of these variants and their translation to clinical practice may help to diagnose, monitor, and manage patients with ATTR amyloidosis. Multiple TTR variants potentially associated with systemic ATTR amyloidosis were identified in the Saudi population. Early diagnosis and intervention, facilitated by familial genetic testing of patients with ATTR amyloidosis, may benefit in the management of this disease. Early diagnosis could be enhanced through inclusion of ATTR variants in existing population-based screening programs.


Policy Inertia on Regulating Food Marketing to Children: A Case Study of Malaysia.
Unhealthy food marketing shapes children's preference towards obesogenic foods. In Malaysia, policies regulating this food marketing were rated as poor compared to global standards, justifying the need to explore barriers and facilitators during policy development and implementation processes. The case study incorporated qualitative methods, including historical mapping, semi-structured interviews with key informants and a search of cited documents. Nine participants were interviewed, representing the Federal government (n = 5), food industry (n = 2) and civil society (n = 2). Even though the mandatory approach to government-led regulation of food marketing to children was the benchmark, more barriers than facilitators in the policy process led to industry self-regulations in Malaysia. Cited barriers were the lack of political will, industry resistance, complexity of legislation, technical challenges, and lack of resources, particularly professional skills. The adoption of industry self-regulation created further barriers to subsequent policy advancement. These included implementer indifference (industry), lack of monitoring, poor stakeholder relations, and policy characteristics linked to weak criteria and voluntary uptake. These underlying barriers, together with a lack of sustained public health advocacy, exacerbated policy inertia. Key recommendations include strengthening pro-public health stakeholder partnerships, applying sustained efforts in policy advocacy to overcome policy inertia, and conducting monitoring for policy compliance and accountability. These form the key lessons for advocating policy reforms.


High throughput film dosimetry in homogeneous and heterogeneous media for a small animal irradiator.
We have established a high-throughput Gafchromic film dosimetry protocol for narrow kilovoltage beams in homogeneous and heterogeneous media for small-animal radiotherapy applications. The kV beam characterization is based on extensive Gafchromic film dosimetry data acquired in homogeneous and heterogeneous media. An empirical model is used for parameterization of depth and off-axis dependence of measured data. We have modified previously published methods of film dosimetry to suit the specific tasks of the study. Unlike film protocols used in previous studies, our protocol employs simultaneous multi-channel scanning and analysis of up to nine Gafchromic films per scan. A scanner and background correction were implemented to improve accuracy of the measurements. Measurements were taken in homogeneous and inhomogeneous phantoms at 220 kVp and a field size of 5 × 5 mm(2). The results were compared against Monte Carlo simulations. Dose differences caused by variations in background signal were effectively removed by the corrections applied. Measurements in homogeneous phantoms were used to empirically characterize beam data in homogeneous and heterogeneous media. Film measurements in inhomogeneous phantoms and their empirical parameterization differed by about 2%-3%. The model differed from MC by about 1% (water, lung) to 7% (bone). Good agreement was found for measured and modelled off-axis ratios. EBT2 films are a valuable tool for characterization of narrow kV beams, though care must be taken to eliminate disturbances caused by varying background signals. The usefulness of the empirical beam model in interpretation and parameterization of film data was demonstrated.


The impact of three commercial sweeteners on cytokine expression by mononuclears impelled by colon carcinoma cells.
The study was designed to examine the immunomodulatory effect of three commercial sweeteners on human peripheral blood mononuclear cells (PBMC) and on the immune dialogue between these and human HT-29 and HuCC colon cancer lines. PBMC were incubated with Sweet'N Low, Splenda and Stevia and the cytokine production was examined. The cytokine release of PBMC co-cultured with colon cancer cells in the presence of sweeteners was evaluated. Sweet'N Low enhanced IFNγ, IL-1β and IL-6 release, and augmented HuCC-induced IL-10 secretion. Splenda reduced IFNγ and TNFα secretion by LPS and HuCC stimulated PBMC and enhanced HuCC-induced IL-10 and IL-1ra production. Stevia reduced IL-1β, TNFα and IL-1ra secretion prompted by HuCC and HT-29 cells and enhanced IL-6 production induced by HuCC. The inhibition of pro-inflammatory- and increased anti-inflammatory cytokines release by Splenda and Stevia indicate that they possess valuable potential as carcinopreventive agents.


The human 5-HT1A receptor expressed in HeLa cells stimulates sodium-dependent phosphate uptake via protein kinase C.
Regulation of phosphate uptake was studied in HeLa cell lines after transfection with DNA encoding the human 5-HT1A receptor. Phosphate uptake was saturable and greater than 90% sodium-dependent, with Vmax approximately 30-35% without changing Km. Treatment with 5-HT or the 5-HT1A-specific agonist 8-OH-2-(di-n-propylamino)1,2,3,4-tetrahydronaphthalene increased Vmax approximately 40% without affecting Km. This effect was blocked by pretreatment with the 5-HT1 antagonists, methiothepine and spiperone, or pertussis toxin. Surprisingly, the stimulation was not secondary to an inhibition of adenylyl cyclase because 5-HT stimulated phosphate uptake approximately 20% in the presence of 1 mM 8-Br-cAMP. Rather, the primary pathway linked to the stimulation of phosphate uptake involved activation of protein kinase C because (i) 5-HT measurably activated protein kinase C in these cells, (ii) activators of protein kinase C (phorbol esters and diacylglycerol analogues) stimulated phosphate uptake in these cells (iii) the half-maximal doses for 5-HT-induced phosphatidylinositol hydrolysis and stimulation of phosphate uptake were virtually equivalent, and both effects were equally sensitive to pertussis toxin, and (iv) the stimulation was markedly attenuated in cells made deficient in protein kinase C. These results demonstrate that the stimulation of phosphatidylinositol hydrolysis by the 5-HT1A receptor can generate physiologically measurable effects on cellular transport and suggest that such accessory pathways may play a prominent role in signal transduction.


[The efficiency of alprazolam for seasonal affective disorder (SAD, autumn/winter type)].
We experienced a 49 years old female SAD patient who showed a good response the next day after alprazolam 1.2 mg administration. The back ground EEG of the patient showed a abnormal EEG with slow waves. The personality was colored with historical features. The nadir of body core temperature from rectum slightly delayed in remission phase compared with depressive phase. The patient became hypomania and calmed down gradually. Alprazolam treatment is seemed to be available for SAD patients.


[Peculiarities of the temporal organization of the behavioral response to caffeine in rats].
Chronic administration of a standard dose of caffeine (40 mg/kg) facilitated the formation of more clear circadian mobility rhythm in rats. The test animals belonging to various chronotypes exhibited a significant difference in sensitivity with respect to this psychostimulant. Rats possessing a more pronounced rhythm organization showed a greater increase in the rhythm amplitude, with the acrophase more significantly shifted toward early night hours. It is suggested that the individual chronotype features have to be taken into account in experimental and clinical pharmacology.


Morphometric studies of catch-up growth in the rat.
It would appear from these results that no simple relationship exists between the ability of the animal to achieve complete catch-up and the degree to which it has fallen behind controls, the maturity of the region at the time the insult is applied, or the relationship of the insult to the timing of the peak growth velocity. The findings of Widdowson and McCance [1963], that postweaning undernutrition has far less serious consequences than preweaning undernutrition, are, however, confirmed. The age of the animal at the time that the insult is applied and the degree to which it falls behind controls would both seem to make a contribution to the eventual catch-up, older animals being better able than younger ones to recover fully from the same degree of deficit. The results show that different regions of the skeleton respond differently to periods of undernutrition, both in the degree to which they fall behind control values and in their ability to achieve complete catch-up. The potential for catch-up is known to vary, depending on the state of cell multiplication at the time that the insult is applied [Enesco and LeBlond, 1962; Winick and Noble, 1965, 1966] and periods of undernutrition are known to result in a disturbance in the structure of cartilage [Silberberg, 1968; Dearden and Espinosa, 1974; Dearden and Mosier, 1974]. Presumably the results presented here reflect differences in the various cartilages of the regions being examined, complete catch-up being impossible in some regions due to permanent abnormalities of structure and/or function having been induced.


Sir3-dependent assembly of supramolecular chromatin structures in vitro.
Baculovirus-expressed recombinant Sir3p (rSir3p) has been purified to near homogeneity, and its binding to naked DNA, mononucleosomes, and nucleosomal arrays has been characterized in vitro. At stoichiometric levels rSir3p interacts with intact nucleosomal arrays, mononucleosomes, and naked DNA, as evidenced by formation of supershifted species on native agarose gels. Proteolytic removal of the core histone tail domains inhibits but does not completely abolish rSir3p binding to nucleosomal arrays. The linker DNA in the supershifted complexes remains freely accessible to restriction endonuclease digestion, suggesting that both the tail domains and nucleosomal DNA contribute to rSir3p--chromatin interactions. Together these data indicate that rSir3p cross-links individual nucleosomal arrays into supramolecular assemblies whose physical properties transcend those of typical 10-nm and 30-nm fibers. Based on these data we hypothesize that Sir3p functions, at least in part, by mediating reorganization of the canonical chromatin fiber into functionally specialized higher order chromosomal domains.


Refinement of a macaque transplantation model: application of a subcutaneous port as a means for long-term enteral drug administration and nutritional supplementation.
A new application of a device enabling the long-term enteral administration of drugs or nutritional supplementation was developed for implementing in research entailing the use of macaques (Macaca fascicularis). After implanting a subcutaneous port, a surgically-placed gastrostomy (SPG) was completed to afford access to the gastric lumen and enable the administration of substances. In this study, the device was left in place for a period ranging between two and 12 months in macaques (n= 16). In five cases, the SPG was used successfully for 8-12 months, until the experimental endpoint was reached. In six cases, the SPG had to be removed earlier due to local infection at the implant site, which promptly regressed after the SPG was removed and antibiotic treatment was administered. One SPG-implanted macaque was euthanized for reasons unrelated to the SPG or the xenotransplantation procedure. In four cases, the SPG was implanted without any complications but has yet to be used to administer substances to the animals. From an ethical standpoint, the SPG device described here minimizes the forced handling of macaques otherwise needed for the oral administration of viscous or unpalatable substances by gavage. The device thus represents an effective refinement that fully complies with the tenet of the '3 Rs' that should be considered by primate centres exposing non-human primates to the long-term daily administration of substances by oral gavage.


Genetics of familial hypercholesterolemia: a tool for development of novel lipid lowering pharmaceuticals?
Familial hypercholesterolemia is characterized by high LDL cholesterol and an elevated risk to develop coronary heart disease. Mutations in LDL receptor-mediated cholesterol uptake are the main cause of familial hypercholesterolemia. However, multiple mutations in various other genes are also associated with high LDL cholesterol and even familial hypercholesterolemia. Thus, pharmaceuticals that target these genes and proteins might be attractive treatment options to reduce LDL cholesterol. This review provides an overview of the recent developments and clinical testing of such pharmaceuticals. About 80 genes are associated with hypercholesterolemia but only pharmaceuticals that inhibit cholesteryl ester transfer protein (CETP), angiopoietin-related protein 3 (ANGPTL3), and apolipoprotein C-III (apoC-III) have recently been tested in clinical trials. Inhibition of CETP and ANGPTL3 lowered LDL cholesterol. ANGPTL3 inhibition had the largest effect and was even effective in familial hypercholesterolemia patients. The effect of apoC-III inhibition on LDL cholesterol is not conclusive. Of the many potential pharmaceutical targets involved in LDL cholesterol, only a few have been studied so far. Of these, pharmaceuticals that inhibit CETP or ANGPTL3 are promising novel treatment options to reduce LDL cholesterol but the effect of apoC-III inhibition requires more research.


Impact of a Preparatory Year Programme on the Students of Health Professions Education Colleges: Perception of students and faculty members.
The preparatory year programme (PYP) at King Abdulaziz University, Jeddah, Saudi Arabia, is a one-year programme for students preparing for a full multi-year degree curriculum at a university. It offers a bridge between high-school and university-level studies of the students. This study aimed to evaluate the impact of the King Abdulaziz University PYP on students of the health professions education colleges from the viewpoints of the students and the faculty. This descriptive study was conducted between May 2019 and January 2020 at King Abdulaziz University, in Jeddah, Saudi Arabia and was based on data collected from both students and faculty to assess their perceptions. The data were collected from students through self-administered questionnaires and from faculty members through structured interviews. Descriptive statistics were used for analysis. A total of 633 students responded to the questionnaire (response rate: 88.3%), of which almost half agreed that the PYP made them self-confident and reinforced their discipline (49.2% and 46.9%, respectively). Less than two-thirds agreed that the preparatory year reinforced their sense of responsibility and helped them adapt to the university educational environment (60.6% and 64.3%, respectively). Conversely, more than half (58.5%) disagreed that the preparatory year classes helped them select their majors as well as that the preparatory year prepared them for their major classes (57.2%). A total of 24 faculty members who taught PYP students claimed that there should be careful consideration of the contents of the courses offered to the students in the preparatory year programme, especially the content related to the healthcare profession education. They argued that it is better to have a separate track in the PYP that includes subjects directly related to the study of health professions (such as molecular sciences, genetics, medical terminology, English for medical purposes, etc.). The impact of the PYP on students attending the health professions colleges was found to be weak as per the perceptions of both students and faculty members. In-depth studies are necessary for further investigation of this impact.


Gene panels to help identify subgroups at high and low risk of coronary heart disease among those randomized to antihypertensive treatment: the GenHAT study.
To identify panels of genetic variants that predict treatment-related coronary heart disease (CHD) outcomes in hypertensive patients on one of four different classes of initial antihypertensive treatment. The goal was to identify subgroups of individuals on the basis of their genetic profile who benefit most from a particular treatment. Candidate genetic variants (n=78) were genotyped in 39 114 participants from Genetics of Hypertension Associated Treatment study, ancillary to Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial. Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial randomized hypertensive participants (≥55 years) to one of four treatments (amlodipine, chlorthalidone, doxazosin, lisinopril). The primary outcome was fatal CHD or nonfatal myocardial infarction (mean follow-up=4.9 years). A pharmacogenetic panel was derived within each of the four treatment groups. Receiver-operating characteristic (ROC) curves estimated the discrimination rate between those with and without a CHD event, on the basis of the addition of the genetic panel risk score. For each treatment group, we identified a panel of genetic variants that collectively improved the prediction of CHD to a small but statistically significant extent. Chlorthalidone (A): NOS3 rs3918226; SELE rs5361; ICAM1 rs1799969; AGT rs5051; GNAS rs7121; ROC comparison, P=0.004; Amlodipine (B): MMP1 rs1799750; Factor5 (F5) rs6025; NPPA rs5065; PDE4D rs6450512; MMP9 rs2274756; ROC comparison, P=0.006; Lisinopril (C): AGT rs5051; PON1 rs705379; MMP12 rs652438; F12 rs1801020; GP1BA rs6065; PDE4D rs27653; ROC comparison, P=0.01; Doxazosin (D): F2 rs1799963; PAI1 rs1799768; MMP7 rs11568818; AGT rs5051; ACE rs4343; MMP2 rs243865; ROC comparison, P=0.007. Each panel was tested for a pharmacogenetic effect; panels A, B, and D showed such evidence (P=0.009, 0.006, and 0.001, respectively) and panel C did not (P=0.09). Because each panel was associated with CHD in a specific treatment group but not the others, this research provides evidence that it may be possible to use gene panel scores as a tool to better assess antihypertensive treatment choices to reduce CHD risk in hypertensive individuals.


Alcohol intake reduction for controlling hypertension.
High blood pressure constitutes one of the leading causes of mortality and morbidity all over the world. At the same time, heavy drinking increases the risk for developing cardiovascular diseases, including cardiomyopathy, hypertension, atrial arrhythmias, or stroke. Several studies have already assessed specifically the relationship between alcohol intake and hypertension. However, the potential effect on blood pressure of alcohol intake reduction interventions is largely unknown. To assess the effect of any intervention to reduce alcohol intake in terms of blood pressure decrease in hypertensive people with alcohol consumption compared to a control intervention or no intervention at all. To determine additional effects related to mortality, major cardiovascular events, serious adverse events, or quality of life. The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to June 2020: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 5, 2020), MEDLINE Ovid (from 1946), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In-Process, Embase Ovid (from 1974), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. Trial authors were contacted when needed and no language restrictions were applied. We included randomised controlled trials with minimum 12 weeks duration and including 50 or more subjects per group with quantitative measurement of alcohol consumption and/or biological measurement of the outcomes of interest. Participants were adults (16 years of age or older) with systolic blood pressure (SBP) greater than 140 mmHg and diastolic blood pressure (DBP) greater than 90 mmHg, and SBP ≥ 130 or DBP ≥ 80 mmHg in participants with diabetes. We included any intervention implemented to reduce their alcohol intake. Two review authors independently assessed search results and extracted data using standard methodological procedures adopted by Cochrane. A total of 1210 studies were screened. We included one randomised controlled trial involving a total of 269 participants with a two-year follow-up. Individual patient data for all participants were provided and used in this review. No differences were found between the cognitive-behavioural intervention group and the control group for overall mortality (RR 0.72, 95% CI 0.16 to 3.17; low-certainty evidence), cardiovascular mortality (not estimable) and cardiovascular events (RR 0.80, 95% CI 0.36 to 1.79; very low-certainty evidence). There was no statistical difference in systolic blood pressure (SBP) reduction (Mean Difference (MD) -0.92 mmHg, 95% confidence interval (CI) -5.66 to 3.82 mmHg; very low-certainty evidence) or diastolic blood pressure (DBP) decrease (MD 0.98 mmHg, 95% CI -1.69 to 3.65 mmHg; low-certainty evidence) between the cognitive-behavioural intervention group and the control group. We also did not find any differences in the proportion of subjects with SBP < 140 mmHg and DBP < 90 mmHg (Risk Ratio (RR) 1.21, 95% CI 0.88 to 1.65; very low-certainty evidence). Concerning secondary outcomes, the alcohol intake was significantly reduced in the cognitive-behavioural intervention compared with the control group (MD 191.33 g, 95% CI 85.36 to 297.30 g). We found no differences between the active and control intervention in the proportion of subjects with lower-risk alcohol intake versus higher-risk and extreme drinkers at the end of the study (RR 1.04, 95% CI 0.68 to 1.60). There were no estimable results for the quality of life outcome. An intervention for decreasing alcohol intake consumption did not result in differences in systolic and diastolic blood pressure when compared with a control intervention, although there was a reduction in alcohol intake favouring the active intervention. No differences were found either for overall mortality, cardiovascular mortality or cardiovascular events. No data on serious adverse events or quality of life were available to assess. Adequate randomised controlled trials are needed to provide additional evidence on this specific question.


Approaches to enabling rapid evaluation of innovations in health and social care: a scoping review of evidence from high-income countries.
The COVID-19 pandemic increased the demand for rapid evaluation of innovation in health and social care. Assessment of rapid methodologies is lacking although challenges in ensuring rigour and effective use of resources are known. We mapped reports of rapid evaluations of health and social care innovations, categorised different approaches to rapid evaluation, explored comparative benefits of rapid evaluation, and identified knowledge gaps. Scoping review. MEDLINE, EMBASE and Health Management Information Consortium (HMIC) databases were searched through 13 September 2022. We included publications reporting primary research or methods for rapid evaluation of interventions or services in health and social care in high-income countries. Two reviewers developed and piloted a data extraction form. One reviewer extracted data, a second reviewer checked 10% of the studies; disagreements and uncertainty were resolved through consensus. We used narrative synthesis to map different approaches to conducting rapid evaluation. We identified 16 759 records and included 162 which met inclusion criteria.We identified four main approaches for rapid evaluation: (1) Using methodology designed specifically for rapid evaluation; (2) Increasing rapidity by doing less or using less time-intensive methodology; (3) Using alternative technologies and/or data to increase speed of existing evaluation method; (4) Adapting part of non-rapid evaluation.The COVID-19 pandemic resulted in an increase in publications and some limited changes in identified methods. We found little research comparing rapid and non-rapid evaluation. We found a lack of clarity about what 'rapid evaluation' means but identified some useful preliminary categories. There is a need for clarity and consistency about what constitutes rapid evaluation; consistent terminology in reporting evaluations as rapid; development of specific methodologies for making evaluation more rapid; and assessment of advantages and disadvantages of rapid methodology in terms of rigour, cost and impact.


Effects of an 8-week physical exercise program on spinal manipulation biomechanical parameters in a group of 1st-year chiropractic students.
To determine the effects of a physical exercise program on spinal manipulation (SM) performance in 1st-year chiropractic students. One hundred and thirteen students from 2 chiropractic schools were assigned to 1 of 2 groups: exercise group (EG) for campus A students or control group (CG) (no training) for campus B students. All participated in 2 1-hour experimental training sessions that were added to the usual technique curriculum. At the beginning and at the end of each session, SM thrust duration and preload force release were recorded as dependent variables in 5 trials performed on a force-sensing table for a total of 10 recorded trials per session. The session consisted of several drills during which augmented feedback was provided to students to improve their skills. The EG performed physical exercises (push-ups, core stabilization, and speeder board exercises) 3 times per week for an 8-week period between the 2 training sessions. The mean thrust duration increased between the 2 sessions [+0.8 ms (±15.6)]. No difference between groups was found using a t test for independent samples (p = .94). The mean preload force release decreased between the 2 sessions (-6.1 N [±17.1]). Differences between groups were found using a t test for independent samples (p = .03); the results showed a reduction of preload force release in the participants in the EG group compared to those in the CG group (-8.1 N [±16.9] vs -0.3 N [±16.5]). A physical exercise program seems to be beneficial in the SM learning process; chiropractic students should therefore be encouraged to do home physical exercises to develop their physical capabilities and improve SM delivery.


Effects of limited and excess protein intakes of pregnant gilts on carcass quality and cellular properties of skeletal muscle and subcutaneous adipose tissue in fattening pigs.
The aim of this study was to investigate whether dietary protein intake of gilts during gestation below (50%) or above (250%) recommendations affects body composition, carcass and meat quality, and properties of skeletal muscle and subcutaneous adipose tissue (SCAT) in offspring at d 83 and 188 of age. German Landrace gilts were fed isoenergetic gestation diets (~13.7 MJ of ME/kg) containing a low (LP, 6.5%; n = 18), an adequate (AP, 12.1%; n = 20), or a high (HP, 30%; n = 16) protein content from mating until farrowing. Within 48 h of birth, offspring were cross-fostered to sows fed a standard diet. On d 83 of age, no effects of the LP diet on BW and body composition were detected, whereas HP pigs showed a slight growth delay (P = 0.06) associated with increased relative weights of small intestine (P < 0.01) and brain (P = 0.08), and reduced relative thymus weight (P < 0.01). On d 188 of age, BW was not different among the dietary groups. However, the carcass of LP pigs contained less (P = 0.01) lean and more (P = 0.07) fat compared with AP and HP pigs, which was only pronounced in pigs originating from large litters (P < 0.05). Like skeletal muscles (P = 0.06), the heart muscle weighed less (P = 0.02) in LP than AP pigs. Compared with AP pigs, LP pigs exhibited a fewer (P = 0.09) total number of myofibers in semitendinosus muscle plus LM both at d 83 and 188 of age, whereas total muscular DNA was less (P = 0.02) at d 188 only. The mRNA abundance of IGF2 measured on d 188 was reduced in SCAT (P = 0.03) and LM (P = 0.07) of LP compared with AP pigs. No changes in muscular fiber type frequency, capillary density, or creatine kinase activity, as well as SCAT adipocyte size and number, were observed at either stages of age. Meat quality characteristics remained unchanged at d 83, whereas Warner-Bratzler shear force value in LM was decreased (P = 0.03) in LP compared with AP pigs on d 188 of age. The results suggest that the maternal LP diet impairs prenatal myofiber formation, reduces the potential of postnatal lean growth related to reduced IGF2 mRNA expression and myonuclear accumulation, and consequently changes carcass quality toward reduced lean proportion and improved tenderness at market weight. In contrast, except for a slight transient growth delay, excess dietary protein during gestation seems to have little effect on the fetal programming of postnatal muscle and adipose tissue phenotype of the progeny.


Studies on the function of pancreatic islet cell membranes.
Pancreatic islets rich in beta-cells were isolated from non-inbred ob/ob-mice and used for studying various aspects of the function of the plasma membrane. A review is given of the authors' work along the following lines: the role of transmembrane transport or membrane binding in the recognition of insulin-releasing sugars, amino acids, sulfonylureas, and sulphydryl-blocking agents; the role of cyclic 3',5'-AMP and cations in the coupling of stimulus recognition to insulin discharge; alloxan beta-cytotoxicity in vitro and its prevention by sugars; the isolation of a subcellular fraction enriched by plasma membranes. 1. It is suggested that D-glucose is recognized as an insulin secretagogue by being metabolized in the beta-cells; the teleological purpose of the transmembrane transport system being to allow fluctuations of the extracellular glucose concentration to be rapidly transmitted to the cell interior. Insulin-releasing sulfonyluraes and sulphydryl reagents are thought to act directly on the beta-cell plasma membrane, however. 2. Although cyclic 3',5'-AMP may amplify the expression of a secretory signal induced by D-glucose, studies with cholera toxin suggest that activation of the adenylate cyclase does not per se elicit secretion. The increase of islet cyclic 3',5'-AMP observed in response to several secretagogues, including D-glucose, may be secondary to membrane depolarization. 3. The possible role of an electrodiffusional mechanism in controlling the electrical potential is emphasized; a decrease of K+ permeability, rather than an increase of Na+ permeability, is suggested to be involved in the depolarizing action of D-glucose. Studies with the lanthanum-wash technique indicated that D-glucose causes a net flux of Ca2+ from the outside to the inside of the beta-cells. Although this uptake may relate to the enhancement of insulin secretion, the detailed mechanisms are unclear. 4. Inhibition of the Na+/K+ pump may be one of the earliest events in damage to the beta-cell by alloxan, on the basis of Rb+ studies. Protective effects of glucose against alloxan toxicity appear to be close related. 5. Studies of enzyme markers, the binding of wheat germ agglutinin, and electron microscopy indicate the presence of plasma membranes in a smooth-membrane fraction obtained by fractionating islet homogenates at consecutive sucrose gradients.


Postoperative analgesic efficacy of fluoroscopy-guided erector spinae plane block after percutaneous nephrolithotomy (PCNL): A randomized controlled study.
Percutaneous nephrolithotomy (PCNL) a minimally invasive method for the removal of renal calculi and is associated with significant pain in postoperative period. Conventionally, intravenous opioids, local anesthetic infiltration, and regional blocks (intercostal/paravertebral blocks) have been tried with less efficacy to control postoperative pain. The present study is conducted to assess the effectiveness of erector spinae plane block (ESPB) performed under fluoroscopy guidance for postoperative analgesia during PCNL. After obtaining ethical clearance, the study was conducted on 61 American Society of Anaesthesiologists (ASA) I and II patients aged between 18-65 years admitted for PCNL. Group I (n = 30) did not receive ESPB while Group II (n = 31) received ESPB under fluoroscopy guidance and 20 ml of 0.375% ropivacaine was administered after PCNL. Patient-reported pain intensity using visual analogue scale (VAS) was considered as a primary outcome. The hemodynamic variables (heart rate, systolic, diastolic, and mean blood pressure) was considered as a secondary outcome. Statistical analysis was performed using Student's t-test and Mann-Whitney U test. Data analysis was performed using the Statistical Package for the Social Sciences version 23.0. Postoperatively VAS score was significantly lower in Group II at 0, 1, 2, 3, 4, 6, 12, 18, and 24 hours after PCNL (P < 0.001). Dose of rescue analgesia significantly decreased in Group II compared to Group I. ESPB performed under fluoroscopic guidance is a simple and effective technique and it provides significantly better postoperative pain relief.


Practice Patterns in the Interventional Treatment of Coronary Bifurcation Lesions: A Global Survey.
The study aim was to assess current procedural strategies and perceptions for percutaneous coronary intervention (PCI) involving bifurcations. We distributed an online survey via email (8050 invitations) and social media. Among 440 responders, median annual PCI volumes were 15 cases (interquartile range [IQR], 10-29 cases) for left main (LM) and 50 cases (IQR, 27-73 cases) for non-LM (nLM) bifurcation lesions. Radial access use was reported in 51% of LM and 82% of nLM cases. An upfront 2-stent strategy, most commonly double-kissing (DK) crush, was reported in 49% of LM and 29% of nLM lesions. Bailout stenting during provisional stenting was reported in 26% of LM-PCIs, usually using the T and protrusion technique. In provisional stenting cases, most operators (<35%) did not report predilating the side branch, but routinely postdilated after successful provisional stenting (>85%), most often using both kissing-balloon inflation and the proximal optimization technique. Intravascular imaging was used in 80% of LM and 46% of nLM cases. Among the survey responders, the DK crush technique was the most frequently used 2-stent strategy for bifurcation PCIs. For LM lesions, bailout stenting was performed after provisional strategy in approximately 25% of cases. For nLM lesions, use of intravascular imaging and coronary physiology was lower than for LM lesions.


Splitting and joining in carbon nanotube/nanoribbon/nanotetrahedron growth.
We report a novel phenomenon for carbon nanotube growth that results in a new carbon nanotube morphology. A carbon nanotube grown via metal nanoparticle-catalyzed chemical vapor deposition splits into two flattened nanotubes during growth and the two flattened nanotubes merge to form a ring of carbon nanotube/nanoribbon. This novel process is revealed by transmission electron microscopy observations of the carbon nanostructures. We propose that the splitting-and-joining process involves only one metal catalyst nanoparticle and a self-folding mechanism that we have named the origami mechanism to explain the process and the formation of nanoribbons and nanotetrahedra.


The mouse major histocompatibility complex: some assembly required.
We have assembled a contig of 81 yeast artificial chromosome clones that spans 8 Mb and contains the entire major histocompatibility complex (Mhc) from mouse strain C57BL/6 (H2b), and we are in the process of assembling an Mhc contig of bacterial artificial chromosome (BAC) clones from strain 129 (H2bc), which differs from C57BL/6 in the H2-Q and H2-T regions. The current BAC contig extends from Tapasin to D17Leh89 with gaps in the class II, H2-Q, and distal H2-M regions. Only four BAC clones were required to link the class I genes of the H2-Q and H2-T regions, and no new class I gene was found in the previous gap. The proximal 1 Mb of the H2-M region has been analyzed in detail and is ready for sequencing; it includes 21 class I genes or fragments, at least 14 olfactory receptor-like genes, and a number of non-class I genes that clearly establish a conserved synteny with the class I regions of the human and rat Mhc.


Rapid discrimination of Mycobacterium tuberculosis strains by random amplified polymorphic DNA analysis.
Investigations of the epidemiology of tuberculosis have been hampered by the lack of strain-specific markers that can be used to differentiate isolates of Mycobacterium tuberculosis. We report the development of a rapid protocol for random amplified polymorphic DNA analysis which included the use of a commercially available DNA extraction kit (GeneReleaser). This was applied to 14 strains of M. tuberculosis, including strains associated with temporal and geographical clusters of tuberculosis in the United Kingdom and those from India, Africa, and Saudi Arabia. Strains of M. tuberculosis could be discriminated in about 8 h by this method, which is therefore a rapid and simple alternative to restriction fragment length polymorphism analysis.


Impact of primary tumor resection and metastasectomy among gastroentero-pancreatic neuroendocrine tumors with liver metastases only on survival.
Despite recommendations for primary tumor resection (PTR) with or without liver resection (LR) in the patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and isolated liver metastases, there are conflicting data for their impact on overall survival (OS). 2320 patients with GEP-NETs and isolated liver metastases were identified from NCDB. Multiple imputations were used to accommodate missing data, and inverse probability of treatment weighting (IPTW) was conducted to minimize bias. Patients with PTR had a greater OS than those without PTR (3-year rate of 88.6% vs. 69.9%, P < 0.001), which was preserved in the adjusted analysis (IPTW-adjusted HR = 0.387, 95% CI: 0.264-0.567; P < 0.001). Patients with LR had a greater OS than those without LR (3-year rate 87.7% vs. 75.2%, P = 0.003), which was also preserved in adjusted analysis (IPTW-adjusted HR = 0.450, 95% CI: 0.229-0.885; P = 0.021). Patients undergoing both PTR and LR had the greatest survival advantage than those with other surgical interventions (P < 0.001). Either PTR or LR is associated with improved survival for GEP-NET patients with isolated liver metastases. However, there remains significant selection bias in the current study, and caution should be exercised when selecting patients for resection.


Does the AVNeo valve reduce wall stress on the aortic wall? A cardiac magnetic resonance analysis with 4D-flow for the evaluation of aortic valve replacement with the Ozaki technique.
Aortic valve neocuspidalization aims to replace the 3 aortic cusps with autologous pericardium pre-treated with glutaraldehyde, and it is a surgical alternative to the classical aortic valve replacement (AVR). Image-based patient-specific computational fluid dynamics allows the derivation of shear stress on the aortic wall [wall shear stress (WSS)]. Previous studies support a potential link between increased WSS and histological alterations of the aortic wall. The aim of this study is to compare the WSS of the ascending aorta in patients undergoing aortic valve neocuspidalization versus AVR with biological prostheses. This is a prospective nonrandomized clinical trial. Each patient underwent a 4D-flow cardiac magnetic resonance scan after surgery, which informed patient-specific computational fluid dynamics models to evaluate WSS at the ascending aortic wall. The adjusted variables were calculated by summing the residuals obtained from a multivariate linear model (with ejection fraction and left ventricle outflow tract-aorta angle as covariates) to the mean of the variables. Ten patients treated with aortic valve neocuspidalization were enrolled and compared with 10 AVR patients. The aortic valve neocuspidalization group showed a significantly lower WSS in the outer curvature segments of the proximal and distal ascending aorta as compared to AVR patients (P = 0.0179 and 0.0412, respectively). WSS levels remained significantly lower along the outer curvature of the proximal aorta in the aortic valve neocuspidalization population, even after adjusting the WSS for the ejection fraction and the left ventricle outflow tract-aorta angle [2.44 Pa (2.17-3.01) vs 1.94 Pa (1.72-2.01), P = 0.02]. Aortic valve neocuspidalization hemodynamical features are potentially associated with a lower WSS in the ascending aorta as compared to commercially available bioprosthetic valves.


A ToxR homolog from Vibrio anguillarum serotype O1 regulates its own production, bile resistance, and biofilm formation.
ToxR, a transmembrane regulatory protein, has been shown to respond to environmental stimuli. To better understand how the aquatic bacterium Vibrio anguillarum, a fish pathogen, responds to environmental signals that may be necessary for survival in the aquatic and fish environment, toxR and toxS from V. anguillarum serotype O1 were cloned. The deduced protein sequences were 59 and 67% identical to the Vibrio cholerae ToxR and ToxS proteins, respectively. Deletion mutations were made in each gene and functional analyses were done. Virulence analyses using a rainbow trout model showed that only the toxR mutant was slightly decreased in virulence, indicating that ToxR is not a major regulator of virulence factors. The toxR mutant but not the toxS mutant was 20% less motile than the wild type. Like many regulatory proteins, ToxR was shown to negatively regulate its own expression. Outer membrane protein (OMP) preparations from both mutants indicated that ToxR and ToxS positively regulate a 38-kDa OMP. The 38-kDa OMP was shown to be a major OMP, which cross-reacted with an antiserum to OmpU, an outer membrane porin from V. cholerae, and which has an amino terminus 75% identical to that of OmpU. ToxR and to a lesser extent ToxS enhanced resistance to bile. Bile in the growth medium increased expression of the 38-kDa OMP but did not affect expression of ToxR. Interestingly, a toxR mutant forms a better biofilm on a glass surface than the wild type, suggesting a new role for ToxR in the response to environmental stimuli.


Gender disparities in fenestrated and branched endovascular aortic repair.
Gender disparities in risk factors and outcomes following aortic repair are important issues in healthcare. To date, no large-scale multicentre study addresses this topic in complex endovascular aortic repair. We aimed to determine the outcomes following fenestrated or branched endovascular aortic repair of aneurysms and dissections in female and male patients. Health insurance claims data of Germany's third largest insurance provider, DAK-Gesundheit, were used to investigate gender disparities in elective fenestrated or branched endovascular aortic repair of thoraco-abdominal or abdominal aortic aneurysms or dissections performed between 2008 and 2017. Elixhauser comorbidities and the linear van Walraven score were used to adjust for confounders in the multivariable analyses. There were 959 patients in the cohort, in whom 163 (17%) were female. The mean age was 73 ± 8 years with no differences between females and males. No gender disparities were observed regarding the van Walraven comorbidity score (6.9 vs 6.8, P = 0.83), but complications occurred more frequently in females. Acute renal failure (relative risk 1.71, 95% confidence interval 1.06-2.77), paraplegia (relative risk 2.71, 95% confidence interval 1.28-5.77) and bleeding or anaemia requiring transfusion (relative risk 1.76, 95% confidence interval 1.39-2.22) were more common in women. In multivariable models, female patients were at a higher risk of in-hospital death (odds ratio 3.206, P < 0.001). Consequently, female gender was associated with lower long-term survival (hazard ratio 1.506, P = 0.006). In complex endovascular aortic repair, females are more likely to experience complications and have worse in-hospital and, consequently, long-term survival when compared to males. Future studies should include anatomic parameters to determine the impact of anatomy on outcome disparities.


Effects of a multidrug chemotherapy regimen on the thymus.
Multidrug chemotherapy regimens are commonly used in the treatment of cancer. The dose limiting tissue for chemotherapeutic treatment is often the bone marrow, as many chemotherapeutic agents selectively target rapidly proliferating cells. Bone marrow transplantation (BMT) has allowed an increase in chemotherapeutic dose; however, this type of therapy is associated with a prolonged suppression of immune function following the BMT. Although it may be possible to augment this immune function, animal models which can be used to test various cytokines have not been well described. We have developed a mouse model of multi-drug chemotherapy which, like the human, demonstrates long term immune suppression following BMT. In this report, we describe the specific effects of this chemotherapy regimen on T cell differentiation in the thymus of treated mice using three color FACS analysis. Results demonstrated that specific populations of thymocytes are extremely susceptible to chemotherapeutic insult. Both thymus cellularity and the immature CD3-CD4+CD8+ double positive population dropped to approximately 3% of their original values by 7 days after chemotherapy initiation. During the same time period, cells expressing both alpha beta and gamma delta T cell receptors demonstrated a 2-6 fold increase in frequency. Similar results were observed for the alpha beta+ CD4-CD8- population of natural suppressor cells. Long-term changes in the proportion of cells expressing the V beta 5 TCR were also observed following chemotherapy. These results demonstrate that chemotherapy regimens may directly influence T cell differentiation within the thymus, and also suggest that long term changes in the T cell V beta repertoire may occur following chemotherapy.


Insights into evolution and coexistence of the colibactin- and yersiniabactin secondary metabolite determinants in enterobacterial populations.
The bacterial genotoxin colibactin interferes with the eukaryotic cell cycle by causing dsDNA breaks. It has been linked to bacterially induced colorectal cancer in humans. Colibactin is encoded by a 54 kb genomic region in Enterobacteriaceae. The colibactin genes commonly co-occur with the yersiniabactin biosynthetic determinant. Investigating the prevalence and sequence diversity of the colibactin determinant and its linkage to the yersiniabactin operon in prokaryotic genomes, we discovered mainly species-specific lineages of the colibactin determinant and classified three main structural settings of the colibactin-yersiniabactin genomic region in Enterobacteriaceae. The colibactin gene cluster has a similar but not identical evolutionary track to that of the yersiniabactin operon. Both determinants could have been acquired on several occasions and/or exchanged independently between enterobacteria by horizontal gene transfer. Integrative and conjugative elements play(ed) a central role in the evolution and structural diversity of the colibactin-yersiniabactin genomic region. Addition of an activating and regulating module (clbAR) to the biosynthesis and transport module (clbB-S) represents the most recent step in the evolution of the colibactin determinant. In a first attempt to correlate colibactin expression with individual lineages of colibactin determinants and different bacterial genetic backgrounds, we compared colibactin expression of selected enterobacterial isolates in vitro. Colibactin production in the tested Klebsiella species and Citrobacter koseri strains was more homogeneous and generally higher than that in most of the Escherichia coli isolates studied. Our results improve the understanding of the diversity of colibactin determinants and its expression level, and may contribute to risk assessment of colibactin-producing enterobacteria.


Medical informatics and the science of cognition.
Recent developments in medical informatics research have afforded possibilities for great advances in health care delivery. These exciting opportunities also present formidable challenges to the implementation and integration of technologies in the workplace. As in most domains, there is a gulf between technologic artifacts and end users. Since medical practice is a human endeavor, there is a need for bridging disciplines to enable clinicians to benefit from rapid technologic advances. This is turn necessitates a broadening of disciplinary boundaries to consider cognitive and social factors pertaining to the design and use of technology. The authors argue for a place of prominence for cognitive science. Cognitive science provides a framework for the analysis and modeling of complex human performance and has considerable applicability to a range of issues in informatics. Its methods have been employed to illuminate different facets of design and implementation. This approach has also yielded insights into the mechanisms and processes involved in collaborative design. Cognitive scientific methods and theories are illustrated in the context of two examples that examine human-computer interaction in medical contexts and computer-mediated collaborative processes. The framework outlined in this paper can be used to refine the process of iterative design, end-user training, and productive practice.


Targeted delivery of an antisense oligonucleotide in the retina: uptake, distribution, stability, and effect.
In this article, we describe the preliminary results of the development of an animal model that will enable us to study the effect of photoreceptor-derived debris accumulation on the normal function of the retina in vivo. An antisense oligonucleotide (Cat 5), saline, and two control oligonucleotides were injected into the vitreous of 7-week-old RCS-rdy+ rats. The uptake, distribution, and persistence of the antisense oligonucleotide in the retina was demonstrated by fluorescent confocal microscopy, and the stability of the oligonucleotide was shown by GeneScan analysis using a fluorescein-labeled derivative of Cat 5 (Cat 5F). The accumulation of photoreceptor-derived debris was monitored by the number of undigested phagosomes in the RPE layer by light microscopy. Following intravitreal injection of Cat 5F, penetration of the oligonucleotide was observed in the ganglion cell layer in 2 hours and in the photoreceptor and pigment epithelial layers 3 days later. However, at 7, 28, and 56 days postinjection, only the RPE layer had significant amounts of Cat 5F present. Using GeneScan analysis, it was demonstrated that the fluorescein-labeled oligonucleotide present in the RPE layer was not degraded and it retained its original 19-mer length. There was no statistically significant difference in the number of phagosomes found in the RPE layer of control uninjected, saline-injected, and two sense and two antisense oligonucleotides-injected animals at 7 and 28 days postinjection. In contrast, the number of phagosomes was significantly higher (p < 0.001) in the RPE layer of Cat 5 antisense oligonucleotide-injected animals at 7 and 28 days postinjection. This difference, however, disappeared by 56 days postinjection. The inner nuclear layers of the retina of control and experimental animals were not affected by the injections.


[Knowledge of the human body. At the 450th anniversary of the first edition of Andreas Vesalius' life work. "De Humani Coporis Fabrica Libri Septem"].
As an introduction to the symposium we pay attention successively: firstly, to the "Magister divinus", to Andreas Vesalius' personality, according to the testimony of his pupil Fallopius; secondly, to his ingenious lifework, the "De Humani Corporis Fabrica", according to the opinion of Sir William Osler, "the greatest medical book ever written", finally, to the historical evolution leading to the Vesalian way of thinking and working. All this proves that Vesalius' work is a fundamental turning point in the development of medicine as well as in the evolution of scientific practice in a general sense. It is also one of the highlights in the construction of mankind's intellectual patrimony.