Mortality amongst patients with influenza-associated severe acute respiratory illness, South Africa, 2009-2013.
Data on the burden and risk groups for influenza-associated mortality from Africa are limited. We aimed to estimate the incidence and risk-factors for in-hospital influenza-associated severe acute respiratory illness (SARI) deaths. Hospitalised patients with SARI were enrolled prospectively in four provinces of South Africa from 2009-2013. Using polymerase chain reaction, respiratory samples were tested for ten respiratory viruses and blood for pneumococcal DNA. The incidence of influenza-associated SARI deaths was estimated at one urban hospital with a defined catchment population. We enrolled 1376 patients with influenza-associated SARI and 3% (41 of 1358 with available outcome data) died. In patients with available HIV-status, the case-fatality proportion (CFP) was higher in HIV-infected (5%, 22/419) than HIV-uninfected individuals (2%, 13/620; p = 0.006). CFPs varied by age group, and generally increased with increasing age amongst individuals >5 years (p<0.001). On multivariable analysis, factors associated with death were age-group 45-64 years (odds ratio (OR) 4.0, 95% confidence interval (CI) 1.01-16.3) and ≥65 years (OR 6.5, 95%CI 1.2-34.3) compared to 1-4 year age-group who had the lowest CFP, HIV-infection (OR 2.9, 95%CI 1.1-7.8), underlying medical conditions other than HIV (OR 2.9, 95%CI 1.2-7.3) and pneumococcal co-infection (OR 4.1, 95%CI 1.5-11.2). The estimated incidence of influenza-associated SARI deaths per 100,000 population was highest in children <1 year (20.1, 95%CI 12.1-31.3) and adults aged 45-64 years (10.4, 95%CI 8.4-12.9). Adjusting for age, the rate of death was 20-fold (95%CI 15.0-27.8) higher in HIV-infected individuals than HIV-uninfected individuals. Influenza causes substantial mortality in urban South Africa, particularly in infants aged <1 year and HIV-infected individuals. More widespread access to antiretroviral treatment and influenza vaccination may reduce this burden.


Succinct synthesis of saturated hydroxy fatty acids and in vitro evaluation of all hydroxylauric acids on FFA1, FFA4 and GPR84.
Saturated hydroxy fatty acids make up a class of underexplored lipids with potentially interesting biological activities. We report a succinct and general synthetic route to saturated hydroxy fatty acids hydroxylated at position 6 or higher, and exemplify this with the synthesis of hydroxylauric acids. All regioisomers of hydroxylauric acids were tested on free fatty acid receptors FFA1, FFA4 and GPR84. The results show that the introduction of a hydroxy group and its position have a high impact on receptor activity.


Sexual conflict over the duration of copulation in Drosophila montana: why is longer better?
Conflicts of interest between the sexes are increasingly recognized as an engine driving the (co-)evolution of reproductive traits. The reproductive behaviour of Drosophila montana suggests the occurrence of sexual conflict over the duration of copulation. During the last stages of copulation, females vigorously attempt to dislodge the mounting male, while males struggle to maintain genital contact and often successfully extend copulations far beyond the females' preferred duration. By preventing female resistance, we show that females make a substantial contribution towards shortening copulations. We staged matings under different sex ratio conditions, and provide evidence that copulation duration is a form of male reproductive investment that responds to the perceived intensity of sperm competition as predicted by game theoretical models. Further, we investigated potential benefits to persistent males, and costs to females coerced into longer matings. While males did not benefit in terms of increased progeny production by protracting copulation, female remating was delayed after long first copulations. Copulation time is a trait subject to sexual conflict. Mating durations exceeding female optima serve males as a form of 'extended mate guarding': by inducing mating refractoriness in the female, a male extends the time over which its sperm is exclusively used to sire progeny and reduces the likelihood of the female being reinseminated by a competitor.


HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy.
Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide and available therapies, including immunotherapies, are ineffective for many patients. HCC is characterized by intratumoral hypoxia, and increased expression of hypoxia-inducible factor 1α (HIF-1α) in diagnostic biopsies is associated with patient mortality. Here we report the development of 32-134D, a low-molecular-weight compound that effectively inhibits gene expression mediated by HIF-1 and HIF-2 in HCC cells, and blocks human and mouse HCC tumor growth. In immunocompetent mice bearing Hepa1-6 HCC tumors, addition of 32-134D to anti-PD1 therapy increased the rate of tumor eradication from 25% to 67%. Treated mice showed no changes in appearance, behavior, body weight, hemoglobin, or hematocrit. Compound 32-134D altered the expression of a large battery of genes encoding proteins that mediate angiogenesis, glycolytic metabolism, and responses to innate and adaptive immunity. This altered gene expression led to significant changes in the tumor immune microenvironment, including a decreased percentage of tumor-associated macrophages and myeloid-derived suppressor cells, which mediate immune evasion, and an increased percentage of CD8+ T cells and natural killer cells, which mediate antitumor immunity. Taken together, these preclinical findings suggest that combining 32-134D with immune checkpoint blockade may represent a breakthrough therapy for HCC.


Protein kinase C pathways modulate respiratory pattern generation in the cat.
1. The significance of protein kinase C (PKC) in respiratory pattern generation was investigated in forty-three expiratory neurones of anaesthetized cats. 2. Intracellular injection of R-2,6-diamino-N-([1-(oxotridecyl)-2-piperidinyl]-methyl)-hexana mide dihydrochloride reversibly hyperpolarized twenty-six neurones. Respiratory drive potentials decreased to 92% of control, and action potential discharges were reduced. Neuronal input resistance (Rin) decreased during inspiration and increased during expiration. 3. Voltage clamp revealed that blockade of PKC induced an increase of inhibitory drive currents and a decrease of excitatory drive currents in sixteen neurones. The amplitude of respiratory drive currents was decreased to 91% of control. The slope of synaptic inward currents during postinspiration was reduced. 4. After blockade of K+ conductances by TEA, additional blockade of PKC caused a hyperpolarization during postinspiration and expiration, but depolarization during inspiration in fourteen neurones. The respiratory drive currents were reduced to 61% of control. Respiratory drive potentials decreased to 72% of control, leading to reduced spontaneous discharge. Rin was increased throughout the respiratory cycle. 5. Stimulus-evoked postsynaptic currents and potentials decreased after blockade of PKC with and without TEA. 6. The results indicate that PKC is endogenously active in expiratory neurones, modulating their excitability in three different ways: (a) it downregulates persistent K+ currents, (b) it upregulates Cl(-)-mediated inhibitory postsynaptic currents (IPSCs), and (c) it upregulates excitatory postsynaptic currents (EPSCs).


Development of Optimized Strategies for Growth Factor Incorporation onto Electrospun Fibrous Scaffolds To Promote Prolonged Release.
Growth factor incorporation in biomedical constructs for their local delivery enables specific pharmacological effects such as the induction of cell growth and differentiation. This has enabled a promising way to improve the tissue regeneration process. However, it remains challenging to identify an appropriate approach that provides effective growth factor loading into biomedical constructs with their following release kinetics in a prolonged manner. In the present work, we performed a systematic study, which explores the optimal strategy of growth factor incorporation into sub-micrometric-sized CaCO3 core-shell particles (CSPs) and hollow silica particles (SiPs). These carriers were immobilized onto the surface of the polymer scaffolds based on polyhydroxybutyrate (PHB) with and without reduced graphene oxide (rGO) in its structure to examine the functionality of incorporated growth factors. Bone morphogenetic protein-2 (BMP-2) and ErythroPOietin (EPO) as growth factor models were included into CSPs and SiPs using different entrapping strategies, namely, physical adsorption, coprecipitation technique, and freezing-induced loading method. It was shown that the loading efficiency, release characteristics, and bioactivity of incorporated growth factors strongly depend on the chosen strategy of their incorporation into delivery systems. Overall, we demonstrated that the combination of scaffolds with drug delivery systems containing growth factors has great potential in the field of tissue regeneration compared with individual scaffolds.


Highly Permeable Perfluorinated Sulfonic Acid Ionomers for Improved Electrochemical Devices: Insights into Structure-Property Relationships.
Rapid improvements in polymer-electrolyte fuel-cell (PEFC) performance have been driven by the development of commercially available ion-conducting polymers (ionomers) that are employed as membranes and catalyst binders in membrane-electrode assemblies. Commercially available ionomers are based on a perfluorinated chemistry comprised of a polytetrafluoroethylene (PTFE) matrix that imparts low gas permeability and high mechanical strength but introduces significant mass-transport losses in the electrodes. These transport losses currently limit PEFC performance, especially for low Pt loadings. In this study, we present a novel ionomer incorporating a glassy amorphous matrix based on a perfluoro(2-methylene-4-methyl-1,3-dioxolane) (PFMMD) backbone. The novel backbone chemistry induces structural changes in the ionomer, restricting ionomer domain swelling under hydration while disrupting matrix crystallinity. These structural changes slightly reduce proton conductivity while significantly improving gas permeability. The performance implications of this trade-off are assessed, which reveal the potential for substantial performance improvement by incorporation of highly permeable ionomers as the functional catalyst binder. These results underscore the significance of tailoring material chemistry to specific device requirements, where ionomer chemistry should be rationally designed to match the local transport requirements of the device architecture.


Quantum Dot Labeling and Visualization of Extracellular Vesicles.
Extracellular vesicles (EVs) are important mediators of intercellular communication. Their role in disease processes, uncovered mostly over the last two decades, makes them potential biomarkers, leading to a need to fundamentally understand EV biology. Direct visualization of EVs can provide insights into EV behavior, but current labeling techniques are often restricted by false-positive signals and rapid photobleaching. Hence, we developed a method of labeling EVs through conjugation with quantum dots (QDs)-high photoluminescent nanosized semi-conductors-using click chemistry. We showed that QD-EV conjugation could be tailored by altering QD to EV ratio or by using a catalyst. This conjugation chemistry was stable in a biological environment and upon storage for up to a week. Using size-exclusion chromatography, QD-EV conjugates could be separated from unconjugated QDs, enabling EV-specific signal detection. We demonstrate that these QD-EV conjugates can be live- and fixed-imaged in high resolution on cells and in tissue sheets, and the conjugates have better photostability compared with the commonly used EV dye DiI. We labeled two distinct EV populations: human semen EVs (sEVs) from fresh semen samples donated by healthy volunteers and brain EVs (bEVs) from excised rat brain tissues. We visualized QD-sEVs in epithelial sheets isolated from human vaginal mucosa and time-lapse imaged QD-bEV interactions with microglial BV-2 cells. The development of the QD-EV conjugate will benefit the study of EV localization, movement, and function and accelerate their potential use as biomarkers, therapeutic agents, or drug-delivery vehicles.


Six-month results of hyperopic and astigmatic LASIK in eyes with primary and secondary hyperopia.
To assess the safety and efficacy of laser in situ keratomileusis (LASIK) for hyperopia and hyperopic astigmatism and develop a LASIK nomogram for primary hyperopia or hyperopia secondary to myopic refractive surgery using the VISX STAR S2. Prospective evaluation of LASIK in 46 primary eyes and 29 secondary eyes with fogged manifest sphere from +0.5 diopters (D) to +6.0 D and cylinder from 0 to +5.0 D. Mean manifest spherical equivalent (SE) in patients with primary hyperopia was +2.50 D +/- 0.93 preoperatively and +0.70 D +/- 1.19 at 6 months. At 6 months, 79% of primary hyperopes had uncorrected visual acuity (UCVA) of 20/40 or better; 63% were within +/- 1 D of emmetropia. One primary hyperope lost 2 lines of best spectacle-corrected vision (BCVA) at 1 month. Complications included transient epithelial defect (6.5%), epithelial cells in the interface (4.3%), diffuse lamellar keratitis (4.3%), haze (2.2%), and mild irregular astigmatism (2.2%). In those with secondary hyperopia, mean manifest SE was +1.70 D +/- 0.82 preoperatively and -0.27 D +/- 0.95 at 6 months. At 6 months, 83% of secondary hyperopes had UCVA of 20/40 or better; 74% were within +/- 1 D of emmetropia. No secondary hyperope lost > or = 2 lines of BCVA. Complications included intraoperative bleeding (3.4%), intraoperative epithelial defect (3.4%), transient interface debris (3.4%), significant dry eye (3.4%), blood in interface (3.4%), irregular astigmatism (6.9%), slight decentration (6.9%), trace haze (6.9%), mild epithelial ingrowth not requiring removal (3.4%), or corneal irregularity (3.4%). These early data suggest that LASIK for hyperopia from +0.5 to +6 D and astigmatism from 0 to +5 D using the VISX STAR S2 benefits from a nomogram adjusted for preoperative refraction, age, and prior refractive surgery and is safe and effective. Patients with secondary hyperopia achieved more correction than those with primary hyperopia, although the accuracy and predictability of LASIK in both groups has improved with the nomogram adjustments.


Characterisation by plasmid profiles, serogroups, and auxotypes of Neisseria gonorrhoeae from Harare, Zimbabwe.
(ABSTRACTOne hundred and fifty five strains of Neisseria gonorrhoeae were regrown from 216 freeze dried cultures originally isolated in Zimbabwe. The gonococci were from men (61 strains) and women (39 strains) attending a referral sexually transmitted diseases (STD) clinic, from women presenting for delivery at hospital with signs of sepsis (22 strains) or with an asymptomatic infection (16 strains), and from babies with ophthalmia neonatorum (17 strains). Seventy five of the 100 isolates from STD clinic patients and 29 of the 55 isolates from hospital patients were penicillinase producing N gonorrhoeae (PPNG). Two thirds of all PPNG strains contained the 24.5 megadalton conjugative plasmid. The 3.2 megadalton resistance plasmid, usually associated with PPNG strains originating in Africa, was present in only one third of the PPNG strains. The 2.6 megadalton cryptic plasmid was present in all strains. Prototrophic and proline requiring auxotypes predominated in both PPNG and non-PPNG strains. Arginine requiring auxotypes were found in four of the 16 isolates from asymptomatic women, whereas three of the 22 strains from women with puerperal sepsis and four of the 61 strains from men with urethritis required both proline and arginine. Fifty eight out of 66 PPNG strains with the 4.4 megadalton plasmid required proline compared with 22/38 PPNG strains with the 3.2 megadalton plasmid and 20 of the 51 non-PPNG strains. Three quarters (38/51) of non-PPNG strains belonged to serogroup WII/III as did 42/66 PPNG strains with the 4.4 megadalton plasmid but only 10/38 PPNG strains with the 3.2 megadalton plasmid. In all, 23 different strain types could be recognized on the basis of plasmid content, auxotype, and serogroup. There was, however, a high degree of homogeneity between PPNG and non-PPNG isolates.


Transverse patterning and human amnesia.
The transverse patterning (TP) task (A+ B-, B+ C-, C+ A-) has played a central role in testing the hypothesis that medial-temporal (and, in particular, hippocampal) brain damage selectively impairs learning on at least some classes of configural (i.e., nonlinear) learning tasks. Results in the animal and human literature generally support that hypothesis. Reed and Squire [Impaired transverse patterning in human amnesia is a special case of impaired memory for two-choice discrimination tasks. Behavioral Neuroscience, 113, 3-9, 1999], however, advanced an alternative account in which impaired TP performance in amnesia reflects a generic scaling artifact arising from the greater difficulty of the TP task compared to the elemental (i.e., linear) control task that is typically used. We begin with a critique of Reed and Squire, countering their conceptual arguments and showing that their results, when analyzed appropriately, support the configural deficit hypothesis. We then report results from eight new amnesic patients and controls on an improved version of the TP task. Despite substantial practice, accuracy of patients with bilateral hippocampal damage due to anoxia reached and maintained an asymptote of only 54% correct, well below the maximum accuracy obtainable (67%) in the absence of configural learning. A patient with selective bilateral damage to the anterior thalamic nuclei exhibited a TP accuracy asymptote that was near 67%, a pattern of two out of three correct consecutive trials, and a pattern of nearly always answering correctly for two of the three TP item pairs. These results are consistent with a set of unique and parameter-free predictions of the configural deficit hypothesis.


Intracellular uptake of EGCG-loaded deformable controlled release liposomes for skin cancer.
Caucasian population groups have a higher propensity to develop skin cancer, and associated clinical interventions often present substantial financial burden on healthcare services. Conventional treatments are often not suitable for all patient groups as a result of poor efficacy and toxicity profiles. The primary objective of this study was to develop a deformable liposomal formulation, the properties of which being dictated by the surfactant Tween 20, for the dermal cellular delivery of epigallocatechin gallatein (EGCG), a compound possessing antineoplastic properties. The results demonstrated a significant (p ≤ 0.05) decrease in liposome deformability index (74 ± 8 to 37 ± 7) as Tween 20 loading increased from 0 to 10% w/w, indicating an increase in elasticity. EGCG release over 24-h demonstrated Tween 20 incorporation directly increased release from 13.7% ± 1.1% to 94.4% ± 4.9% (for 0 and 10% w/w Tween 20 respectively). Finally, we demonstrated DilC-loaded deformable liposomes were localized intracellularly within human dermal fibroblast and keratinocyte cells within 2 h. Thus, it was evident that deformable liposomes may aid drug penetration into dermal cells and would be useful in developing a controlled-release formulation.


Multilayer coating of gold nanorods for combined stability and biocompatibility.
Engineering plasmonic nanostructures that simultaneously achieve high colloidal stability, high photothermal stability, low non-specific binding to biological specimens, and low toxicity is of significant interest to research in bionanotechnology. Using gold nanorods, we solved this problem by encapsulating them with a multilayer structure, silica, hydrophobic ligands, and amphiphilic-polymers. In comparison with nanorods covered with the conventional surface chemistries, such as surfactants, polyelectrolytes, thiolated polymers, and silica shells alone, the new nanorods remain single in various solutions and show remarkable stability against laser irradiation. We further demonstrated specific targeting and effective treatment of prostate tumor cells using nanorod-aptamer bioconjugates. This exquisitely formulated nanoencapsulation technology could potentially help stabilize other plasmonic nanostructures that are not in the most thermodynamically or chemically stable states, and should open exciting opportunities in nanotechnology-based imaging and therapeutics.


Continuous flow strategies for using fluorinated greenhouse gases in fluoroalkylations.
Large quantities of fluorinated gases are generated as intermediates or byproducts from fluorinated polymer production annually, and they are effective ozone depleting substances or greenhouse gases. On the other hand, the incorporation of fluoroalkyl groups into drug molecules or bioactive compounds has been shown to enhance biological properties such as the bioavailability, binding selectivity, and metabolic stability. Extraction of fluoroalkyl sources, including trifluoromethyl and difluoromethyl groups, from the fluorinated gases is highly desirable, yet challenging under regular batch reaction conditions. Flow chemistry is an emerging and promising technique to address long-standing challenges in gas-liquid batch reactions such as insufficient interfacial contact and scalability issues. In this review, we highlight recent advances in continuous flow strategies toward enabling the use of fluorinated greenhouse gases in organic synthesis.


Tumor diameter as a predictor of lymphatic dissemination in endometrioid endometrial cancer.
To assess the utility of tumor diameter (TD) for predicting lymphatic dissemination (LD) and determining need for lymphadenectomy following diagnosis of endometrioid endometrial cancer. Patients diagnosed with stage I-III endometrioid endometrial cancer during 2003-2013 who underwent pelvic or para-aortic lymphadenectomy during hysterectomy were studied. Intraoperative predictors of LD included TD, grade, myometrial invasion (MI), age, body mass index, and race/ethnicity. Candidate logistic regression models of LD were evaluated for model fit and predictive power. Of 737 cancer patients, 68 (9.2%) were node-positive. Single-variable models with only continuous TD (c-statistic 0.77, 95% CI 0.71-0.83) and dichotomous TD with 50-mm cut-off (TD50; c-statistic 0.73, 95% CI 0.67-0.78) were significantly more predictive than with the standard 20-mm cut-off (c-statistic 0.56, 95% CI 0.53-0.59). Overall, the most important LD predictors were TD50 and MI3rds (three-category form). The best candidate model (c-statistic 0.84, 95% CI 0.80-0.88) suggested odds of LD were five times greater for TD >50mm than ≤50mm (OR 4.91, 95% CI 2.73-8.82) and six and ten times greater for MI >33% to ≤66% (OR, 5.70; 95% CI, 2.25-14.5) and >66% (OR 10.2, 95% CI 4.11-25.4), respectively, than ≤33%. Best-model false-negative (0%) and positive (57.2%) rates demonstrated marked improvement over traditional risk-stratification false-negative (1.5%) and positive (76.2%) rates (c-statistic 0.77, 95% CI 0.72-0.82). Tumor diameter is an important predictor of LD. Our risk model, containing modified forms of MI and TD, yielded a lower false-negative rate and can significantly decrease the number of lymphadenectomies performed on low-risk women.


Fever and regional blood flows in wethers and parturient ewes.
To determine whether the reported absence of fever in full-term-pregnant ewes might be associated with shifts of regional blood flows from thermogenic tissues to placenta during this critical period, fevers were induced twice by injections of Escherichia coli lipopolysaccharide (LPS, 0.25 microgram/kg iv) into each of six Merino ewes from 8 to 1 days prepartum, and their regional blood flow distribution was measured with radioactive, 15-microns-diam microspheres before and during the rise in fever (when their rectal temperature had risen approximately 0.4 degree C). Unexpectedly, fever always developed, rising to heights not significantly different at any time before parturition [4-8 days prepartum = 0.81 +/- 0.23 degree C (SE); 1-3 days prepartum = 0.75 +/- 0.17 degree C) and similar to those in three wethers treated similarly (0.90 +/- 0.10 degree C). Generally, during rising fever, blood flow in the ewes shifted away from heat loss tissues (e.g., skin, nose) to heat production tissues (e.g., shivering muscle, fat) and cardiac output increased; blood flow through redistribution organs (e.g., splanchnic bed) decreased. The reverse occurred during defervescence. Utero-placental blood flow remained high in the febrile ewes. These regional blood flow distributions during febrigenesis and lysis are essentially the same as those during exposures to ambient cold and heat, respectively. Some differences in the responses of cardiac output and its redistribution, however, were apparent between wethers and pregnant ewes. We conclude that 1) the previously reported "absence of fever in the full-term-pregnant sheep" should not be regarded as a general phenomenon and 2) full-term-pregnant sheep support fever production without sacrificing placental blood flow.


The uses of heparin to treat burn injury.
To assess the evidence for using heparin in the treatment of burn injury or the complications of burn injury in adults and children. The following databases were searched: MEDLINE (1966-current), EMBASE (1980-current), Cumulative Index to Nursing & Allied Health (CINAHL) (1982-current), The Cochrane Central Database of Controlled Trials (1995-current), Web of Science (1976-current), and BIOSIS (1976-current). Additional data sources included the U.S. and European Patent Offices, technical experts, the partner organization, and reference lists. Studies identified from the data sources went through two levels of title and abstract screening. Passing studies advanced to full text screening. Studies that met the full text screening criteria were abstracted. Criteria for abstraction included publication in any language, human patients of any age, and burns of any type, grade, or total body surface area. All formulations of heparin, and all application methods (e.g., topical, subcutaneous), were eligible for inclusion in the report. Abstracted studies required a comparison group. Outcomes of interest included mortality, pain, length of stay in hospital, thrombosis and emboli, psychiatric adjustment, and adverse effects (e.g., bleeding). Nineteen articles from 18 unique studies were abstracted and included in this report. In these articles, there were multiple uses of heparin to treat burns (e.g., wound healing, inhalation injury, sepsis, pain). However, the overall quality of the articles was weak. Examples of weakness included unclear or inappropriate treatment allocation, no blinding, no control of confounding, poorly defined burn characteristics (e.g., thickness), unclear duration of treatment, incomplete description of heparin treatment, and use of inadequately described or invalid outcome measures. Overall, the evidence from these weak articles was insufficient to determine whether the effectiveness of heparin to treat burn injury was different from the effectiveness of other treatments, or whether treatment effectiveness varied according to (a) the method of applying heparin to (b) burn etiology. Four studies mentioned contraindications to using heparin to treat burns. These contraindications were bleeding diathesis, bleeding history, active bleeding or associated trauma with potential bleeding, active intestinal ulcer, thrombocytopenia, liver disease, renal disorders, or allergy to heparin. There is no strong evidence in the 19 abstracted articles to suggest that heparin should be used in the treatment of burn injury on account of its non-anticoagulant properties.


Development of a hybrid decision support model for optimal ventricular assist device weaning.
Despite the small but promising body of evidence for cardiac recovery in patients that have received ventricular assist device (VAD) support, the criteria for identifying and selecting candidates who might be weaned from a VAD have not been established. A clinical decision support system was developed based on a Bayesian Belief Network that combined expert knowledge with multivariate statistical analysis. Expert knowledge was derived from interviews of 11 members of the Artificial Heart Program at the University of Pittsburgh Medical Center. This was supplemented by retrospective clinical data from the 19 VAD patients considered for weaning between 1996 and 2004. Artificial Neural Networks and Natural Language Processing were used to mine these data and extract sensitive variables. Three decision support models were compared. The model exclusively based on expert-derived knowledge was the least accurate and most conservative. It underestimated the incidence of heart recovery, incorrectly identifying 4 of the successfully weaned patients as transplant candidates. The model derived exclusively from clinical data performed better but misidentified 2 patients: 1 weaned successfully, and 1 that needed a cardiac transplant ultimately. An expert-data hybrid model performed best, with 94.74% accuracy and 75.37% to 99.07% confidence interval, misidentifying only 1 patient weaned from support. A clinical decision support system may facilitate and improve the identification of VAD patients who are candidates for cardiac recovery and may benefit from VAD removal. It could be potentially used to translate success of active centers to those less established and thereby expand use of VAD therapy.


Current Competencies of Game Facilitators and Their Potential Optimization in Higher Education: Multimethod Study.
Serious games can be a powerful learning tool in higher education. However, the literature indicates that the learning outcome in a serious game depends on the facilitators' competencies. Although professional facilitators in commercial game-based training have undergone specific instruction, facilitators in higher education cannot rely on such formal instruction, as game facilitation is only an occasional part of their teaching activities. This study aimed to address the actual competencies of occasional game facilitators and their perceived competency deficits. Having many years of experience as professional and occasional facilitators, we (n=7) defined requirements for the occasional game facilitator using individual reflection and focus discussion. Based on these results, guided interviews were conducted with additional occasional game facilitators (n=4) to check and extend the requirements. Finally, a group of occasional game facilitators (n=30) answered an online questionnaire based on the results of the requirement analysis and existing competency models. Our review produced the following questions: Which competencies are needed by facilitators and what are their training needs? What do current training courses for occasional game facilitators in higher education look like? How do the competencies of occasional game facilitators differ from other competencies required in higher education? The key findings of our analysis are that a mix of managerial and technical competencies is required for facilitating serious games in higher educational contexts. Further, there is a limited or no general competence model for game facilitators, and casual game facilitators rarely undergo any specific, formal training. The results identified the competencies that game facilitators require and a demand for specific formal training. Thus, the study contributes to the further development of a competency model for game facilitators and enhances the efficiency of serious games.


Male human papillomavirus prevalence and association with condom use in Brazil, Mexico, and the United States.
Reported associations of condom use and human papillomavirus (HPV) infection have been inconsistent. We investigated self-reported frequency of condom use and detection of genital HPV among men. A cross-sectional analysis was conducted in men aged 18-70 years from Brazil, Mexico, and the United States. Men completed questionnaires on sexual history, condom use, and sociodemographic characteristics. Among 2621 men reporting recent vaginal sex, prevalence of any HPV, any oncogenic type, and nononcogenic types only was estimated by frequency of condom use ("always" or "not always"). Multivariable models were used to estimate prevalence ratios (PRs) for HPV according to frequency of condom use. The prevalence of any HPV was 70.5%; any oncogenic type, 34%, and nononcogenic types only, 22.2%. The adjusted PR for always vs not always using condoms was 0.87 (95% confidence interval [CI], .77-.97) for all countries combined. The association was stronger in the United States (PR, 0.70; CI, .55-.90) than in Brazil (PR, 0.84; CI, .71-1.01) or Mexico (PR, 1.05; CI, .89-1.25) (P for interaction = .025). HPV prevalence was high even among those who reported always using condoms, and its associations with always using condoms varied among countries.


Glucocorticoid hypertension and nonadrenal phenylethanolamine N-methyltransferase.
Several drugs that block epinephrine synthesis by inhibiting phenylethanolamine N-methyltransferase (PNMT) lower blood pressure in hypertensive rats. We investigated the mechanism by which these drugs lower blood pressure in rats made hypertensive with the glucocorticoid dexamethasone. We performed adrenalectomy or sham operation on several rats and then gave them either dexamethasone chronically or vehicle. The dexamethasone-treated adrenalectomized rats also received either the centrally acting PNMT inhibitor SKF 64139 chronically or an equal dose of the primarily peripherally acting PNMT inhibitor SKF 29661. Both SKF 64139 and SKF 29661 reduced blood pressure by more than 25 mm Hg. SKF 64139 also reduced PNMT activity in hypothalamus, medulla oblongata, skeletal muscle, and cardiac atria and ventricles; SKF 29661 inhibited PNMT in muscle and heart tissue by 40-75%, did not inhibit PNMT in hypothalamus, and inhibited PNMT by only 29% in medulla oblongata. PNMT activity in peripheral tissues was also more highly correlated with blood pressure than was PNMT activity in the brain areas studied. Neither drug reduced tissue epinephrine levels, but SKF 64139 elevated dopamine or norepinephrine levels or both in several tissues. We conclude that the blood pressure-lowering action of PNMT-inhibiting drugs in glucocorticoid hypertensive rats may be due to inhibition of peripheral nonadrenal PNMT. We speculate that elevations in nonadrenal PNMT may mediate glucocorticoid hypertension.


Patient-reported outcomes in the ProtecT randomized trial of clinically localized prostate cancer treatments: study design, and baseline urinary, bowel and sexual function and quality of life.
To present the baseline patient-reported outcome measures (PROMs) in the Prostate Testing for Cancer and Treatment (ProtecT) randomized trial comparing active monitoring, radical prostatectomy and external-beam conformal radiotherapy for localized prostate cancer and to compare results with other populations. A total of 1643 randomized men, aged 50-69 years and diagnosed with clinically localized disease identified by prostate-specific antigen (PSA) testing, in nine UK cities in the period 1999-2009 were included. Validated PROMs for disease-specific (urinary, bowel and sexual function) and condition-specific impact on quality of life (Expanded Prostate Index Composite [EPIC], 2005 onwards; International Consultation on Incontinence Questionnaire-Urinary Incontinence [ICIQ-UI], 2001 onwards; the International Continence Society short-form male survey [ICSmaleSF]; anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), generic mental and physical health (12-item short-form health survey [SF-12]; EuroQol quality-of-life survey, the EQ-5D-3L) were assessed at prostate biopsy clinics before randomization. Descriptive statistics are presented by treatment allocation and by men's age at biopsy and PSA testing time points for selected measures. A total of 1438 participants completed biopsy questionnaires (88%) and 77-88% of these were analysed for individual PROMs. Fewer than 1% of participants were using pads daily (5/754). Storage lower urinary tract symptoms were frequent (e.g. nocturia 22%, 312/1423). Bowel symptoms were rare, except for loose stools (16%, 118/754). One third of participants reported erectile dysfunction (241/735) and for 16% (118/731) this was a moderate or large problem. Depression was infrequent (80/1399, 6%) but 20% of participants (278/1403) reported anxiety. Sexual function and bother were markedly worse in older men (65-70 years), whilst urinary bother and physical health were somewhat worse than in younger men (49-54 years, all P < 0.001). Bowel health, urinary function and depression were unaltered by age, whilst mental health and anxiety were better in older men (P < 0.001). Only minor differences existed in mental or physical health, anxiety and depression between PSA testing and biopsy assessments. The ProtecT trial baseline PROMs response rates were high. Symptom frequencies and generic quality of life were similar to those observed in populations screened for prostate cancer and control subjects without cancer.


Endochondral bone formation in toothless (osteopetrotic) rats: failures of chondrocyte patterning and type X collagen expression.
The pacemaker of endochondral bone growth is cell division and hypertrophy of chondrocytes. The developmental stages of chondrocytes, characterized by the expression of collagen types II and X, are arranged in arrays across the growth zone. Mutations in collagen II and X genes as well as the absence of their gene products lead to different, altered patterns of chondrocyte stages which remain aligned across the growth plate (GP). Here we analyze GP of rats bearing the mutation toothless (tl) which, apart from bone defects, develop a progressive, severe chondrodystrophy during postnatal weeks 3 to 6. Mutant GP exhibited disorganized, non-aligned chondrocytes and mineralized metaphyseal bone but without cartilage mineralization or cartilaginous extensions into the metaphysis. Expression of mRNA coding for collagen types II (Col II) and X (Col X) was examined in the tibial GP by in situ hybridization. Mutant rats at 2 weeks exhibited Col II RNA expression and some hypertrophied chondrocytes (HC) but no Col X RNA was detected. By 3rd week, HC had largely disappeared from the central part of the mutant GP and Col II RNA expression was present but weak and in 2 separate bands. Peripherally the GP contained HC but without Col X RNA expression. This abnormal pattern was exacerbated by the fourth week. Bone mineralized but cartilage in the GP did not. These data suggest that the tl mutation involves a regulatory function for chondrocyte maturation, including Col X RNA synthesis and mineralization, and that the GP abnormalities are related to the Col X deficiency. The differences in patterning in the tl rat GP compared to direct Col X mutations may be explained by compensatory effects.


First Report of Artichoke Bacterial Stem Rot Caused by Pectobacterium carotovorum subsp. carotovorum in China.
A new disease on globe artichoke (Cynara scolymus L.) was observed in the springs of 2008 and 2009 and during the spring and fall seasons of 2010 in commercial fields (nearly 1,000 ha) in Changde, Hunan Province, China. Characteristic symptoms were wilting and necrosis of the outermost leaves and dark brown discoloration of the vascular tissue and pith of the stem base. Eventually, the plants wilted and died. Nearly 5, 35, and 4% (2008, 2009, and 2010, respectively) of the artichoke fields were destroyed because of the disease. Manual weeding and cuttings often led to the development of typical soft rot during propagation. To investigate the causal agent of the disease, isolations were made from rotted stems of field artichoke plants on nutrient agar (NA). Bacteria consistently isolated from the diseased tissues formed gray-white, glossy, convex, translucent, and round colonies on NA. The bacterial cells were gram-negative rods with two to eight peritrichous flagella. Ten isolates were negative for oxidase, arginine dehydrolase, H2S, gelatin liquefaction, and tryptophan ammonialyase. Isolates were positive for catalase, reduced NO3 to NO2, indole, glucuroide, galactosidase, Voges-Proskauer test, and β-galactosidase, along with being facultatively anaerobic and insensitive to erythromycin (40 μg/ml). Negative results were obtained for utilization of maltose, gluconate, and phenylacetic acid, and positive results were obtained from arabinose, glucose, mannose, N-acetyl-glucosamine, mannitol, and sodium citrate for all isolates. Acid was produced from glucose, inositol, rhamnose, melibiose, arabinose, mannitol, sucrose, and amarogentin. All test results were similar to reference strain PCC1000 (GenBank Accession No. JF721959) of Pectobacterium carotovorum subsp. carotovorum. These isolates could also cause soft rot of Chinese cabbage stem, carrot slice, pepper, lettuce and artichoke stems, and tomato and potato slices within 48 h at 28°C in an artificial inoculation test (3). PCR amplification was carried out by utilizing universal 16S rDNA primer pair 16SF/16SR and pel gene primers Y1/Y2 (1). The 16S rDNA and pel gene sequences of isolate HNXDT002 (GenBank Accession Nos. JF721958 and JF721960, respectively) had 99 and 93% nucleotide identity with strains of P. carotovorum subsp. carotovorum (GenBank Accession Nos. U80197 and CP001657, respectively). Pathogenicity was confirmed by needle-stab inoculation (1 × 108 CFU/ml) at the stem on three healthy artichoke plants held at 28°C for 48 h. Sterile distilled water was used as a negative control. Within 72 h after inoculation, water-soaking and soft-rot symptoms were observed on all inoculated artichoke plants, while controls remained healthy. The bacterium was recovered only from rotted stems of inoculated plants. In recent years, P. carotovorum was reported on such plants as Pinellia ternata (4) and Chinese cabbage (2) in China. To our knowledge, this is the first report of bacterial rot disease caused by P. carotovorum subsp. carotovorum on artichoke in China. References: (1) D. J. Brenner et al. Bergey's Manual of Systematic Bacteriology. Vol. 2. Springer, NY, 2005. (2)Y. Fang et al. Acta Microbiol. Sinica 44:136, 2004. (3) H. Yi-Bo et al. Acta Phytopathol. Sinica 37:338, 2007. (4) F. X. Ying et al. Plant Dis. 91:1359, 2007.


Introducing the Brassica Information Portal: Towards integrating genotypic and phenotypic Brassica crop data.
The Brassica Information Portal (BIP) is a centralised repository for Brassica phenotypic data. Trait data associated with Brassica research and breeding experiments conducted on Brassica crops, used as vegetables, for livestock fodder and biofuels, is hosted on the site, together with information on the experimental plant materials used, as well as trial design. BIP is an open access and open source project, built on the schema of CropStoreDB, and as such can provide trait data management strategies for any crop data. A new user interface and programmatic submission/retrieval system helps to simplify data access for scientists and breeders. BIP opens up the opportunity to apply big data analyses to data generated by the Brassica Research Community. Here, we present a short description of the current status of the repository.


Redirecting substrate regioselectivity using engineered ΔN123-GBD-CD2 branching sucrases for the production of pentasaccharide repeating units of S. flexneri 3a, 4a and 4b haptens.
The (chemo-)enzymatic synthesis of oligosaccharides has been hampered by the lack of appropriate enzymatic tools with requisite regio- and stereo-specificities. Engineering of carbohydrate-active enzymes, in particular targeting the enzyme active site, has notably led to catalysts with altered regioselectivity of the glycosylation reaction thereby enabling to extend the repertoire of enzymes for carbohydrate synthesis. Using a collection of 22 mutants of ΔN123-GBD-CD2 branching sucrase, an enzyme from the Glycoside Hydrolase family 70, containing between one and three mutations in the active site, and a lightly protected chemically synthesized tetrasaccharide as an acceptor substrate, we showed that altered glycosylation product specificities could be achieved compared to the parental enzyme. Six mutants were selected for further characterization as they produce higher amounts of two favored pentasaccharides compared to the parental enzyme and/or new products. The produced pentasaccharides were shown to be of high interest as they are precursors of representative haptens of Shigella flexneri serotypes 3a, 4a and 4b. Furthermore, their synthesis was shown to be controlled by the mutations introduced in the active site, driving the glucosylation toward one extremity or the other of the tetrasaccharide acceptor. To identify the molecular determinants involved in the change of ΔN123-GBD-CD2 regioselectivity, extensive molecular dynamics simulations were carried out in combination with in-depth analyses of amino acid residue networks. Our findings help to understand the inter-relationships between the enzyme structure, conformational flexibility and activity. They also provide new insight to further engineer this class of enzymes for the synthesis of carbohydrate components of bacterial haptens.


Strain-promoted azide-alkyne cycloaddition for protein-protein coupling in the formation of a bis-hemoglobin as a copper-free oxygen carrier.
Conventional chemical approaches to protein-protein coupling present challenges due to the intrinsic competition between the desired interactions of reagents with groups of the protein as well as reactions with water. Biorthogonal Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC)-processes provide a basis to direct reactivity without functional group interference. However, the requirement for Cu(i) in CuAAC leads to complications that result from the metal ion's interactions with the protein. In principle, a similar but metal-free alternative approach to coupling could employ the reaction of an alkyne that is strained in combination with an azide (strain-promoted azide-alkyne cycloaddition, SPAAC). The method is exemplified by the combination of a cyclooctyne derivative of hemoglobin with an azide-modified hemoglobin. The bis-hemoglobin tetramer that is produced has properties consistent with those sought for use as a hemoglobin-based oxygen carrier (HBOC).


Hepatocyte-specific deletion of the antiapoptotic protein myeloid cell leukemia-1 triggers proliferation and hepatocarcinogenesis in mice.
Regulation of hepatocellular apoptosis is crucial for liver homeostasis. Increased sensitivity of hepatocytes toward apoptosis results in chronic liver injury, whereas apoptosis resistance is linked to hepatocarcinogenesis and nonresponsiveness to therapy-induced cell death. Recently, we have demonstrated an essential role of the antiapoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) in hepatocyte survival. In mice lacking Mcl-1 specifically in hepatocytes (Mcl-1(Deltahep)), spontaneous apoptosis caused severe liver damage. Here, we demonstrate that chronically increased apoptosis of hepatocytes coincides with strong hepatocyte proliferation resulting in hepatocellular carcinoma (HCC). Liver cell tumor formation was observed in >50% of Mcl-1(Deltahep) mice already by the age of 8 months, whereas 12-month-old wild-type (wt) and heterozygous Mcl-1(flox/wt) mice lacked tumors. Tumors revealed a heterogenous spectrum ranging from small dysplastic nodules to HCC. The neoplastic nature of the tumors was confirmed by histology, expression of the HCC marker glutamine synthetase and chromosomal aberrations. Liver carcinogenesis in Mcl-1(Deltahep) mice was paralleled by markedly increased levels of Survivin, an important regulator of mitosis which is selectively overexpressed in common human cancers. This study provides in vivo evidence that increased apoptosis of hepatocytes not only impairs liver homeostasis but is also accompanied by hepatocyte proliferation and hepatocarcinogenesis. Our findings might have implications for understanding apoptosis-related human liver diseases.


The role of cerebral oxygenation and regional cerebral blood flow on tolerance to central hypovolemia.
Tolerance to central hypovolemia is highly variable, and accumulating evidence suggests that protection of anterior cerebral blood flow (CBF) is not an underlying mechanism. We hypothesized that individuals with high tolerance to central hypovolemia would exhibit protection of cerebral oxygenation (ScO2), and prolonged preservation of CBF in the posterior vs. anterior cerebral circulation. Eighteen subjects (7 male/11 female) completed a presyncope-limited lower body negative pressure (LBNP) protocol (3 mmHg/min onset rate). ScO2 (via near-infrared spectroscopy), middle cerebral artery velocity (MCAv), posterior cerebral artery velocity (PCAv) (both via transcranial Doppler ultrasound), and arterial pressure (via finger photoplethysmography) were measured continuously. Subjects who completed ≥70 mmHg LBNP were classified as high tolerant (HT; n = 7) and low tolerant (LT; n = 11) if they completed ≤60 mmHg LBNP. The minimum difference in LBNP tolerance between groups was 193 s (LT = 1,243 ± 185 s vs. HT = 1,996 ± 212 s; P < 0.001; Cohen's d = 3.8). Despite similar reductions in mean MCAv in both groups, ScO2 decreased in LT subjects from -15 mmHg LBNP (P = 0.002; Cohen's d=1.8), but was maintained at baseline values until -75 mmHg LBNP in HT subjects (P < 0.001; Cohen's d = 2.2); ScO2 was lower at -30 and -45 mmHg LBNP in LT subjects (P ≤ 0.02; Cohen's d ≥ 1.1). Similarly, mean PCAv decreased below baseline from -30 mmHg LBNP in LT subjects (P = 0.004; Cohen's d = 1.0), but remained unchanged from baseline in HT subjects until -75 mmHg (P = 0.006; Cohen's d = 2.0); PCAv was lower at -30 and -45 mmHg LBNP in LT subjects (P ≤ 0.01; Cohen's d ≥ 0.94). Individuals with higher tolerance to central hypovolemia exhibit prolonged preservation of CBF in the posterior cerebral circulation and sustained cerebral tissue oxygenation, both associated with a delay in the onset of presyncope.


Communication of radiation-induced stress or bystander signals between fish in vivo.
We report data in this paper suggesting that fish irradiated to 0.5 Gy total body dose can release factors into the water that signal other unexposed fish and cause induction of bystander effects expressed as increased cell death in a reporter system. Radiation-induced bystander effects, resulting in the appearance of radiation damage or induction of typical radiation responses in unirradiated cells and tissues are now an established consequence of exposure to low doses of ionizing radiation, however little work has been done in vivo or in species other than humans or mice. In these experiments rainbow trout were irradiated and then paired with unirradiated fish for two hours. Additionally, unirradiated fish were placed in water which had previously been used to hold irradiated fish for 2 h. Sham-irradiated fish and absolute control fish were also examined all using blind protocols. Following a two h incubation period, at these various exposure regimes, the fish were killed by a blow to the head and dissected. Five organs were removed from each fish and tissue explants were cultured using an established technique. After 2 days, the culture medium was harvested and used in a reporter assay to determine whether a bystander effect had been induced. The explants were cultured on in Clonetics growth medium for a further 14 days then fixed for assay of radiation response proteins. The responses varied according to the cell type in the original explants, with the gill and fin showing the most pronounced response. The results suggest that communication signals leading to a typical radiation response can be passed between fish and seem to involve secretion of a chemical messenger into the water.


Two years clinical outcomes with the state-of-the-art PCI for the treatment of bifurcation lesions: A sub-analysis of the SYNTAX II study.
Bifurcation PCI is associated with a lower rate of procedural success, especially in multivessel disease patients. We aimed to determine the impact of bifurcation treatment on 2-years clinical outcomes when a state-of-the-art PCI strategy (heart team decision-making using the SYNTAX score II, physiology guided coronary stenosis assessment, thin strut bioresorbable polymer drug-eluting stent, and intravascular ultrasound guidance) is followed. Three-vessel disease patients enrolled in the SYNTAX II trial (n = 454) were categorized in patients with (a) ≥1 treated bifurcation (n = 126), and (b) without bifurcation (n = 281). The primary endpoint was the occurrence of major adverse cardio and cerebrovascular events (MACCE-a composite of all-cause death, stroke, any myocardial infarction, or any revascularization) at 2 years. Secondary endpoints were the occurrence of target lesion failure (TLF) defined as cardiac death, target-vessel myocardial infarction and ischemia-driven target lesion revascularization, and the individual components of the composite primary endpoint, as well as stent thrombosis. A total of 145 bifurcation were treated in 126 patients. At 2 years, MACCE occurred in 75/407 patients (20.7% for bifurcation versus 17.5% for nonbifurcation, hazard ratio [HR] of 1.28, CI95% 0.78-2.08, p = .32). TLF presented a trend toward higher occurrence in bifurcation (16.8% vs. 10.8%, HR 1.75, CI95% 0.99-3.09, p = .053). Definite stent thrombosis did not differ at 2-year between groups (0.8% for the bifurcation vs. 0.7% for the nonbifurcation, p = .92). Bifurcation treatment in patients with three-vessel disease undergoing state-of-the-art PCI had similar event rate of MACCE but was associated with a trend toward higher incidence of TLF compared with nonbifurcation lesions.


Control strategies for tuberculosis epidemics: new models for old problems.
Tuberculosis, although preventable and curable, causes more adult deaths than any other infectious disease. A theoretical framework for designing effective control strategies is developed and used to determine treatment levels for eradication, to assess the effects of noneradicating control, and to examine the global goals of the World Health Organization. The theory is extended to assess how suboptimal control programs contribute to the evolution of drug resistance. A new evaluation criterion is defined and used to suggest how control strategies can be improved. In order to control tuberculosis, treatment failure rates must be lower in developing countries than in developed countries.


Peer Education strategies for promoting prevention of doping in different populations.
In the field of doping prevention, alongside the traditional functions of repression and control of the phenomenon, educational aspects are becoming increasingly important. Article 18 of the World Anti doping Code obliges the signatories to invest in anti-doping education with the aim of preserving the spirit of sport. The educational commitment should involve young people in health promotion interventions for the prevention of risk behaviors. Therefore, our attention has focused on finding the mechanisms that lead people to make certain behavioral choices. In the context of preventive programs, to counter the doping phenomenon through health promotion programs, the most recognized method is peer education, particularly with adolescents. It is an educational method according to which some members of a group are empowered and trained to carry out specific activities with their peers. It is constituted as an example of equal relationship and finds its basis in cooperation and solidarity with the aim of increasing empowerment and a healthy development of the identity and collective dimension in young people. Numerous experts - biologists / nutritionists, hygienists, sports coaches, psychologists, teachers of physical education in secondary schools and other stakeholders have actively participated in the co-construction of a training package aimed at activating cascade training processes on the knowledge and skills of peer education in contexts of youth aggregation, such as schools, gyms, sports associations, social gatherings of all kinds. The path allowed to define a peer education model capable of enabling the participants to activate health promotion interventions for the prevention of doping risk behaviors, each in their own setting. In conclusion, we can say that prevention programs are the more effective the more they are addressed to young people and adolescents and provide interactive and action-oriented interventions. Successful initiatives aim to emphasize the development of life skills and to influence numerous determinants of behavior, including individual attitudes, knowledge, motivations, interpersonal relationships and social norms. If the aim is to act on the change of behavior, the efforts will be more successful if the content of the intervention will give due consideration to the context in which it applies and the target population, involving it and addressing its specific needs and values.


Hyperdynamic circulation and the insulin resistance syndrome ("syndrome X").
The insulin resistance syndrome ("syndrome X") consists of hyperinsulinemia, glucose intolerance, dyslipidemia, and hypertension, although the inclusion of hypertension has been challenged. Insulin has biological effects that could produce a hyperdynamic circulation. We therefore postulated that an insulin-induced hyperdynamic circulation is an early feature of the insulin resistance syndrome and that this circulatory abnormality leads to later fixed hypertension. The San Antonio Heart Study cohort, a population-based cohort of 3,301 Mexican Americans and 1,857 non-Hispanic whites, was used to define individuals who were hyperdynamic (pulse pressure and heart rate in the upper quartile of their respective distributions), intermediate, and hypodynamic (pulse pressure and heart rate in the bottom quartile). The characteristics of the insulin resistance syndrome were then examined according to these three hemodynamic categories. We also examined the 8-year incidence of hypertension and of type II diabetes according to these hemodynamic categories. A hyperdynamic circulation was associated with statistically significant increases in body mass index (BMI) (p < 0.001), subscapular-to-triceps skinfold ratio (p = 0.042), triglyceride (p = 0.002), 2-hour glucose (p = 0.002), and fasting and 2-hour insulin (p = 0.019 and 0.006). When hemodynamic status was examined separately in lean (BMI < 27 kg/m2) and obese (BMI > or = 27 kg/m2) individuals, the above effects persisted, although they were somewhat attenuated. The odds ratio for the hyperdynamic state as a predictor of future hypertension was 1.66, although this was not statistically significant (p = 0.304). The odds ratio for predicting future type II diabetes was 3.97, which was statistically significant (p = 0.047).(ABSTRACT TRUNCATED AT 250 WORDS)


Urban groundwater quality in sub-Saharan Africa: current status and implications for water security and public health.
Groundwater resources are important sources of drinking water in Africa, and they are hugely important in sustaining urban livelihoods and supporting a diverse range of commercial and agricultural activities. Groundwater has an important role in improving health in sub-Saharan Africa (SSA). An estimated 250 million people (40% of the total) live in urban centres across SSA. SSA has experienced a rapid expansion in urban populations since the 1950s, with increased population densities as well as expanding geographical coverage. Estimates suggest that the urban population in SSA will double between 2000 and 2030. The quality status of shallow urban groundwater resources is often very poor due to inadequate waste management and source protection, and poses a significant health risk to users, while deeper borehole sources often provide an important source of good quality drinking water. Given the growth in future demand from this finite resource, as well as potential changes in future climate in this region, a detailed understanding of both water quantity and quality is required to use this resource sustainably. This paper provides a comprehensive assessment of the water quality status, both microbial and chemical, of urban groundwater in SSA across a range of hydrogeological terrains and different groundwater point types. Lower storage basement terrains, which underlie a significant proportion of urban centres in SSA, are particularly vulnerable to contamination. The relationship between mean nitrate concentration and intrinsic aquifer pollution risk is assessed for urban centres across SSA. Current knowledge gaps are identified and future research needs highlighted.


Relationship between physical disabilities or long-term health problems and health risk behaviors or conditions among US high school students.
This study explores the relationship between self-reported physical disabilities or long-term health problems and health risk behaviors or adverse health conditions (self-reported engagement in violent behaviors, attempted suicide, cigarette smoking, alcohol and other drug use, sexual activity, physical activity, dietary behaviors, self-reported overweight [based on height and weight], physical health, and mental health) among US high school students. Data were from the Centers for Disease Control and Prevention's 2005 national Youth Risk Behavior Survey, a cross-sectional paper-and-pencil survey collected from a representative sample of public and private high school students (grades 9 through 12) in the United States. Significantly more students with physical disabilities or long-term health problems than without described their health as fair or poor and reported being in a physical fight, being forced to have sexual intercourse, feeling sad or hopeless, seriously considering and attempting suicide, cigarette smoking, using alcohol and marijuana, engaging in sexual activity, using computers 3 or more hours per day, and being overweight (for all, p < or = .05). For none of the health risk behaviors analyzed were the rates significantly lower among students with physical disabilities or long-term health problems than among other students. Young people who live with physical disabilities or long-term health problems may be at greater risk for poor health outcomes. Public health and school health programs, with guidance from health care providers, need to work with these adolescents and their families to develop and implement appropriate interventions, with particular emphasis on promoting mental health.


Predicting missing biomarker data in a longitudinal study of Alzheimer disease.
To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD). The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005-2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI. CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ(42). Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD. The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.


Paramagnetic lanthanide chelates for multicontrast MRI.
The preparation of a paramagnetic chelator that serves as a platform for multicontrast MRI, and can be utilized either as a T1-weighted, paraCEST or (19)F MRI contrast agent is reported. Its europium(iii) complex exhibits an extremely slow water exchange rate which is optimal for the use in CEST MRI. The potential of this platform was demonstrated through a series of MRI studies on tube phantoms and animals.


Comparison of fMRI activation at 3 and 1.5 T during perceptual, cognitive, and affective processing.
Previous studies comparing fMRI data acquired at 1.5 T and higher field strengths have focused on examining signal increases in the visual and motor cortices. No information is, however, available on the relative gain, or the comparability of data, obtained at higher field strengths for other brain regions such as the prefrontal and other association cortices. In the present study, we investigated fMRI activation at 1.5 and 3 T during visual perception, visuospatial working memory, and affect-processing tasks. A 23% increase in striate and extrastriate activation volume was observed at 3 T compared with that for 1.5 T during the visual perception task. During the working memory task significant increases in activation volume were observed in frontal and parietal association cortices as well as subcortical structures, including the caudate, globus pallidus, putamen, and thalamus. Increases in working memory-related activation volume of 82, 73, 83, and 36% were observed in the left frontal, right frontal, left parietal, and right parietal lobes, respectively, for 3 T compared with 1.5 T. These increases were characterized by increased activation at 3 T in several prefrontal and parietal cortex regions that showed activation at 1.5 T. More importantly, at 3 T, activation was detected in several regions, such as the ventral aspects of the inferior frontal gyrus, orbitofrontal gyrus, and lingual gyrus, which did not show significant activation at 1.5 T. No difference in height or extent of activation was detected between the two scanners in the amygdala during affect processing. Signal dropout in the amygdala from susceptibility artifact was greater at 3 T, with a 12% dropout at 3 T compared with a 9% dropout at 1.5 T. The spatial smoothness of T2* images was greater at 3 T by less than 1 mm, suggesting that the greater extent of activation at 3 T beyond these spatial scales was not due primarily to increased intrinsic spatial correlations at 3 T. Rather, the increase in percentage of voxels activated reflects increased sensitivity for detection of brain activation at higher field strength. In summary, our findings suggest that functional imaging of prefrontal and other association cortices can benefit significantly from higher magnetic field strength.


Reactivation of gammaHV68 induces neointimal lesions in pulmonary arteries of S100A4/Mts1-overexpressing mice in association with degradation of elastin.
S100A4/Mts-overexpressing mice have thick elastic laminae and mild pulmonary arterial hypertension (PAH), and the occasional older mouse develops occlusive neointimal lesions and perivascular inflammation. We hypothesized that a vasculotropic virus could induce neointimal lesions in the S100A4/Mts1 mouse by facilitating breakdown of elastin and migration and proliferation of smooth muscle cells. To test this hypothesis, we infected S100A4/Mts1 mice with gammaherpesvirus 68 (gammaHV68). We observed, 6 mo after gammaHV68 [4 x 10(3) plaque-forming units (PFU)], perivascular inflammation in 10/15 S100A4/Mts1 mice and occlusive neointimal formation in 3/10 mice, accompanied by striking degradation of elastin. We then compared the early response after high-dose gammaHV68 (4 x 10(6) PFU) in C57Bl/6 and S100A4/Mts1 mice. In S100A4/Mts1 mice only, significant PAH, muscularization of distal vessels, and elastase activity were observed 6 wk after gammaHV68. These features resolved by 3 mo without neointimal formation. We therefore infected mice with the M1-gammaHV68 strain that reactivates from latency with higher efficiency and observed neointimal lesions at 3 mo in 2/5 C57Bl/6 (5-9% of vessels) and in 5/5 S100A4/Mts1 mice (13-40% of vessels) accompanied by mild PAH, heightened lung elastase activity, and intravascular viral expression. This suggested that enhanced generation of elastin peptides in S100A4/Mts1 mice may promote increased viral entry in the vessel wall. Using S100A4/Mts1 PA organ culture, we showed, in response to elastase activity, heightened production of elastin peptides associated with invasion of inflammatory cells and intravascular viral antigen. We therefore propose that early viral access to the vessel wall may be a critical determinant of the extent of vascular pathology following reactivation.


Tests for gene clustering.
Comparing chromosomal gene order in two or more related species is an important approach to studying the forces that guide genome organization and evolution. Linked clusters of similar genes found in related genomes are often used to support arguments of evolutionary relatedness or functional selection. However, as the gene order and the gene complement of sister genomes diverge progressively due to large scale rearrangements, horizontal gene transfer, gene duplication and gene loss, it becomes increasingly difficult to determine whether observed similarities in local genomic structure are indeed remnants of common ancestral gene order, or are merely coincidences. A rigorous comparative genomics requires principled methods for distinguishing chance commonalities, within or between genomes, from genuine historical or functional relationships. In this paper, we construct tests for significant groupings against null hypotheses of random gene order, taking incomplete clusters, multiple genomes, and gene families into account. We consider both the significance of individual clusters of prespecified genes and the overall degree of clustering in whole genomes.


Stereoselective and region-specific induction of immediate early gene expression in rat parietal cortex by blockade of neurokinin 1 receptors.
Antagonists at neurokinin 1 (NK1) receptors are attracting attention as potential treatments for depressive states in light of their actions in behavioural models predictive of antidepressant properties, their modulation of corticolimbic monoaminergic transmission, and their influence upon neural plasticity. Here, we evaluated the influence of NK1 receptor blockade upon two immediate early genes, Arc and c-fos, implicated in mechanisms of synaptic plasticity. Administration of the selective NK1 receptor antagonist, GR 205,171 (40, but not 1, 5 or 10 mg/kg i.p.), elicited a pronounced elevation in mRNA encoding Arc in both outer and inner layers of the parietal cortex of rat brain. This action was region-specific inasmuch as Arc expression did not change in other cortical territories examined including frontal cortex, nor in CA1, CA3 and the dentate gyrus of the hippocampus. In comparison to GR 205,171, its less active isomer GR 226,206 (1-40 mg/kg) did not significantly modify Arc gene expression in parietal cortex or other cortical areas. GR 205,171 (40 mg/kg) also increased the abundance of c-fos mRNA in outer and inner parietal cortex and caused a corresponding increase in c-fos immunoreactivity in this region. GR 226,206 (40 mg/kg i.p.) had no effect on either c-fos mRNA or protein in parietal cortex. In conclusion, administration of GR 205,171 elicits a stereospecific increase in Arc and c-fos expression in rat parietal cortex but not in other cortical regions. These data suggest that the parietal cortex plays a role in the central actions of NK1 receptor antagonists.


Subknots in ideal knots, random knots, and knotted proteins.
We introduce disk matrices which encode the knotting of all subchains in circular knot configurations. The disk matrices allow us to dissect circular knots into their subknots, i.e. knot types formed by subchains of the global knot. The identification of subknots is based on the study of linear chains in which a knot type is associated to the chain by means of a spatially robust closure protocol. We characterize the sets of observed subknot types in global knots taking energy-minimized shapes such as KnotPlot configurations and ideal geometric configurations. We compare the sets of observed subknots to knot types obtained by changing crossings in the classical prime knot diagrams. Building upon this analysis, we study the sets of subknots in random configurations of corresponding knot types. In many of the knot types we analyzed, the sets of subknots from the ideal geometric configurations are found in each of the hundreds of random configurations of the same global knot type. We also compare the sets of subknots observed in open protein knots with the subknots observed in the ideal configurations of the corresponding knot type. This comparison enables us to explain the specific dispositions of subknots in the analyzed protein knots.


Epidemiologic factors in sexual abuse of boys.
To increase understanding of sexual abuse in boys, we reviewed records of 142 victimized boys ranging in age from 6 months to 17 years. They represented 14% of victims under 18 years of age during a four-year period. Most had histories of single assaults (87%) that involved attempted anal intercourse (78%) by know assailants (59%). Half of the assaults were violent, with evidence of trauma found in 24%. Patterns of abuse were associated with the victim's age and the assailant-victim relationship. Younger victims reported more non-stranger assaults, less violence, and less anal intercourse. Assaults by strangers tended to involve older children and more violence and to occur away from home. Male children are at significant risk of sexual abuse, often at younger ages than girls. Consequences of sexual abuse remain unknown, but may relate to future child abuse.


Validity of a two-item physical activity questionnaire for assessing attainment of physical activity guidelines in youth.
As physical activity is important for health and well-being, it is essential to monitor population prevalence of physical activity. Surveillance is dependent on the use of valid and reliable measurement tools. The PACE+ questionnaire is used globally in youth and has acceptable reliability; however it has not been validated in a European sample. The purpose of this study is to validate this instrument in a sample of 10-18 year old Irish youth. Participants (n = 419, 45.7 % male) completed the PACE+ two-item questionnaire and were asked to wear an Actigraph accelerometer for eight consecutive days. Freedson cut-points were used to estimate moderate to vigorous physical activity from accelerometer counts. Analyses compared self-report and accelerometry data in participants with (1) ≥5 and (2) seven valid accelerometer days. Calculations were performed for the whole sample, and were stratified by sex and school level (primary; post-primary). Spearman correlations between self-reported physical activity levels and accelerometry derived minutes of moderate-to-vigorous physical activity per day were small (r = 0.27; seven valid days) to moderate (r = 0.34; ≥5 valid days). Higher correlations were found in older participants (post-primary r = 0.39; primary r = 0.24) and females (r = 0.39; males r = 0.27) using ≥5 valid days. The agreement level was high (68-96 %). The accuracy of classifying those not meeting the guidelines (specificity) was moderate to high (59-100 %). The PACE+ self-report instrument has acceptable validity for assessing non-achievement of the adolescent physical activity recommendations. The validity is higher in females and increases with age. The continued use of the tool is recommended and will allow for comparability between studies, tracking of physical activity over time including trends in youth population prevalence.


[The polycystic ovarian syndrome].
The polycystic ovarian syndrome remains one of the enigmas of gynaecological endocrinology. A review of the literature is presented, with emphasis on practical aspects, as illustrated by the results of a study of 139 patients with this condition. In the majority of patients the diagnosis entails clinical judgement combined with minimal biochemical determinations. However, the differential diagnosis may depend on sophisticated investigations. Since the treatment of some of these patients is as yet unsatisfactory, early diagnosis with prevention of androgenic side-effects is desirable.


Changes in seroprevalence of West Nile virus across Illinois in free-ranging birds from 2001 through 2004.
Of the 5,236 birds sampled for antibodies to West Nile virus (WNV) in Illinois from 2001 through 2004, 348 (6.6%) birds were seropositive. Our multiple year surveillance identified several avian species that had particularly high percentages of seropositive individuals. The importance of these species in the enzootic and/or epizootic transmission of WNV is discussed relative to their regional abundance and literature on host competency. The species with the highest exposure rates to WNV differed both temporally and regionally. In general, birds that bred or were born in Illinois were more likely to have antibodies than transient birds. There was also a significant difference in the seroprevalence between adults (12.1%) and juveniles (5.5%), indicating that the acquired antibody response from previous years is a critical concern when interpreting seroprevalence rates in wild-caught birds. The most common hosts for St. Louis encephalitis virus were also the most common hosts for WNV, which strongly supports the role of similar vectors for both flaviviruses. Avian species with high WNV seroprevalence rates tended to be those that bred throughout the year, have open cup nests, and live in close proximity to humans.


Increased gyrification, but comparable surface area in adolescents with autism spectrum disorders.
Autism spectrum disorders are associated with atypically excessive early brain growth. Recent studies suggest that later cortical development, specifically cortical thickness, during adolescence and young adulthood is also aberrant. Nevertheless, previous studies of other surface-based metrics (e.g. surface area and gyrification) at high-resolution in autism spectrum disorders are limited. Forty-one males with autism spectrum disorders and 39 typically developing males matched on age (mean ≈ 17; range = 12-24 years) and IQ (mean ≈ 113; range = 85-143) provided high-resolution 3 T anatomical magnetic resonance imaging scans. The FreeSurfer image analysis suite quantified vertex-level surface area and gyrification. There were gyrification increases in the autism spectrum disorders group (relative to typically developing subjects) localized to bilateral posterior cortices (cluster corrected P < 0.01). Furthermore, the association between vocabulary knowledge and gyrification in left inferior parietal cortex (typically developing group: positive correlation; autism spectrum disorders group: no association) differed between groups. Finally, there were no group differences in surface area, and there was no interaction between age and group for either surface area or gyrification (both groups showed decreasing gyrification with increasing age). The present study complements and extends previous work by providing the first evidence of increased gyrification (though no differences in surface area) at high resolution among adolescents and young adults with autism spectrum disorders and by showing a dissociation in the relationship between vocabulary and gyrification in autism spectrum disorders versus typically developing subjects. In contrast with previous findings of age-related cortical thinning in this same autism spectrum disorders sample, here we find that increases in gyrification are maintained across adolescence and young adulthood, implicating developmentally dissociable cortical atypicalities in autism spectrum disorders.


Professional competence: factors described by nurses as influencing their development.
To discuss the results of a study that explored factors that may influence competence development. Competence, a controversial issue in health care settings, affects many aspects of the nursing profession, including education, practice and management. Although a number of research and discussion papers have explored the issue, in particular the meaning and assessment of nursing competence, to date little research has explored factors identified by nurses themselves as influencing their development of professional competence. A purposive sample of 27 registered nurses was recruited from two university-affiliated hospitals. Data collection was by tape-recorded semi-structured interviews. Interviews were transcribed verbatim and analysed according to the qualitative methodology of content analysis. Six descriptive categories were identified from the data: experience, opportunities, environment, personal characteristics, motivation and theoretical knowledge. The findings suggest that the factors influencing the process of developing professional competence in nursing extend across personal and extra-personal domains. An understanding of these factors may enhance the ability of nursing managers and educators to enable student and qualified nurses to pursue effective competency development pathways to prepare them to provide a high standard of care. These findings, which may have important implications for nursing practice, management and education, are being further tested in a larger study.


Oral Rehabilitation with Implant-Retained Overdenture in a Patient with Down Syndrome.
Down syndrome, known as trisomy 21, is the most common chromosomal disorder. The disorder affects mental and systemic development as well as oral structure, including dental anomalies, high susceptibility of periodontal disease, and poor quality of alveolar bone. This report presents a case of dental rehabilitation by means of dental implants of a patient with Down syndrome. Two titanium dental implants were placed in the maxilla, and three titanium dental implants were installed in the mandible. One implant was lost during the osseointegration period. The prosthetic rehabilitation was performed with implant-retained maxillary and mandibular overdentures with the Locator attachment system. After a 2-year follow-up period, the patient was doing well, and all implants were clinically stable with no signs of bone loss or inflammation. The present study emphasizes that implant-retained overdentures with Locator attachment system could be a therapeutic option even for patients with Down syndrome. This therapy prevents crestal bone loss around the implants, improves functional and esthetic outcomes, and provides optimum oral hygiene for patients with mild mental impairment. Careful patient selection and education of patients and caregivers are essential considerations for a successful and safe treatment with dental implants in Down syndrome patients.


How big does a coloured overlay have to be?
Coloured overlays and coloured lenses can both increase reading speed, but when they do their colour is not necessarily the same, suggesting that the beneficial effects of a coloured filter might depend upon the area of the visual field that it colours. We investigated the effects of overlays on reading speed and varied the size of the overlay and the colour of the surround. Children who had been assessed with coloured overlays were required to read a passage of randomly ordered common words. The words were printed in black ink as a block of text positioned centrally on an A4 page of white paper in landscape orientation. The speed of reading was compared under four conditions: (1) without an overlay; (2) with an overlay of the chosen colour covering the entire page; (3) with the overlay cut so that it just covered the text but left the margin white; (4) with the overlay of the chosen colour covering the text but with the margin coloured a complementary colour, using a second overlay. The children who were using an overlay read more quickly with the overlay; those who were no longer using the overlay did not. Although the block of text covered less than half the page, the colour and nature of the margin did not affect reading speed significantly. These findings suggest that in order to be effective at improving reading speed an overlay needs to cover the text, but not necessarily the remainder of the page, which means that smaller overlays may sometimes be sufficient.


Temperature Dependence of the Superconducting Gap Anisotropy in Bi2Sr2CaCu2O8+x.
Detailed data on the momentum-resolved temperature dependence of the superconducting gap of Bi(2)Sr(2)CaCu(2)O(8+x) are presented, complemented by similar data on the intensity of the photoemission superconducting condensate spectral area. The gap anisotropy between the Gamma-Mand Gamma-X directions increases markedly with increasing temperature, contrary to what happens for conventional anisotropic-gap superconductors, such as lead. Specifically, the size of the superconducting gap along the Gamma-X direction decreases to values indistinguishable from zero at temperatures for which the gap retains virtually full value along the Gamma-M direction. These data rule out the simplest type of d-wave order parameter.


The PRECEDE-PROCEED model as a tool in Public Health screening: a systematic review.
The aim of this systematic review was to summarize the scientific literature concerning the use of the Precede-Proceed model (PPM) applied to educational programs and health screenings contextsV. Systematic review. The search process was based on a selection of publications listed in Medline and Scopus. The keywords used were "Precede-Proceed" AND ("screening" OR "educational programs"). Studies included in the systematic review were subdivided into those applying the model in a screening context, and those applying it within educational programs. Twenty-seven studies were retrieved, mostly performed in the USA and, generally, the promoting center was the University. In the context of cancer screening, the PPM model was most of all applied to Mammography Screening (5 of 13 studies in cancer screening), and Cervical Cancer Screening (5 of 13). Another three studies within the cancer field investigated Menopause-Inducing Cancer Treatments, Oral cancer prevention, and cancer screening in general. In the remaining studies, the model was applied in various screening areas, particularly chronic and degenerative diseases. There were many different study designs, most of which cross-sectional (8), though several RTCs (8) and focus groups (5) were also found. For the cross-sectional studies the methodological quality varied between 3/10 and 9/10, whilst for the RCTs it ranged from 2/5 to 3/5. The PPM provides an excellent framework for health intervention programs especially in screening contexts, and could improve the understanding of the relationship between variables such as knowledge and screening. Given the complexity of a behavioral change process, certain important predisposing factors could be measured in future studies, and during health intervention planning.


Postoperative radiotherapy for non-small cell lung cancer.
The role of postoperative radiotherapy (PORT) in the treatment of patients with completely resected non-small cell lung cancer (NSCLC) was not clear. A systematic review and individual participant data meta-analysis was undertaken to evaluate available evidence from randomised controlled trials (RCTs). These results were first published in Lung Cancer in 2013. To evaluate the effects of PORT on survival and recurrence in patients with completely resected NSCLC. To investigate whether predefined patient subgroups benefit more or less from PORT. We supplemented MEDLINE and CANCERLIT searches (1965 to 8 July 2016) with information from trial registers, handsearching of relevant meeting proceedings and discussion with trialists and organisations. We included trials of surgery versus surgery plus radiotherapy, provided they randomised participants with NSCLC using a method that precluded prior knowledge of treatment assignment. We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. We sought data on all participants from those responsible for the trial. We obtained updated individual participant data (IPD) on survival and date of last follow-up, as well as details on treatment allocation, date of randomisation, age, sex, histological cell type, stage, nodal status and performance status. To avoid potential bias, we requested information on all randomised participants, including those excluded from investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. We identified 14 trials evaluating surgery versus surgery plus radiotherapy. Individual participant data were available for 11 of these trials, and our analyses are based on 2343 participants (1511 deaths). Results show a significant adverse effect of PORT on survival, with a hazard ratio of 1.18, or an 18% relative increase in risk of death. This is equivalent to an absolute detriment of 5% at two years (95% confidence interval (CI) 2% to 9%), reducing overall survival from 58% to 53%. Subgroup analyses showed no differences in effects of PORT by any participant subgroup covariate.We did not undertake analysis of the effects of PORT on quality of life and adverse events. Investigators did not routinely collect quality of life information during these trials, and it was unlikely that any benefit of PORT would offset the observed survival disadvantage. We considered risk of bias in the included trials to be low. Results from 11 trials and 2343 participants show that PORT is detrimental to those with completely resected non-small cell lung cancer and should not be used in the routine treatment of such patients. Results of ongoing RCTs will clarify the effects of modern radiotherapy in patients with N2 tumours.


Pattern of cellular quiescence over the hibernation cycle in liver of thirteen-lined ground squirrels.
Mammalian hibernation is a state of seasonal heterothermy that consists of long periods of torpor at low body temperature interspersed with short periods of arousal back to euthermia. Entry into the hypometabolic state of torpor is achieved via a strong coordinated reduction of energy expenditures, particularly ATP-expensive activities, such as transcription and translation. The present study analyzes the status of the cell cycle during hibernation in liver of thirteen-lined ground squirrels (Ictidomys tridecemlineatus) and examines the expression levels of cell cycle regulators over six stages of the torpor-arousal cycle. Immunoblot analysis showed that the protein expression levels of cyclin D1 and cyclin E were reduced in liver (by 31% and 48%, respectively) during long-term torpor; however, during arousal from torpor, PCR analysis showed an upregulation of cyclin D1 transcript levels of about 1.5-fold. Protein expression of cyclin A and cyclin B1 were also elevated (1.57-fold and 2.44-fold, respectively) during early arousal from torpor, and in addition, cyclin A2 transcript levels increased by about 1.8-fold during arousal. Protein levels of two CKIs, p15(INK4b) and p21(CIP1), each increased by about 1.4-fold during torpor, and transcript levels of p15(INK4b) also rose by 1.7-2.1 fold during torpor, whereas p21(CIP1) transcripts increased by 1.5-1.7-fold. A reduction in cyclin D and E protein expression coupled with upregulation of p15(INK4b) and p21(CIP1) inhibitors during torpor reflects markers of cell cycle arrest during hibernation. Elevated expression of cyclin A and B protein expression during arousal stages of torpor suggests cell cycle progression is reversibly arrested during torpor and is reinitiated upon return to euthermia.


Sustaining community-based interventions for people affected by dementia long term: the SCI-Dem realist review.
Community-based support for people with earlier-stage dementia and their care partners, such as regularly meeting groups and activities, can play an important part in postdiagnostic care. Typically delivered piecemeal in the UK, by a variety of agencies with inconsistent funding, provision is fragmented and many such interventions struggle to continue after only a short start-up period. This realist review investigates what can promote or hinder such interventions in being able to sustain long term. Key sources of evidence were gathered using formal searches of electronic databases and grey literature, together with informal search methods such as citation tracking. No restrictions were made on article type or study design; only data pertaining to regularly meeting, ongoing, community-based interventions were included. Data were extracted, assessed, organised and synthesised and a realist logic of analysis applied to trace context-mechanism-outcome configurations as part an overall programme theory. Consultation with stakeholders, involved with a variety of such interventions, informed this process throughout. Ability to continually get and keep members; staff and volunteers; the support of other services and organisations; and funding/income were found to be critical, with multiple mechanisms feeding into these suboutcomes, sensitive to context. These included an emphasis on socialising and person-centredness; lowering stigma and logistical barriers; providing support and recognition for personnel; networking, raising awareness and sharing with other organisations, while avoiding conflict; and skilled financial planning and management. This review presents a theoretical model of what is involved in the long-term sustainability of community-based interventions. Alongside the need for longer-term funding and skilled financial management, key factors include the need for stigma-free, person-centred provision, sensitive to members' diversity and social needs, as well as the need for a robust support network including the local community, health and care services. Challenges were especially acute for small scale and rural groups.


Genetics of microstructure of cerebral white matter using diffusion tensor imaging.
We analyzed the degree of genetic control over intersubject variability in the microstructure of cerebral white matter (WM) using diffusion tensor imaging (DTI). We performed heritability, genetic correlation and quantitative trait loci (QTL) analyses for the whole-brain and 10 major cerebral WM tracts. Average measurements for fractional anisotropy (FA), radial (L( perpendicular)) and axial (L( vertical line)) diffusivities served as quantitative traits. These analyses were done in 467 healthy individuals (182 males/285 females; average age 47.9+/-13.5 years; age range: 19-85 years), recruited from randomly-ascertained pedigrees of extended families. Significant heritability was observed for FA (h(2)=0.52+/-0.11; p=10(-7)) and L( perpendicular) (h(2)=0.37+/-0.14; p=0.001), while L( vertical line) measurements were not significantly heritable (h(2)=0.09+/-0.12; p=0.20). Genetic correlation analysis indicated that the FA and L( perpendicular) shared 46% of the genetic variance. Tract-wise analysis revealed a regionally diverse pattern of genetic control, which was unrelated to ontogenic factors, such as tract-wise age-of-peak FA values and rates of age-related change in FA. QTL analysis indicated linkages for whole-brain average FA (LOD=2.36) at the marker D15S816 on chromosome 15q25, and for L( perpendicular) (LOD=2.24) near the marker D3S1754 on the chromosome 3q27. These sites have been reported to have significant co-inheritance with two psychiatric disorders (major depression and obsessive-compulsive disorder) in which patients show characteristic alterations in cerebral WM. Our findings suggest that the microstructure of cerebral white matter is under a strong genetic control and further studies in healthy as well as patients with brain-related illnesses are imperative to identify the genes that may influence cerebral white matter.


No evidence for costs of being large in females of Orgyia spp. (Lepidoptera, Lymantriidae): larger is always better.
Strong correlation between female body size and potential fecundity is often observed in insects. Directional selection favouring increased body sizes is thus predicted in the absence of opposing selection pressure. The evolutionary forces capable of counterbalancing such a 'fecundity advantage' are poorly documented. This study focuses on revealing the costs of large body size in the wingless females of Orgyia antiqua and O. leucostigma, two related species of lymantriid moths. Extreme behavioural simplicity of these animals allows systematic assessment of various fitness components in conditions that are close to natural. A linear relationship between pupal weight and potential fecundity was observed. This association was found to be independent of particular rearing conditions. There was no evidence that the relationship between fecundity and body mass becomes asymptotic when body sizes increases. No component of fitness showed a negative phenotypic correlation with body size; some displayed a weakly positive one. In particular, pupal mortality, adult longevity, mating and oviposition success, as well as egg hatching rate and egg size, were established as independent of body size in a series of field and laboratory experiments. There was a very high overall efficiency of converting resources accumulated during the larval stage to egg masses. With no costs of large adult size, selective forces balancing the fecundity advantage should operate in the course of immature development. The strong dependence of realized fecundity on body size is considered characteristic of the capital breeding strategy.