Ultrafast excited-state dynamics of strongly coupled porphyrin/core-substituted-naphthalenediimide dyads.
The photophysics and excited-state dynamics of two dyads consisting of either a free-base or a zinc-tetraphenylporphyrin linked through a rigid bridge to a core-substituted naphthalenediimide (NDI) have been investigated by femtosecond-resolved spectroscopy. The absorption and fluorescence spectra differ substantially from those of the individual units, pointing to a substantial coupling and to a delocalisation of the excitation over the whole molecule, as confirmed by quantum chemistry calculations. A strong dependence of their excited-state dynamics on the solvent polarity has been observed. In toluene, the fluorescence quantum yield of the dyads is of the order of a few percent and the main decay channel of the emitting state is proposed as intersystem-crossing to the triplet state. However, in a medium polarity solvent like dichloromethane, the emitting state undergoes charge separation from the porphyrin to the NDI unit within 1-3 ps, and the ensuing charge-separated state recombines in about 10-20 ps. This solvent dependence can be explained by the weak driving force for charge separation in polar solvents and the large electronic coupling between the porphyrin and NDI moieties, making charge separation a solvent-controlled adiabatic process.


Competition of two microbial populations for a single resource in a chemostat when one of them exhibits wall attachment.
It is known that two microbial populations competing for a single resource in a homogeneous environment with time-invariant inputs cannot coexist in a steady state. The case where two microbial populations compete for a single resource in a chemostat but one of them exhibits attachment to the chemostat walls is studied theoretically. Because of the cells' attachment to the walls, the environment is no longer homogeneous. The present article considers the case where the attached cells form no more than a monolayer. Other situations occur, often frequently, but we do not consider them here. Two models are used to represent the attachment to the walls: the Topiwala-Hamer model and a model which assumes that the attachment of microbial cells to the solid surfaces is a reversible process. The first model does not allow the population that exhibits wall attachment to wash out from the chemostat, in contrast to the second model (which nevertheless reduces to the first one in the limit). It has been found that in most of the possible cases for both models, the two competitors can coexist in a stable steady state for a wide range of the operating parameters space. The results of the stability analysis are discussed and analytical expressions for the conditions and the boundaries of the domains of stable coexistence are given for all the possible situations that may arise.


Correlation of the cross-over ratio of the cross-over sign on conventional pelvic radiographs with computed tomography retroversion measurements.
To find a correlation between the cross-over ratio of the cross-over sign on conventional anteroposterior (AP) pelvic radiographs and retroversion measurements ('roof-edge angle' and 'equatorial-edge angle) on computed tomography (CT) scans. This would facilitate the interpretation of the cross-over sign regarding the amount of acetabular retroversion. Correctly projected AP pelvic radiographs (2,925 hips) were examined for the presence of the cross-over sign (COS), and the overlap ratio of the COS was measured. On CT scans of the same patients the 'roof-edge angle' (RE angle) and the 'equatorial-edge angle' (EE angle) were also calculated. A statistically significant but only weak relationship could be found between the overlap ratio of the COS and the 'roof-edge angle' (P < 0.0001; correlation coefficient -0.486) and between this ratio and the 'equatorial-edge angle' (P < 0.0001; correlation coefficient -0.395). A relationship between the overlap ratio and orientation measurements on CT scans could be found, but it was less strong than expected.


Rates and factors associated with major modifications to first-line combination antiretroviral therapy: results from the Asia-Pacific region.
In the Asia-Pacific region many countries have adopted the WHO's public health approach to HIV care and treatment. We performed exploratory analyses of the factors associated with first major modification to first-line combination antiretroviral therapy (ART) in resource-rich and resource-limited countries in the region. We selected treatment naive HIV-positive adults from the Australian HIV Observational Database (AHOD) and the TREAT Asia HIV Observational Database (TAHOD). We dichotomised each country's per capita income into high/upper-middle (T-H) and lower-middle/low (T-L). Survival methods stratified by income were used to explore time to first major modification of first-line ART and associated factors. We defined a treatment modification as either initiation of a new class of antiretroviral (ARV) or a substitution of two or more ARV agents from within the same ARV class. A total of 4250 patients had 961 major modifications to first-line ART in the first five years of therapy. The cumulative incidence (95% CI) of treatment modification was 0.48 (0.44-0.52), 0.33 (0.30-0.36) and 0.21 (0.18-0.23) for AHOD, T-H and T-L respectively. We found no strong associations between typical patient characteristic factors and rates of treatment modification. In AHOD, relative to sites that monitor twice-yearly (both CD4 and HIV RNA-VL), quarterly monitoring corresponded with a doubling of the rate of treatment modifications. In T-H, relative to sites that monitor once-yearly (both CD4 and HIV RNA-VL), monitoring twice-yearly corresponded to a 1.8 factor increase in treatment modifications. In T-L, no sites on average monitored both CD4 & HIV RNA-VL concurrently once-yearly. We found no differences in rates of modifications for once- or twice-yearly CD4 count monitoring. Low-income countries tended to have lower rates of major modifications made to first-line ART compared to higher-income countries. In higher-income countries, an increased rate of RNA-VL monitoring was associated with increased modifications to first-line ART.


Where's Dad? The Importance of Integrating Fatherhood and Parenting Programming into Substance Use Treatment for Men.
Large numbers of men enter substance use disorder treatment each year, yet very little attention is paid to the fatherhood and parenting status of these men. Substance use treatment programs rarely incorporate a parenting component into their treatment planning, despite increased success of women's treatment programs that focus on gender and motherhood. This paper provides: 1) a review of the literature on the fathering of substance using men, what has been learned from substance use disorder treatment for mothers, and the implications for children and families; 2) pilot quantitative and qualitative outcomes on implementation of a fatherhood focused intervention for men in a residential substance use treatment program; and 3) recommendations for the application of these findings for fathers in substance use disorder treatment and the implications of program modifications and increased focus on fathers for child welfare.


Grading evidence from test accuracy studies: what makes it challenging compared with the grading of effectiveness studies?
Guideline panels need to process a sizeable amount of information to issue a decision on whether to recommend a health technology or not. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) is being frequently applied in guideline development to facilitate this task, typically for the synthesis of effectiveness research. Questions regarding the accuracy of medical tests are ubiquitous, and they temporally precede questions about therapy. However, literature summarising the experience of applying GRADE approach to accuracy evaluations is not as rich as one for effectiveness evidence. Type of study design (cross-sectional), two-dimensional nature of the performance measures (sensitivity and specificity), propensity towards a higher level of between-study heterogeneity, poor reporting of quality features and uncertainty about how best to assess for publication bias among other features make this task challenging. This article presents solutions adopted to addresses above challenges for judicious estimation of the strength of test accuracy evidence used to inform evidence syntheses for guideline development.


On the value of preprints: An early career researcher perspective.
Peer-reviewed journal publication is the main means for academic researchers in the life sciences to create a permanent public record of their work. These publications are also the de facto currency for career progress, with a strong link between journal brand recognition and perceived value. The current peer-review process can lead to long delays between submission and publication, with cycles of rejection, revision, and resubmission causing redundant peer review. This situation creates unique challenges for early career researchers (ECRs), who rely heavily on timely publication of their work to gain recognition for their efforts. Today, ECRs face a changing academic landscape, including the increased interdisciplinarity of life sciences research, expansion of the researcher population, and consequent shifts in employer and funding demands. The publication of preprints, publicly available scientific manuscripts posted on dedicated preprint servers prior to journal-managed peer review, can play a key role in addressing these ECR challenges. Preprinting benefits include rapid dissemination of academic work, open access, establishing priority or concurrence, receiving feedback, and facilitating collaborations. Although there is a growing appreciation for and adoption of preprints, a minority of all articles in life sciences and medicine are preprinted. The current low rate of preprint submissions in life sciences and ECR concerns regarding preprinting need to be addressed. We provide a perspective from an interdisciplinary group of ECRs on the value of preprints and advocate their wide adoption to advance knowledge and facilitate career development.


Clinical use of allogeneic hematopoietic stem cells from sources other than bone marrow.
Peripheral blood stem cells (PBSC) are being increasingly used as an alternative to conventional allogeneic bone marrow (BM) transplantation. This has prompted the Working Group on CD34-Positive Hematopoietic Cells to evaluate the current utilization of allogeneic PBSC in clinical hematology. The method employed for preparing this review was that of informal consensus development. Members of the Working Group met three times, and the participants at these meetings examined a list of problems previously prepared by the chairman. They discussed the single points in order to reach an agreement on different opinions and eventually approved the final manuscript. Some of the authors of the present review have been working in the field of stem cell transplantation and have contributed original papers in peer-reviewed journals. In addition, the material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. Review of the current literature shows that unmanipulated allogeneic PBSC give prompt and stable engraftment in HLA-identical sibling recipients. Despite the much higher number of T-cells infused, the incidence and severity of acute GVHD after PBSC transplant seems comparable to that observed with bone marrow (BM) cells. In comparison to the latter, PBSC probably ensure faster immunologic reconstitution in the early post-transplant period. Controversial results on the incidence and severity of acute-GVHD have been reported when CD34+ selection methods are used. Prospective randomized trials are underway to compare the results of PBSC and BM allogeneic transplantation. In mismatched family donor transplants, T-cell depleted PBSC successfully engraft immune-myeloablated recipients through a megacell-dose effect able to overcome the HLA barrier. Experience with PBSC in the context of unrelated donor transplants is currently anecdotal and prospective trials should be completed before that practice becomes routine. Finally, there is also limited evidence that, following induction chemotherapy, the addition of PBSC to donor lymphocyte infusion (DLI) for treatment of leukemia relapse after BMT may improve the safety and effectiveness of DLI itself. Concerning cord blood (CB) transplants, the most interesting aspects are the ease of CB collection and storage, the low risk of viral contamination and the low immune reactivity of CB cells. This last property has its clinical counterpart in an apparently reduced incidence and severity of acute GVHD both in sibling and unrelated CB transplants, probably making the level of donor/recipient HLA disparity acceptable a greater degree with respect to what is required for transplants from other sources.


Defining EGFR amplification status for clinical trial inclusion.
Precision medicine trials targeting the epidermal growth factor receptor (EGFR) in glioblastoma patients require selection for EGFR-amplified tumors. However, there is currently no gold standard in determining the amplification status of EGFR or variant III (EGFRvIII) expression. Here, we aimed to determine which technique and which cutoffs are suitable to determine EGFR amplification status. We compared fluorescence in-situ hybridization (FISH) and real-time quantitative (RT-q)PCR data from patients screened for trial inclusion into the Intellance 2 clinical trial, with data from a panel-based next generation sequencing (NGS) platform (both DNA and RNA). By using data from >1000 samples, we show that at least 50% of EGFR amplified nuclei should be present to define EGFR gene amplification by FISH. Gene amplification (as determined by FISH) correlates with EGFR expression levels (as determined by RT-qPCR) with receiver operating characteristics analysis showing an area under the curve of up to 0.902. EGFR expression as assessed by RT-qPCR therefore may function as a surrogate marker for EGFR amplification. Our NGS data show that EGFR copy numbers can strongly vary between tumors, with levels ranging from 2 to more than 100 copies per cell. Levels exceeding 5 gene copies can be used to define EGFR-amplification by NGS; below this level, FISH detects very few (if any) EGFR amplified nuclei and none of the samples express EGFRvIII. Our data from central laboratories and diagnostic sequencing facilities, using material from patients eligible for clinical trial inclusion, help define the optimal cutoff for various techniques to determine EGFR amplification for diagnostic purposes.


Sequestration of Voriconazole and Vancomycin Into Contemporary Extracorporeal Membrane Oxygenation Circuits: An in vitro Study.
Background: Bacterial and fungal infections are common and often contribute to death in patients undergoing extracorporeal membrane oxygenation (ECMO). Drug disposition is altered during ECMO, and adsorption in the circuit is an established causative factor. Vancomycin and voriconazole are widely used, despite the lack of evidence-based prescription guidelines. Objective: The objective of this study was to determine the extraction of voriconazole and vancomycin by the Xenios/Novalung ECMO circuits. Methods: We have set up nine closed-loop ECMO circuits, consisting of four different iLAActivve ® kits for neonatal, pediatric, and adult support: three iLA-ActivveMiniLung ® petite kits, two iLA-ActivveMiniLung ® kits, two iLA-ActivveiLA ® kits, and two iLA-Activve X-lung ® kits. The circuits were primed with whole blood and maintained at physiologic conditions for 24 h. Voriconazole and vancomycin were injected as a single-bolus age-related dose into the circuits. Pre-membrane (P2) blood samples were obtained at baseline and after drug injection at 2, 10, 30, 180, 360 min, and 24 h. A control sample at 2 min was collected for spontaneous drug degradation testing at 24 h. Results: Seventy-two samples were analyzed in triplicate. The mean percentage of drug recovery at 24 h was 20% for voriconazole and 62% for vancomycin. Conclusions: The extraction of voriconazole and vancomycin by contemporary ECMO circuits is clinically relevant across all age-related circuit sizes and may result in reduced drug exposure in vivo.


Visualizing Mobility of Public Transportation System.
Public transportation systems (PTSs) play an important role in modern cities, providing shared/massive transportation services that are essential for the general public. However, due to their increasing complexity, designing effective methods to visualize and explore PTS is highly challenging. Most existing techniques employ network visualization methods and focus on showing the network topology across stops while ignoring various mobility-related factors such as riding time, transfer time, waiting time, and round-the-clock patterns. This work aims to visualize and explore passenger mobility in a PTS with a family of analytical tasks based on inputs from transportation researchers. After exploring different design alternatives, we come up with an integrated solution with three visualization modules: isochrone map view for geographical information, isotime flow map view for effective temporal information comparison and manipulation, and OD-pair journey view for detailed visual analysis of mobility factors along routes between specific origin-destination pairs. The isotime flow map linearizes a flow map into a parallel isoline representation, maximizing the visualization of mobility information along the horizontal time axis while presenting clear and smooth pathways from origin to destinations. Moreover, we devise several interactive visual query methods for users to easily explore the dynamics of PTS mobility over space and time. Lastly, we also construct a PTS mobility model from millions of real passenger trajectories, and evaluate our visualization techniques with assorted case studies with the transportation researchers.


Effect of meal size and frequency on postprandial thermogenesis in dogs.
The influence of meal size and frequency on postprandial thermogenesis was studied in nine mongrel dogs (congruent to 18 kg). Oxygen uptake (VO2) and respiratory quotient (R) were continuously monitored by indirect calorimetry during the following experiments. In expt 1, four dogs were fed on alternated days either a large (3.1 MJ) or small meal (0.77 MJ). In expt 2, five different dogs were fed on alternated days either one large meal (3.1 MJ) or four consecutive small meals (0.77 MJ) spaced at 1.5-h intervals. In expt 3, the four dogs of expt 1 after being sham fed 3 times at 1.5-h intervals were given one large meal (3.1 MJ). The VO2 increase during the initial or cephalic phase (congruent to 50 min) was independent of the meal size but it was directly proportional to the amount of food ingested during the digestive phase. The total thermogenic response to four small meals (125 g) fed at 1.5-h intervals was twice as large as that of one large meal (500 g). One large meal (500 g) preceded by three periods of sham feeding was also found to be more thermogenic than a large meal only. For all experiments the changes in R were seen to parallel the postprandial fluctuations in VO2. These findings indicate that the enhanced heat production obtained when meal frequency is increased is caused by the repeated sensory stimulation produced by palatable food.


Evaluating the impact of patients' online access to doctors' visit notes: designing and executing the OpenNotes project.
Providers and policymakers are pursuing strategies to increase patient engagement in health care. Increasingly, online sections of medical records are viewable by patients though seldom are clinicians' visit notes included. We designed a one-year multi-site trial of online patient accessible office visit notes, OpenNotes. We hypothesized that patients and primary care physicians (PCPs) would want it to continue and that OpenNotes would not lead to significant disruptions to doctors' practices. Using a mixed methods approach, we designed a quasi-experimental study in 3 diverse healthcare systems in Boston, Pennsylvania, and Seattle. Two sites had existing patient internet portals; the third used an experimental portal. We targeted 3 key areas where we hypothesized the greatest impacts: beliefs and attitudes about OpenNotes, use of the patient internet portals, and patient-doctor communication. PCPs in the 3 sites were invited to participate in the intervention. Patients who were registered portal users of participating PCPs were given access to their PCPs' visit notes for one year. PCPs who declined participation in the intervention and their patients served as the comparison groups for the study. We applied the RE-AIM framework to our design in order to capture as comprehensive a picture as possible of the impact of OpenNotes. We developed pre- and post-intervention surveys for online administration addressing attitudes and experiences based on interviews and focus groups with patients and doctors. In addition, we tracked use of the internet portals before and during the intervention. PCP participation varied from 19% to 87% across the 3 sites; a total of 114 PCPs enrolled in the intervention with their 22,000 patients who were registered portal users. Approximately 40% of intervention and non-intervention patients at the 3 sites responded to the online survey, yielding a total of approximately 38,000 patient surveys. Many primary care physicians were willing to participate in this "real world" experiment testing the impact of OpenNotes on their patients and their practices. Results from this trial will inform providers, policy makers, and patients who contemplate such changes at a time of exploding interest in transparency, patient safety, and improving the quality of care.


Human stearoyl-CoA desaturase: alternative transcripts generated from a single gene by usage of tandem polyadenylation sites.
A critical step in the synthesis of unsaturated fatty acids is catalysed by stearoyl-CoA desaturase (Scd). To determine the regulation of human Scd, we characterized the gene and its transcripts. Screening a human keratinocyte cDNA library and analysis of 3'-RACE (rapid amplification of cDNA ends) products from various tissues yielded a 5.2 kb cDNA encoding a 359 amino acid protein with a calculated molecular mass of 41.5 kDa. Analysis of 3'-RACE products suggested that alternative usage of polyadenylation sites generates two transcripts of 3.9 and 5.2 kb, a result consistent with Northern analysis. Southern analysis demonstrated the existance of two SCD loci in the human genome. Chromosomal mapping localized one locus to chromosome 10, and the second locus to chromosome 17. Characterization of genomic clones isolated from chromosome-specific libraries revealed that only the locus on chromosome 10 contained introns. Sequence analysis of the intron-less locus displayed multiple nucleotide insertions and deletions, as well as in-frame stop codons. Reverse transcriptase-PCR analysis performed with primers specific to the intron-less locus failed to produce a PCR product from brain, liver and skin RNA, indicating that the locus on chromosome 17 is most likely a transcriptionally inactive, fully processed pseudogene. These results suggest strongly that there is one structural SCD gene in the human genome, and that it generates two transcripts by use of alternative polyadenyation sites. Although the primary sequence and intron-exon structure of SCD is phylogenetically conserved, divergence between rodent and human is seen in the number of SCD genes and in the generation of alternative transcripts, suggesting a species-specific component of SCD regulation and function.


Ambulatory measurement of ground reaction forces.
The measurement of ground reaction forces is important in the biomechanical analysis of gait and other motor activities. Many applications require full ambulatory measurement of these forces, but this is not supported by current measurement systems. We propose the use of two six-degrees-of-freedom force and moment sensors under each shoe, which enables the ambulatory measurement of ground reaction forces and centers of pressure (CoP). The feasibility of this method is illustrated by experimental results in a healthy subject, using a force plate as a reference. The ground reaction forces and CoP recordings show good correspondence when they are evaluated for forces above 40 N and when it is simply assumed that the sensors are flat on the ground when they are loaded. The root mean square (rms) difference of the magnitude of the ground reaction force over 12 gait trials was 15 +/- 2 N, corresponding to 1.9 +/- 0.3% of the maximum ground reaction force magnitude. The rms difference of the horizontal component of the ground reaction force was 3 +/- 2 N, corresponding to 0.4 +/- 0.2% of the maximum ground reaction force magnitude and to 2 +/- 1% of the maximum of the horizontal component of the ground reaction force. The rms distance between both CoP recordings is 2.9 +/- 0.4 mm, corresponding to 1.1 +/- 0.2% of the length of the shoe, when the trajectories are optimally aligned.


Exploring the parameter space of a rabbit ventricular action potential model to investigate the effect of variation on action potential and calcium transients.
Computational models for cardiomyocyte action potentials (AP) often make use of a large parameter set. This parameter set can contain some elements that are fitted to experimental data independently of any other element, some elements that are derived concurrently with other elements to match experimental data, and some elements that are derived purely from phenomenological fitting to produce the desired AP output. Furthermore, models can make use of several different data sets, not always derived for the same conditions or even the same species. It is consequently uncertain whether the parameter set for a given model is physiologically accurate. Furthermore, it is only recently that the possibility of degeneracy in parameter values in producing a given simulation output has started to be addressed. In this study, we examine the effects of varying two parameters (the L-type calcium current (I(CaL)) and the delayed rectifier potassium current (I(Ks))) in a computational model of a rabbit ventricular cardiomyocyte AP on both the membrane potential (V(m)) and calcium (Ca(2+)) transient. It will subsequently be determined if there is degeneracy in this model to these parameter values, which will have important implications on the stability of these models to cell-to-cell parameter variation, and also whether the current methodology for generating parameter values is flawed. The accuracy of AP duration (APD) as an indicator of AP shape will also be assessed.


The association between hospital volume and total shoulder arthroplasty outcomes.
The purpose of this study was to evaluate the relationship between increasing hospital volume and the following outcomes for total shoulder arthroplasties done in the state of New York: length of stay, hospital costs, readmission within 60 days, revision surgery within 24 months, and death within 60 days. The Statewide Planning and Research Cooperative System (SPARCS) database from the New York State Department of Health, a census of all hospital discharges in the state, was used to evaluate the relationship between hospital volume and outcomes for total shoulder arthroplasties for 1996 to 1999. One thousand three hundred seven total shoulder arthroplasties were done in New York from 1996 to 1999. Nearly (1/2) were done at the five highest-volume hospitals. Middle-volume hospitals has the least lengths of stay and hospital costs. Independent of age and comorbidities, patients at hospitals with greater volumes of total shoulder arthroplasties were at reduced risk of patients being readmitted within 60 days. No other outcomes were significantly associated with hospital volume. The finding that greater hospital volume decreases risk of readmission may have important public health implications, but additional research is needed before implementing policy changes.


Efficacy of recombinant allergens for diagnosis of cockroach allergy in patients with asthma and/or rhinitis.
Immunoglobulin E (IgE) reactivity to individual allergens among cockroach-allergic patients has revealed wide variability. The aim of this study was to assess the effectiveness of recombinant cockroach allergens for skin testing, and to determine sensitization profiles among cockroach-allergic patients living in Brazil. Fifty-seven cockroach-allergic patients with asthma and/or rhinitis were recruited. Skin testing with recombinant (r) allergens from Periplaneta americana (rPer a 1 and rPer a 7) and Blattella germanica (rBla g 2, rBla g 4 and rBla g 5) were performed at 10 μg/ml and 5 μg/ml (rPer a 1). IgE antibodies to rPer a 7 and rPer a 1 were quantitated by ELISA. Of 57 patients tested, 3 (5.3%), 24 (42.1%), 4 (7%), 3 (5.3%) and 4 (7%) showed positive reactions to rPer a 1, rPer a 7, rBla g 2, rBla g 4 and rBla g 5, respectively. Twenty-eight patients (49.1%) had positive tests to at least one allergen. In keeping with skin test results, 31/57 patients (54.4%) and 5/55 patients (9%) had detectable IgE to rPer a 7 and rPer a 1, respectively. Levels of IgE to rPer a 7 were higher in patients with positive tests to rPer a 7 than those with negative tests (geometric mean 13.2 and 1.8 IU/ml, p < 0.05). There was good concordance of results of skin tests and measurements of serum IgE to rPer a 7. IgE reactivity to rPer a 7 (P. americana tropomyosin) was dominant among patients in Brazil. However, 50% of the patients did not present reactivity to any of the recombinant allergens tested.


Time series analysis of the impact of tobacco control policies on smoking prevalence among Australian adults, 2001-2011.
To determine the impact of tobacco control policies and mass media campaigns on smoking prevalence in Australian adults. Data for calculating the average monthly prevalence of smoking between January 2001 and June 2011 were obtained via structured interviews of randomly sampled adults aged 18 years or older from Australia's five largest capital cities (monthly mean number of adults interviewed: 2375). The influence on smoking prevalence was estimated for increased tobacco taxes; strengthened smoke-free laws; increased monthly population exposure to televised tobacco control mass media campaigns and pharmaceutical company advertising for nicotine replacement therapy (NRT), using gross ratings points; monthly sales of NRT, bupropion and varenicline; and introduction of graphic health warnings on cigarette packs. Autoregressive integrated moving average (ARIMA) models were used to examine the influence of these interventions on smoking prevalence. The mean smoking prevalence for the study period was 19.9% (standard deviation: 2.0%), with a drop from 23.6% (in January 2001) to 17.3% (in June 2011). The best-fitting model showed that stronger smoke-free laws, tobacco price increases and greater exposure to mass media campaigns independently explained 76% of the decrease in smoking prevalence from February 2002 to June 2011. Increased tobacco taxation, more comprehensive smoke-free laws and increased investment in mass media campaigns played a substantial role in reducing smoking prevalence among Australian adults between 2001 and 2011.


Particle engineering in pharmaceutical solids processing: surface energy considerations.
During the past 10 years particle engineering in the pharmaceutical industry has become a topic of increasing importance. Engineers and pharmacists need to understand and control a range of key unit manufacturing operations such as milling, granulation, crystallisation, powder mixing and dry powder inhaled drugs which can be very challenging. It has now become very clear that in many of these particle processing operations, the surface energy of the starting, intermediate or final products is a key factor in understanding the processing operation and or the final product performance. This review will consider the surface energy and surface energy heterogeneity of crystalline solids, methods for the measurement of surface energy, effects of milling on powder surface energy, adhesion and cohesion on powder mixtures, crystal habits and surface energy, surface energy and powder granulation processes, performance of DPI systems and finally crystallisation conditions and surface energy. This review will conclude that the importance of surface energy as a significant factor in understanding the performance of many particulate pharmaceutical products and processes has now been clearly established. It is still nevertheless, work in progress both in terms of development of methods and establishing the limits for when surface energy is the key variable of relevance.


Furanodienone induces cell cycle arrest and apoptosis by suppressing EGFR/HER2 signaling in HER2-overexpressing human breast cancer cells.
Overexpression of EGFR and HER2 is seen in breast cancers and results in poor prognosis and decreased patient survival. Clinically, EGFR and HER2 are effective therapeutic targets. The objective of this study is to investigate the in vitro effects of furanodienone, an active chemical component isolated from Rhizoma Curcumae, on the activation of EGFR/HER2 signaling, cell cycle, and apoptosis in HER2-overexpressing BT474 and SKBR3 cells. Cell growth was assessed by SRB protein assay. Cell cycle analysis was carried out by flow cytometry, and apoptosis was observed by Annexin V and DAPI staining. Effects of furanodienone on the activation of EGFR/HER2 signaling-related proteins were analyzed by western blotting. Furanodienone inhibited cell growth in BT474 and SKBR3 cells. Furanodienone caused G1 arrest in BT474 cells and induced apoptosis in SKBR3 cells. Furanodienone interfered with EGFR/HER2 signaling in treated cells as shown by decreases in phosphorylated EGFR, HER2, Akt, Gsk3β and an increase in p27(kip1) protein. Accordingly, furanodienone inhibited EGF-induced phosphorylation of EGFR, HER2, Akt, and Gsk3β. EGFR-specific siRNA knockdown did not affect the cell growth inhibitory effect of furanodienone. On the contrary, specific siRNA knockdown of HER2 increased cellular resistance to furanodienone toxicity. In HER-2-deficient MDA-MB-231 cells, the transfection and expression of HER2 increased the sensitivity of cells to furanodienone toxicity. Furanodienone inhibited EGFR/HER2 signaling pathway in BT474 and SKBR3 cells. More importantly, the effect of furanodienone was specifically dependent on HER2, but not EGFR, expression.


The MFS efflux pump EmrKY contributes to the survival of Shigella within macrophages.
Efflux pumps are membrane protein complexes conserved in all living organisms. Beyond being involved in antibiotic extrusion in several bacteria, efflux pumps are emerging as relevant players in pathogen-host interactions. We have investigated on the possible role of the efflux pump network in Shigella flexneri, the etiological agent of bacillary dysentery. We have found that S. flexneri has retained 14 of the 20 pumps characterized in Escherichia coli and that their expression is differentially modulated during the intracellular life of Shigella. In particular, the emrKY operon, encoding an efflux pump of the Major Facilitator Superfamily, is specifically and highly induced in Shigella-infected U937 macrophage-like cells and is activated in response to a combination of high K+ and acidic pH, which are sensed by the EvgS/EvgA two-component system. Notably, we show that following S. flexneri infection, macrophage cytosol undergoes a mild reduction of intracellular pH, permitting EvgA to trigger the emrKY activation. Finally, we present data suggesting that EmrKY is required for the survival of Shigella in the harsh macrophage environment, highlighting for the first time the key role of an efflux pump during the Shigella invasive process.


Surveys in Papua New Guinea to detect the presence of Trypanosoma evansi infection.
To confirm serological evidence that Trypanosoma evansi is present in Papua New Guinea. Three surveys were undertaken in PNG during 1997/1998. Animals were selected for sampling on the basis of convenience. Samples of blood were examined for the presence of T evansi by the haematocrit centrifugation technique (HCT) and mouse inoculation test (MI). Sera were tested in the field using the card agglutination test for trypanosomiasis/T evansi (CATT). Bovine sera were tested at James Cook University using an antibody-detection ELISA (Ab-ELISA). Results from testing bovine sera with the Ab-ELISA and sera from wallabies with the CATT were analysed using FreeCalc to determine the probability that animals in these populations were infected with T evansi. A total of 545 serum samples were collected, during the three surveys of which 39 cattle, two pig and three agile wallaby samples were positive with the CATT. All bovine sera collected were negative when tested with an Ab-ELISA. T evansi was not isolated using the HCT or the MI from any of these animals. Based on the Ab-ELISA results it was concluded that T evansi infection was not present in cattle in villages around Balimo at a minimum expected prevalence of 10% (P < 0.05) and, based on the CATT results, that infection was not present in wallabies on the Bula plain at a minimum expected prevalence of 10% (P < 0.1). These results indicate that it is unlikely that T evansi is endemic in PNG.


In vivo olfactory model of APP-induced neurodegeneration reveals a reversible cell-autonomous function.
Amyloid precursor protein (APP) has long been linked to the neurodegeneration of Alzheimer's disease (AD), but the associated cell death has been difficult to capture in vivo, and the role of APP in effecting neuron loss is still unclear. Olfactory dysfunction is an early symptom of AD with amyloid pathology in the olfactory epithelium correlating well to the brain pathology of AD patients. As olfactory sensory neurons (OSNs) regenerate continuously with immature and mature OSNs coexisting in the same olfactory epithelium, we sought to use this unique system to study APP-induced neurodegeneration. Here we have developed an olfactory-based transgenic mouse model that overexpresses humanized APP containing familial AD mutations (hAPP) in either mature or immature OSNs, and found that despite the absence of extracellular plaques a striking number of apoptotic neurons were detected by 3 weeks of age. Importantly, apoptosis was restricted to the specific population overexpressing hAPP, either mature or immature OSNs, sparing those without hAPP. Interestingly, we observed that this widespread neurodegeneration could be rapidly rescued by reducing hAPP expression levels in immature neurons. Together, these data argue that overexpressing hAPP alone could induce cell-autonomous apoptosis in both mature and immature neurons, challenging the notion that amyloid plaques are necessary for neurodegeneration. Furthermore, we show that hAPP-induced neurodegeneration is reversible, suggesting that AD-related neural loss could potentially be rescued. Thus, we propose that this unique in vivo model will not only help determine the mechanisms underlying AD-related neurodegeneration but also serve as a platform to test possible treatments.


A mouse model for polycystic kidney disease through a somatic in-frame deletion in the 5' end of Pkd1.
Autosomal dominant polycystic kidney disease, a leading cause of end-stage renal disease in adults, is characterized by progressive focal cyst formation in the kidney. Embryonic lethality of Pkd1-targeted mice limits the use of these mice. Here we developed a floxed allele of Pkd1 exons 2-6. Global deletion mutants developed polyhydramnios, hydrops fetalis, polycystic kidney and pancreatic disease. Somatic Pkd1 inactivation in the kidney was achieved by crossing Pkd1(flox) mice with transgenic mice expressing Cre controlled by a gamma-glutamyltranspeptidase promoter. These mutants developed cysts in both proximal and distal nephron segments and survived for about 4 weeks. Somatic loss of heterozygosity was shown in a reporter mouse strain to cause cystogenesis. Some cysts in young mice are positive for multiple tubular markers and a mesenchymal marker, suggesting a delay in tubular epithelial differentiation. A higher cell proliferation rate was observed in distal nephron segments probably accounting for the faster growth rate of distal cysts. Although we observed an overall increase in apoptosis in cystic kidneys, there was no difference between proximal or distal nephron segments. We also found increased cyclic AMP, aquaporin 2 and vasopressin type 2 receptor mRNA levels, and apical membrane translocation of aquaporin 2 in cystic kidneys, all of which may contribute to the differential cyst growth rate observed. The accelerated polycystic kidney phenotype of these mice provides an excellent model for studying molecular pathways of cystogenesis and to test therapeutic strategies.


A Pathway-Centered Analysis of Pig Domestication and Breeding in Eurasia.
Ascertaining the molecular and physiological basis of domestication and breeding is an active area of research. Due to the current wide distribution of its wild ancestor, the wild boar, the pig (Sus scrofa) is an excellent model to study these processes, which occurred independently in East Asia and Europe ca. 9000 yr ago. Analyzing genome variability patterns in terms of metabolic pathways is attractive since it considers the impact of interrelated functions of genes, in contrast to genome-wide scans that treat genes or genome windows in isolation. To that end, we studied 40 wild boars and 123 domestic pig genomes from Asia and Europe when metabolic pathway was the unit of analysis. We computed statistical significance for differentiation (Fst) and linkage disequilibrium (nSL) statistics at the pathway level. In terms of Fst, we found 21 and 12 pathways significantly differentiated at a q-value < 0.05 in Asia and Europe, respectively; five were shared across continents. In Asia, we found six significant pathways related to behavior, which involved essential neurotransmitters like dopamine and serotonin. Several significant pathways were interrelated and shared a variable percentage of genes. There were 12 genes present in >10 significant pathways (in terms of Fst), comprising genes involved in the transduction of a large number of signals, like phospholipase PCLB1, which is expressed in the brain, or ITPR3, which has an important role in taste transduction. In terms of nSL, significant pathways were mainly related to reproductive performance (ovarian steroidogenesis), a similarly important target trait during domestication and modern animal breeding. Different levels of recombination cannot explain these results, since we found no correlation between Fst and recombination rate. However, we did find an increased ratio of deleterious mutations in domestic vs. wild populations, suggesting a relaxed functional constraint associated with the domestication and breeding processes. Purifying selection was, nevertheless, stronger in significantly differentiated pathways than in random pathways, mainly in Europe. We conclude that pathway analysis facilitates the biological interpretation of genome-wide studies. Notably, in the case of pig, behavior played an important role, among other physiological and developmental processes.


HIV epidemic among men who have sex with men in India: national scenario of an unfinished agenda.
Although India has demonstrated success in the overall reduction of human immunodeficiency virus (HIV) incidence by 57% in the past 10 years, its control among men who have sex with men (MSM) remains a critical challenge. This paper describes the current status, geographic variability, and factors associated with HIV among MSM from the national perspective. DATA ON THE LEVELS AND TRENDS OF HIV SEROPOSITIVITY AND ASSOCIATED RISK BEHAVIORS AMONG MSM WERE ANALYZED AND PRESENTED FROM THE FOLLOWING DATA SOURCES: 1) annual HIV Sentinel Surveillance (HSS) conducted during 2003-10, 2) two rounds of the high-risk group size estimation conducted in 2005 and 2009, 3) two rounds of the Behavioral Surveillance Survey conducted in 2006 and 2009, and 4) the Integrated Bio-behavioral Assessment Round 2. Data were analyzed according to selected sociodemographic characteristics and sexual identities of MSM to understand the factors associated with high HIV prevalence. HSS data indicate that at the national level, HIV prevalence among MSM overall is declining (from 12.3% in 2003 to 4.43% in 2010). However, marginal increasing trends were observed in Chandigarh (from 1.4% in 2004 to 2.8% in 2008) and Haryana (from 0% in 2006 to 3.2% in 2008). HSS data indicate high (>5%) levels and increasing trends in HIV prevalence among MSM in eight states of India during 2003-10. Analysis of 2010 HSS data indicates that HIV prevalence was >10% in seven states. The factors associated with high HIV prevalence among MSM were being a kothi (the receptive partner in oral and anal sex, and typically with effeminate mannerisms) or a double-decker (both penetrative and receptive partner) rather than being a panthi (the penetrative partner in oral or anal sex) (8% vs 4.3%; P<0.05), being older than 25 years in age than their younger counterparts (9% vs 4.5%; P<0.05), illiterate rather than literate MSM (9.5% vs 6.9%; P<0.05), and employed versus unemployed MSM (9.1% vs 7.8%; P<0.05). While HIV prevalence among MSM at the national level is declining, it continues to remain high in some states and cities. Programs need to build on the successes in reducing HIV among female sex workers in order to control the high HIV prevalence among MSM in India.


Education does not slow cognitive decline with aging: 12-year evidence from the victoria longitudinal study.
Although the relationship between education and cognitive status is well-known, evidence regarding whether education moderates the trajectory of cognitive change in late life is conflicting. Early studies suggested that higher levels of education attenuate cognitive decline. More recent studies using improved longitudinal methods have not found that education moderates decline. Fewer studies have explored whether education exerts different effects on longitudinal changes within different cognitive domains. In the present study, we analyzed data from 1014 participants in the Victoria Longitudinal Study to examine the effects of education on composite scores reflecting verbal processing speed, working memory, verbal fluency, and verbal episodic memory. Using linear growth models adjusted for age at enrollment (range, 54-95 years) and gender, we found that years of education (range, 6-20 years) was strongly related to cognitive level in all domains, particularly verbal fluency. However, education was not related to rates of change over time for any cognitive domain. Results were similar in individuals older or younger than 70 at baseline, and when education was dichotomized to reflect high or low attainment. In this large longitudinal cohort, education was related to cognitive performance but unrelated to cognitive decline, supporting the hypothesis of passive cognitive reserve with aging.


Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization.
A properly established and maintained podocyte intercellular junction, or slit diaphragm, is a necessary component of the selective permeability barrier of the kidney glomerulus. The observation that mutation or deletion of the slit diaphragm transmembrane protein nephrin results in failure of podocyte foot process morphogenesis and concomitant proteinuria first suggested the hypothesis that nephrin serves as a component of a signaling complex that directly integrates podocyte junctional integrity with cytoskeletal dynamics. The observations made herein provide the first direct evidence to our knowledge for a phosphorylation-mediated signaling mechanism by which this integrative function is derived. Our data support the model that during podocyte intercellular junction formation, engagement of the nephrin ectodomain induces transient Fyn catalytic activity that results in nephrin phosphorylation on specific nephrin cytoplasmic domain tyrosine residues. We found that this nephrin phosphorylation event resulted in recruitment of the SH2-SH3 domain-containing adapter protein Nck and assembly of actin filaments in an Nck-dependent fashion. Considered in the context of the role of nephrin family proteins in other organisms and the integral relationship of actin dynamics and junction formation, these observations establish a function for nephrin in regulating actin cytoskeletal dynamics.


Epigenetics of proteasome inhibition in the liver of rats fed ethanol chronically.
To examine the effects of ethanol-induced proteasome inhibition, and the effects of proteasome inhibition in the regulation of epigenetic mechanisms. Rats were fed ethanol for 1 mo using the Tsukamoto-French model and were compared to rats given the proteasome inhibitor PS-341 (Bortezomib, Velcade(TM)) by intraperitoneal injection. Microarray analysis and real time PCR were performed and proteasome activity assays and Western blot analysis were performed using isolated nuclei. Chronic ethanol feeding caused a significant inhibition of the ubiquitin proteasome pathway in the nucleus, which led to changes in the turnover of transcriptional factors, histone-modifying enzymes, and, therefore, affected epigenetic mechanisms. Chronic ethanol feeding was related to an increase in histone acetylation, and it is hypothesized that the proteasome proteolytic activity regulated histone modifications by controlling the stability of histone modifying enzymes, and, therefore, regulated the chromatin structure, allowing easy access to chromatin by RNA polymerase, and, thus, proper gene expression. Proteasome inhibition by PS-341 increased histone acetylation similar to chronic ethanol feeding. In addition, proteasome inhibition caused dramatic changes in hepatic remethylation reactions as there was a significant decrease in the enzymes responsible for the regeneration of S-adenosylmethionine, and, in particular, a significant decrease in the betaine-homocysteine methyltransferase enzyme. This suggested that hypomethylation was associated with proteasome inhibition, as indicated by the decrease in histone methylation. The role of proteasome inhibition in regulating epigenetic mechanisms, and its link to liver injury in alcoholic liver disease, is thus a promising approach to study liver injury due to chronic ethanol consumption.


Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function.
Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.


Changes in genomic methylation patterns during the formation of triploid asexual dandelion lineages.
DNA methylation is an epigenetic mechanism that has the potential to affect plant phenotypes and that is responsive to environmental and genomic stresses such as hybridization and polyploidization. We explored de novo methylation variation that arises during the formation of triploid asexual dandelions from diploid sexual mother plants using methylation-sensitive amplified fragment length polymorphism (MS-AFLP) analysis. In dandelions, triploid apomictic asexuals are produced from diploid sexual mothers that are fertilized by polyploid pollen donors. We asked whether the ploidy level change that accompanies the formation of new asexual lineages triggers methylation changes that contribute to heritable epigenetic variation within novel asexual lineages. Comparison of MS-AFLP and AFLP fragment inheritance in a diploid x triploid cross revealed de novo methylation variation between triploid F(1) individuals. Genetically identical offspring of asexual F(1) plants showed modest levels of methylation variation, comparable to background levels as observed among sibs in a long-established asexual lineage. Thus, the cross between ploidy levels triggered de novo methylation variation between asexual lineages, whereas it did not seem to contribute directly to variation within new asexual lineages. The observed background level of methylation variation suggests that considerable autonomous methylation variation could build up within asexual lineages under natural conditions.


Innovative Coatings Based On Peppermint Essential Oil on Titanium and Steel Substrates: Chemical and Mechanical Protection Ability.
A coating that was made of peppermint essential oil was obtained on different metal substrates: Ti6Al4V alloy (mechanically polished and chemically etched) and 316L stainless steel (mechanically polished and mechanically ground). The final aim is to get a multifunctional (chemical and mechanical) protection of metal surfaces in contact with water media. The coatings were characterized by means of fluorescence microscopy, contact angle measurements, and Fourier Transformed Infrared spectroscopy (FTIR) spectroscopy. The chemical stability of the coatings was tested by means of soaking in water for different times (up to seven days) and washing with different alkaline or acidic solutions. The mechanical adhesion of the coating was tested by tape adhesion test (before and after soaking) and scratch tests to verify whether it has protection ability with respect to the metal substrate. All of the performed characterizations show that the coatings are chemically stable on all of the substrates and are nor dissolved or removed by water during soaking or by alkaline solutions during washing. The adhesion is high and classified as 4B or 5B (on the chemically etched or mechanically ground substrates) according to ASTM D3359-97, depending on the substrate roughness, both before and after soaking. In the case of scratch test (up to 10 N), the coating is not removed and it has a protection action that is able to avoid the surface damage, even if the substrate has a plastic deformation.


Outcome of Nonfunctioning Pituitary Adenomas That Regrow After Primary Treatment: A Study From Two Large UK Centers.
Despite the major risk of regrowth of clinically nonfunctioning pituitary adenomas (CNFAs) after primary treatment, systematic data on the probability of further tumor progression and the effectiveness of management approaches are lacking. To assess the probability of further regrowth(s), predictive factors, and outcomes of management approaches in patients with CNFA diagnosed with adenoma regrowth after primary treatment. Retrospective cohort study of 237 patients with regrown CNFA managed in two UK centers. Median follow-up was 5.9 years (range, 0.4 to 37.7 years). The 5-year second regrowth rate was 35.3% (36.2% after surgery; 12.5% after radiotherapy; 12.7% after surgery combined with radiotherapy; 63.4% with monitoring). Of those managed with monitoring, 34.8% eventually were offered intervention. Type of management and sex were risk factors for second regrowth. Among those with second adenoma regrowth, the 5-year third regrowth rate was 26.4% (24.4% after surgery; 0% after radiotherapy; 0% after surgery combined with radiotherapy; 48.3% with monitoring). Overall, patients with a CNFA regrowth had a 4.4% probability of a third regrowth at 5 years and a 10.0% probability at 10 years; type of management of the first regrowth was the only risk factor. Malignant transformation was diagnosed in two patients. Patients with regrown CNFA after primary treatment continue to carry considerable risk of tumor progression, necessitating long-term follow-up. Management approach to the regrowth was the major factor determining this risk; monitoring had >60% risk of progression at 5 years, and a substantial number of patients ultimately required intervention.


Broad metabolic sensitivity profiling of a prototrophic yeast deletion collection.
Genome-wide sensitivity screens in yeast have been immensely popular following the construction of a collection of deletion mutants of non-essential genes. However, the auxotrophic markers in this collection preclude experiments on minimal growth medium, one of the most informative metabolic environments. Here we present quantitative growth analysis for mutants in all 4,772 non-essential genes from our prototrophic deletion collection across a large set of metabolic conditions. The complete collection was grown in environments consisting of one of four possible carbon sources paired with one of seven nitrogen sources, for a total of 28 different well-defined metabolic environments. The relative contributions to mutants' fitness of each carbon and nitrogen source were determined using multivariate statistical methods. The mutant profiling recovered known and novel genes specific to the processing of nutrients and accurately predicted functional relationships, especially for metabolic functions. A benchmark of genome-scale metabolic network modeling is also given to demonstrate the level of agreement between current in silico predictions and hitherto unavailable experimental data. These data address a fundamental deficiency in our understanding of the model eukaryote Saccharomyces cerevisiae and its response to the most basic of environments. While choice of carbon source has the greatest impact on cell growth, specific effects due to nitrogen source and interactions between the nutrients are frequent. We demonstrate utility in characterizing genes of unknown function and illustrate how these data can be integrated with other whole-genome screens to interpret similarities between seemingly diverse perturbation types.


SMN is required for the maintenance of embryonic stem cells and neuronal differentiation in mice.
Survival motor neuron (SMN) is the determining factor in spinal muscular atrophy, the most common genetic cause of childhood mortality. We have previously found that SMN regulates stem cell division, proliferation and differentiation in Drosophila. However, it is unknown whether a similar effect exists in vertebrates. Here, we show that SMN is enriched in highly proliferative embryonic stem cells (ESCs) in mice and reduction of SMN impairs the pluripotency of ESCs. Moreover, we find that SMN reduction activates ERK signaling and affects neuronal differentiation in vitro. Teratomas with reduced SMN grow more slowly and show weaker signals of neuronal differentiation than those with a normal level of SMN. Finally, we show that over-expression of SMN is protective for ESCs from retinoic acid-induced differentiation. Taken together, our results suggest that SMN plays a role in the maintenance of pluripotent ESCs and neuronal differentiation in mice.


A boron-centered radical: a potassium-crown ether stabilized boryl radical anion.
A boron radical contact ion-pair Mes2B{4-(3,5-dimethylpyridinyl)}K(18-crown-6)(THF) (1K) has been isolated and characterized by electron paramagnetic resonance (EPR) spectroscopy, UV-vis absorption spectroscopy and single crystal X-ray diffraction. The geometry, bonding and spin density distribution are shown to be affected by the NK interaction. The unpaired electron resides mainly on the boron atom and falls between those of triarylboron radical anions and neutral boron radicals. The work provides a novel boron-centered radical intermediate, connecting anionic and neutral boryl radicals.


Experimental verification of a virtual-mode treatment for the excitation of surface plasmon polaritons by attenuated total reflection.
Attenuated-total-reflection spectra obtained by the optical excitation of surface plasmon polaritons can be interpreted in terms of two different virtual modes. It is shown that the HWHM of absorptance as a function of the incidence angle can be described by the decay constant of one of the modes. The attenuated-total-reflection resonance angle, on the other hand, is determined by the phase of another virtual mode. An experimental verification of this virtual-mode treatment is carried out for thick aluminum films.


The change in haemoglobin concentration between the first and third trimesters of pregnancy: a population study.
The physiological fall in haemoglobin concentration from the 1st to the 3rd trimester of pregnancy is often quoted as 5 g/L. However, other studies have suggested varying levels of fall between 8 and 13 g/L. We evaluated the change in haemoglobin concentration between the 1st and 3rd trimesters of pregnancy in a multi-ethnic population of pregnant women. A retrospective cohort analysis of 7054 women with singleton pregnancies, giving birth during 2013-15 in a single urban maternity unit in England. We calculated the changes in haemoglobin concentration from 1st to 3rd trimester using the first trimester haemoglobin as the reference point. The population was stratified into sub-groups to explore any differences that existed within the population. In general the fall in haemoglobin concentration was in the order of 14 g/L or 11% of the first trimester value. This fall was consistent for the majority of sub-groups of the population. The fall was lower (7.7%) in the most deprived section of the population, IMD1, but it increased to 11.7% when we restricted that sub-group to pregnant women without health problems during the index pregnancy. Conversely, there was an increase in haemoglobin of 10.2% in women whose first trimester haemoglobin concentration was in the lowest 5% of the total study population. The population fall in haemoglobin was 10.2 g/L (7.8%), after excluding cases above the 95th and below the 5th centiles, and women with a medical and/or obstetric disorder during the pregnancy. The fall in haemoglobin during pregnancy is in the order of 14 g/L or 11% of the first trimester level. This is 2 to 3 times higher than suggested by some guidelines and higher than previously published work. The results challenge the current accepted thresholds for practice, and have broader implications for diagnosis and managment of antenatal anaemia. Fall in haemoglobin across pregnancy is around 14 g/L (11%) and significantly higher than previously stated in the pregnant population. This poses questions over currently accepted thresholds for anaemia in pregnancy.


Climate change and temperature-dependent biogeography: oxygen limitation of thermal tolerance in animals.
Recent years have shown a rise in mean global temperatures and a shift in the geographical distribution of ectothermic animals. For a cause and effect analysis the present paper discusses those physiological processes limiting thermal tolerance. The lower heat tolerance in metazoa compared with unicellular eukaryotes and bacteria suggests that a complex systemic rather than molecular process is limiting in metazoa. Whole-animal aerobic scope appears as the first process limited at low and high temperatures, linked to the progressively insufficient capacity of circulation and ventilation. Oxygen levels in body fluids may decrease, reflecting excessive oxygen demand at high temperatures or insufficient aerobic capacity of mitochondria at low temperatures. Aerobic scope falls at temperatures beyond the thermal optimum and vanishes at low or high critical temperatures when transition to an anaerobic mitochondrial metabolism occurs. The adjustment of mitochondrial densities on top of parallel molecular or membrane adjustments appears crucial for maintaining aerobic scope and for shifting thermal tolerance. In conclusion, the capacity of oxygen delivery matches full aerobic scope only within the thermal optimum. At temperatures outside this range, only time-limited survival is supported by residual aerobic scope, then anaerobic metabolism and finally molecular protection by heat shock proteins and antioxidative defence. In a cause and effect hierarchy, the progressive increase in oxygen limitation at extreme temperatures may even enhance oxidative and denaturation stress. As a corollary, capacity limitations at a complex level of organisation, the oxygen delivery system, define thermal tolerance limits before molecular functions become disturbed.


Glucocorticoids regulate glutamine synthetase expression in lung epithelial cells.
During septic states efflux of glutamine from the lung increases, a response sustained by an increase in glutamine synthetase (IGS) activity. We have used a cell culture model employing a rat epithelial cell line of pulmonary origin (L2 cells) to study the effect of several hormones and cytokines which mediate the septic shock response on GS expression. We found that GS mRNA and GS protein contents increased rapidly and severalfold in response to physiologically relevant levels of the synthetic glucocorticoid dexamethasone (Dex). In contrast, GS expression was not markedly induced by Escherichia coli lipopolysaccharide (LPS), cytokines, activated complement C5a, or prostaglandins. Dex did not alter the kinetics of GS mRNA decay in the presence of actinomycin D. The increase in GS mRNA in response to Dex was completely blocked by RU-38486 and by actinomycin D, but not by cycloheximide (CHX). CHX together with Dex caused a superinduction of GS mRNA. GS mRNA decay kinetics suggested that this superinduction is at least in part caused by an approximately twofold increase in GS mRNA half-life caused by CHX. In addition, actinomycin D was found to increase GS mRNA half-life by approximately 50%. Actinomycin D plus CHX acted synergistically to cause a profound inhibition of GS mRNA decay. Our results are consistent with regulation of lung GS expression via a direct glucocorticoid receptor-mediated response. In addition, GS mRNA decay in L2 cells seems to be regulated by two independent mechanisms, one which is sensitive to CHX and one which is sensitive to actinomycin D.


Investigation of the vitamin D receptor polymorphisms in acromegaly patients.
The genetic structural alterations in the majority of somatotroph adenomas are not clarified and the search for novel candidate genes is still a challenge. We aimed to investigate possible associations between vitamin D receptor (VDR) polymorphisms and acromegaly. 52 acromegaly patients (mean age 45.7 ± 1.9 years) and 83 controls (mean age 43.1 ± 2.6 years) were recruited to the study. VDR polymorphism was determined by polymerase chain reaction-based restriction fragment length polymorphism methods. The distribution of VDR genotypes showed a significant difference in the frequencies of VDR FokI genotypes between patients and controls (P = 0.034). VDR FokI ff genotype was significantly decreased in acromegaly patients (P = 0.035) and carriers of FokI Ff genotype had a 1.5-fold increased risk for acromegaly (OR: 1.5, 95% CI: 1.07-2.1; P = 0.020). IGF1 levels after treatment were significantly higher in patients carrying the Ff genotype compared to carrying ff genotype (P = 0.0049). 25(OH)D3 levels were significantly lower in acromegaly patients (P < 0.001). Our study suggests that VDR FokI genotypes might affect the development of acromegaly and VDR polymorphisms may play a role in the course of acromegaly as a consequence of altering hormonal status.


Restoring the spinal pain gate: GABA(A) receptors as targets for novel analgesics.
GABAA receptors (GABA(A)Rs) and glycine receptors are key elements of the spinal control of nociception and pain. Compromised functioning of these two transmitter systems contributes to chronic pain states. Restoring their proper function through positive allosteric modulators should constitute a rational approach to the treatment of chronic pain syndromes involving diminished inhibitory spinal pain control. Although classical benzodiazepines (i.e., full agonists at the benzodiazepine binding site of GABA(A)Rs) potentiate synaptic inhibition in spinal pain controlling circuits, they lack clinically relevant analgesic activity in humans. Recent data obtained from experiments in GABA(A)R point-mutated mice suggests dose-limiting sedative effects of classical nonspecific benzodiazepines as the underlying cause. Experiments in genetically engineered mice resistant to the sedative effects of classical benzodiazepines and studies with novel less sedating benzodiazepines have indeed shown that profound antihyperalgesia can be obtained at least in preclinical pain models. Present evidence suggests that compounds with high intrinsic activity at α2-GABA(A)R and minimal agonistic activity at α1-GABA(A)R should possess relevant antihyperalgesic activity without causing unwanted sedation. On-going preclinical studies in genetically engineered mice and clinical trials with more selective benzodiazepine site agonists should soon provide additional insights into this emerging topic.


Resting sympathetic activity is associated with the sympathetically mediated component of energy expenditure following a meal.
Individuals with high plasma norepinephrine (NE) levels at rest have a smaller reduction in resting energy expenditure (REE) following β-adrenergic blockade. If this finding extends to the response to a meal, it could have important implications for the role of the sympathetic nervous system in energy balance and weight gain. We hypothesized high muscle sympathetic nerve activity (MSNA) would be associated with a low sympathetically mediated component of energy expenditure following a meal. Fourteen young, healthy adults completed two visits randomized to continuous saline (control) or intravenous propranolol to achieve systemic β-adrenergic blockade. Muscle sympathetic nerve activity and REE were measured (indirect calorimetry) followed by a liquid mixed meal (Ensure). Measures of energy expenditure continued every 30 min for 5 h after the meal and are reported as an area under the curve (AUC). Sympathetic support of energy expenditure was calculated as the difference between the AUC during saline and β-blockade (AUCPropranolol-AUCSaline, β-REE) and as a percent (%) of control (AUCPropranolol÷AUCSaline × 100). β-REE was associated with baseline sympathetic activity, such that individuals with high resting MSNA (bursts/100 heart beats) and plasma NE had the greatest sympathetically mediated component of energy expenditure following a meal (MSNA: β-REE R = -0.58, P = 0.03; %REE R = -0.56, P = 0.04; NE: β-REE R = -0.55, P = 0.0535; %REE R = -0.54, P = 0.0552). Contrary to our hypothesis, high resting sympathetic activity is associated with a greater sympathetically mediated component of energy expenditure following a liquid meal. These findings may have implications for weight maintenance in individuals with varying resting sympathetic activity.


Epidermal growth factor receptor, C-kit, and Her2/neu immunostaining in advanced or recurrent thymic epithelial neoplasms staged according to the 2004 World Health Organization in patients treated with octreotide and prednisone: an Eastern Cooperative Oncology Group study.
Advanced or recurrent nonresectable thymic epithelial tumors show only a modest response to standard chemotherapy. A recent study using octreotide and prednisone in thymic tumors, Eastern Cooperative Oncology Group study E1C97, was conducted to verify the activity of octreotide for thymic tumors. The aim of this study was to determine whether epidermal growth factor receptor (EGFR) immunoreactivity correlated with outcomes and to identify new biologic markers for potential targeted therapy. Three markers, EGFR, C-kit, and Her2/neu, were selected for evaluation in patients with advanced thymic epithelial tumors treated on E1C97. Of the 42 patients entered onto E1C97, 34 patients (World Health Organization [WHO] categories: type A = 1, type AB = 1, type B1 = 10, type B2 = 11 type B3 = 8, and type C = 3) had sufficient tissue available for immunohistologic study. Each tumor was assessed to have 0, 1+, 2+, or 3+ immunoreactivity in the cytoplasm or membranes of the neoplastic cells for Her2/neu and EGFR and for the presence or absence of C-kit immunoreactivity. EGFR immunoreactivity of 2+ or 3+ was associated with more aggressive thymic tumors (WHO types B2 and B3). However, strong EGFR immunoreactivity was not consistently seen with thymic carcinoma. The presence of EGFR within cells was associated with a significantly improved progression-free survival (PFS) and a trend for overall survival (OS). Twelve patients demonstrated C-kit immunoreactivity; the lack of C-kit immunoreactivity was significantly associated with superior PFS but not OS. Her2/neu immunoreactivity was uniformly negative for all tumors evaluated. There was no association between response and biomarker status. High EGFR immunoreactivity is seen in more aggressive thymic neoplasms as classified according to the 2004 WHO, but regardless of classification, the presence of EGFR in tumor cells (1+, 2+, and 3+) is associated with improved performance free survival (PFS) and a trend for better OS. In contrast, the absence of C-kit immunoreactivity was associated with improved PFS. These data suggest that EGFR and C-kit may be prognostic, and further studies of these markers in subcategories of thymic malignancies is warranted.


Capsule complication during cataract surgery: Case-control study of preoperative and intraoperative risk factors: Swedish Capsule Rupture Study Group report 2.
To identify preoperative and intraoperative factors associated with a capsule complication; that is, a capsule tear or a zonular dehiscence during cataract surgery. Ten ophthalmic surgery departments in Sweden. A retrospective review of files of patients with a capsule complication and control patients with no complication operated on in 2003 was performed. The review comprised 324 patients with a capsule complication and 331 control patients. In the logistic regression analyses, preoperative conditions associated with a capsule complication were previous trauma, white and brunescent/hard cataract, and phacodonesis. The intraoperative factors of loose zonules, the use of trypan blue, and miosis were all statistically significantly overrepresented in the capsule complication group. The same was true for eyes operated on by surgeons with the least experience. By preoperatively identifying cataract cases with the identified risk factors and allocating them to surgeons with the longest experience, the number of capsule complications could be kept low. Operating early in the course of the disease to prevent the cataract from becoming a poor surgical risk and improving training of junior surgeons should further reduce the frequency of capsule complications.


A conserved regulator controls asexual sporulation in the fungal pathogen Candida albicans.
Transcription factor Rme1 is conserved among ascomycetes and regulates meiosis and pseudohyphal growth in Saccharomyces cerevisiae. The genome of the meiosis-defective pathogen Candida albicans encodes an Rme1 homolog that is part of a transcriptional circuitry controlling hyphal growth. Here, we use chromatin immunoprecipitation and genome-wide expression analyses to study a possible role of Rme1 in C. albicans morphogenesis. We find that Rme1 binds upstream and activates the expression of genes that are upregulated during chlamydosporulation, an asexual process leading to formation of large, spherical, thick-walled cells during nutrient starvation. RME1 deletion abolishes chlamydosporulation in three Candida species, whereas its overexpression bypasses the requirement for chlamydosporulation cues and regulators. RME1 expression levels correlate with chlamydosporulation efficiency across clinical isolates. Interestingly, RME1 displays a biphasic pattern of expression, with a first phase independent of Rme1 function and dependent on chlamydospore-inducing cues, and a second phase dependent on Rme1 function and independent of chlamydospore-inducing cues. Our results indicate that Rme1 plays a central role in chlamydospore development in Candida species.


Raman micro-spectroscopy can be used to investigate the developmental stage of the mouse oocyte.
In recent years, the uptake of assisted reproductive techniques such as in vitro fertilisation has risen exponentially. However, there is much that is still not fully understood about the biochemical modifications that take place during the development and maturation of the oocyte. As such, it is essential to further the understanding of how oocyte manipulation during these procedures ultimately affects its developmental potential; yet, there are few methods currently available which are capable of providing a quantitative measure of oocyte quality. Raman spectroscopy enables investigation of the global biochemical profile of intact cells without the need for labelling. Here, Raman spectra were acquired from the ooplasm of mouse oocytes at various stages of development, from late pre-antral follicles, collected after in vitro maturation within their ovarian follicles and from unstimulated and stimulated ovulatory cycles. Using a combination of univariate and multivariate statistical methods, it was found that ooplasm lipid content could be used to discriminate between different stages of oocyte development. Furthermore, the spectral profiles of mature oocytes revealed that oocytes which have developed in vitro are protein-deficient when compared to in vivo grown oocytes. Finally, the ratio of two Raman peak intensities, namely 1605∶1447 cm⁻¹, used as a proxy for the protein-to-lipid ratio of the ooplasm, was shown to be indicative of the oocyte's quality. Together, results indicate that Raman spectroscopy may present an alternative analytical tool for investigating the biochemistry of oocyte developmental stage and quality.


Global diets link environmental sustainability and human health.
Diets link environmental and human health. Rising incomes and urbanization are driving a global dietary transition in which traditional diets are replaced by diets higher in refined sugars, refined fats, oils and meats. By 2050 these dietary trends, if unchecked, would be a major contributor to an estimated 80 per cent increase in global agricultural greenhouse gas emissions from food production and to global land clearing. Moreover, these dietary shifts are greatly increasing the incidence of type II diabetes, coronary heart disease and other chronic non-communicable diseases that lower global life expectancies. Alternative diets that offer substantial health benefits could, if widely adopted, reduce global agricultural greenhouse gas emissions, reduce land clearing and resultant species extinctions, and help prevent such diet-related chronic non-communicable diseases. The implementation of dietary solutions to the tightly linked diet-environment-health trilemma is a global challenge, and opportunity, of great environmental and public health importance.


The role of adipokines as regulators of skeletal muscle fatty acid metabolism and insulin sensitivity.
Several adipose-derived cytokines (adipokines) have been suggested to act as a link between accumulated fat mass and altered insulin sensitivity. Resistin and tumour necrosis factor-alpha (TNF-alpha) have been implicated in impairing insulin sensitivity in rodents; conversely, two other adipokines, leptin and adiponectin, increase insulin sensitivity in lean and obese rodents. Currently, there is considerable focus on the concept that lipid accumulation in skeletal muscle leads to the development of insulin resistance. Adiponectin and leptin have each been demonstrated to increase rates of fatty acid (FA) oxidation and decrease muscle lipid content, which may in part be the underlying mechanism to their insulin sensitizing effect. These effects on FA metabolism appear to be mediated in part through the activation of AMP-activated protein kinase. Evidence derived from animal and human studies suggests that the ability of leptin and adiponectin to stimulate FA oxidation in muscle is impaired in the obese condition. Thus, leptin and adiponectin resistance may be an initiating factor in the accumulation of intramuscular lipids, such as diacylglycerol and ceramide, and the ensuing development of insulin resistance. Lifestyle factors such as diet and exercise are able to restore the sensitivity of muscle to leptin. The actual physiological roles of resistin and TNF-alpha in altering muscle lipid metabolism are more controversial, but each has been shown to directly impair insulin signalling and consequently, insulin stimulated glucose uptake in muscle. However, the possibility that resistin and TNF-alpha reduces insulin sensitivity in muscle by directly impairing FA metabolism in this tissue leading to lipid accumulation, has been virtually unexamined. Thus, the contribution of various adipokines to the development of insulin resistance is complex and not fully understood. Finally, the effects of these adipokines on metabolism and insulin sensitivity are generally studied in isolation, making it difficult to predict the interactive effects and the net impact on insulin sensitivity.


Locus affecting regulation of the colicin I receptor by iron.
Using a strain containing a cir-lac operon fusion and a selective medium, we isolated a regulatory mutant of the colicin I receptor, which we have designated cirR. Cells carrying the cirR mutation were defective in the transcriptional regulation of cir by iron, but synthesis of other iron-regulated proteins was unaffected. cirR was found to be cis dominant. This is in contrast to previously described mutations in iron regulation which are pleiomorphic and trans dominant. Temperature regulation of colicin I receptor production was unaffected by cirR.


The influence of speaker gaze on listener comprehension: contrasting visual versus intentional accounts.
Previous research has shown that listeners follow speaker gaze to mentioned objects in a shared environment to ground referring expressions, both for human and robot speakers. What is less clear is whether the benefit of speaker gaze is due to the inference of referential intentions (Staudte and Crocker, 2011) or simply the (reflexive) shifts in visual attention. That is, is gaze special in how it affects simultaneous utterance comprehension? In four eye-tracking studies we directly contrast speech-aligned speaker gaze of a virtual agent with a non-gaze visual cue (arrow). Our findings show that both cues similarly direct listeners' attention and that listeners can benefit in utterance comprehension from both cues. Only when they are similarly precise, however, does this equality extend to incongruent cueing sequences: that is, even when the cue sequence does not match the concurrent sequence of spoken referents can listeners benefit from gaze as well as arrows. The results suggest that listeners are able to learn a counter-predictive mapping of both cues to the sequence of referents. Thus, gaze and arrows can in principle be applied with equal flexibility and efficiency during language comprehension.


The MARCOPOLO Study of Ustekinumab Utilization and Efficacy in a Real-World Setting: Treatment of Patients with Plaque Psoriasis in Asia-Pacific Countries.
Ustekinumab is a fully human monoclonal antibody approved for the treatment of chronic moderate-to-severe plaque psoriasis in adults. However, factors including efficacy, tolerability, ease of use, and cost burden may affect ustekinumab utilization. Noncompliance may, in turn, affect treatment response. To evaluate ustekinumab utilization in the real-world setting in Asia-Pacific countries. In this phase 4 observational study conducted in Indonesia, Malaysia, Singapore, Korea, and Taiwan, adults with plaque psoriasis receiving ustekinumab were followed for up to 52 weeks. Study endpoints were the proportion of all patients using ustekinumab according to label-recommended intervals and the proportion of Korean patients who achieved a psoriasis area severity index 75 response at week 16. Safety was assessed by monitoring adverse events. Overall, 169 patients received ustekinumab (Korea, n=102; other countries, n=67). Just over half (56.2%) of patients used ustekinumab with the label-recommended interval from baseline to week 40; the proportion was higher in Korea (73.5%) than in other countries (29.9%), probably because ustekinumab was provided without charge for Korean patients up to week 40. Noncompliance increased after week 40 in Korea and from week 28 in other Asia-Pacific countries, with cost cited as the most common reason. At week 16, 56.9% of Korean patients achieved a Psoriasis Area Severity Index 75 response. Safety results were in line with those seen in previous studies. More than half of all patients in Asia-Pacific countries used ustekinumab as per the label-recommended dose interval, but reimbursement variations between countries may have confounded overall results.


Social determinants of oral health inequalities: implications for action.
For over 30 years, the WHO has been advocating an integrated approach in chronic disease prevention. The concept of the common risk factor approach (CRFA) highlighted shared risk factors for chronic conditions including oral diseases has provided the basis for closer integration of oral and general health promotion activities. Although considerable progress has been undoubtedly made in combating the isolation and compartmentalization of oral health, this paper will argue that future action on tackling oral health inequalities requires a reorientation of oral health policy away from a fixation on changing oral health behaviours to instead action on the common social determinants of oral health inequalities. The narrow and restricted interpretation of the CRFA is a serious threat to developing effective action to address oral health inequalities. Based upon the WHO conceptual framework on the social determinants of health inequalities, an overview will be presented of a range of actions that could be implemented to tackle the social gradients in oral health outcomes.


A Review of Long QT Syndrome: Everything a Hospitalist Should Know.
In this article, we will review various aspects of long QT syndrome (LQTS) necessary for hospitalists who care for children, adolescents, and young adults who have known LQTS and also review presenting features that should make one consider LQTS as a cause of hospitalization. Pediatric hospitalists care for patients who have suffered near-drowning, unexplained motor vehicular accidents, brief resolved unexpected events, sudden infant death syndrome, recurrent miscarriages, syncope, or seizures. These common conditions can be clinical clues in patients harboring 1 of 16 LQTS genetic mutations. LQTS is commonly caused by a channelopathy that can cause sudden cardiac death. Over the years, guidelines on management and recommendations for sports participation have evolved with our understanding of the disease and the burden of arrhythmias manifested in the pediatric age group. This review will include the genetic causes of LQTS, clinical features, and important historical information to obtain when these presentations are encountered. We will review medical and surgical treatments available to patients with LQTS and long-term care recommendations and prognosis for those diagnosed with LQTS.


Mapping mutational effects along the evolutionary landscape of HIV envelope.
The immediate evolutionary space accessible to HIV is largely determined by how single amino acid mutations affect fitness. These mutational effects can shift as the virus evolves. However, the prevalence of such shifts in mutational effects remains unclear. Here, we quantify the effects on viral growth of all amino acid mutations to two HIV envelope (Env) proteins that differ at [Formula: see text]100 residues. Most mutations similarly affect both Envs, but the amino acid preferences of a minority of sites have clearly shifted. These shifted sites usually prefer a specific amino acid in one Env, but tolerate many amino acids in the other. Surprisingly, shifts are only slightly enriched at sites that have substituted between the Envs-and many occur at residues that do not even contact substitutions. Therefore, long-range epistasis can unpredictably shift Env's mutational tolerance during HIV evolution, although the amino acid preferences of most sites are conserved between moderately diverged viral strains.


Effect of soybean (Glycine max (L.) Merr.) flour inclusion on the nutritional properties and consumer preference of fritters for improved household nutrition.
Diets in populations of most developing countries are often deficient in protein, carbohydrates, and fat, leading to protein-energy malnutrition (PEM). Diet-based strategies are the most promising approach for a sustainable control of PEM. This study aimed to investigate the effects of soy flour inclusion on the nutritional properties, consumer preference, purchase intent, and willingness to pay for wheat-based fritters. The proximate composition of both types of fritters was determined using standard methods, Consumer preference survey on organoleptic properties was carried out among 291 participants (93 men, 198 women) in Chipata, Katete, and Lundazi districts of Eastern Zambia. The soy-fortified fritters had significantly higher (p < 0.05) levels of ash, fat, amylose, crude fiber, and protein than the unfortified fritters. Protein, crude fiber, amylose, and ash contents of soy-fortified fritters were considerably increased by 55.5%, 18.9%, 98%, and 30.6%, respectively. The overall preference showed no significant difference (p > 0.05) between unfortified and soy-fortified fritters. A larger percentage of participants in Katete (38%) and Chipata (41%) preferred the soy-fortified fritters to the nonfortified one. In addition, no significant difference (p > 0.05) was also observed for intention to purchase between both types of fritters across the three locations. In conclusion, incorporating 20% soybean flour into fritters, which showed better nutrients quality, could be used to alleviate PEM among fritters consuming populations of developing countries, particularly in Sub-Saharan Africa.


Acceptance of shared decision making with reference to an electronic library of decision aids (arriba-lib) and its association to decision making in patients: an evaluation study.
Decision aids based on the philosophy of shared decision making are designed to help patients make informed choices among diagnostic or treatment options by delivering evidence-based information on options and outcomes. A patient decision aid can be regarded as a complex intervention because it consists of several presumably relevant components. Decision aids have rarely been field tested to assess patients' and physicians' attitudes towards them. It is also unclear what effect decision aids have on the adherence to chosen options. The electronic library of decision aids (arriba-lib) to be used within the clinical encounter has a modular structure and contains evidence-based decision aids for the following topics: cardiovascular prevention, atrial fibrillation, coronary heart disease, oral antidiabetics, conventional and intensified insulin therapy, and unipolar depression. We conducted an evaluation study in which 29 primary care physicians included 192 patients. After the consultation, patients filled in questionnaires and were interviewed via telephone two months later. We used generalised estimation equations to measure associations within patient variables and traditional crosstab analyses. Patients were highly satisfied with arriba-lib and the process of shared decision making. Two-thirds of patients reached in the telephone interview wanted to be counselled again with arriba-lib. There was a high congruence between preferred and perceived decision making. Of those patients reached in the telephone interview, 80.7% said that they implemented the decision, independent of gender and education. Elderly patients were more likely to say that they implemented the decision. Shared decision making with our multi-modular electronic library of decision aids (arriba-lib) was accepted by a high number of patients. It has positive associations to general aspects of decision making in patients. It can be used for patient groups with a wide range of individual characteristics.


Changes in Spectra and Conformation of Hairpin DNA-Stabilized Silver Nanoclusters Induced by Stem Sequence Perturbations.
It is well-known that even small perturbations of the DNA sequence can drastically and unpredictably disrupt or alter the fluorescence of DNA-stabilized silver nanoclusters (DNA-AgNCs). Understanding how the structure of DNA affects the nanocluster that it stabilizes is the key to rationalizing such effects. We approach this challenge by strategically modifying the stem sequence of a hairpin DNA that hosts a spectrally pure, red-emitting nanocluster. Most of our modifications (base composition, sequence orientation, and loop location) reduce AgNC fluorescence in purity and shift it in wavelength, but one modification (appending poly(thymidine) to the 3' end of the stem) is inert with respect to fluorescence. Microfluidic capillary electrophoresis reveals that all of the modifications induce conformational changes of the DNA and that the original, spectrally pure nanocluster exists in two structurally distinct conformations. Interestingly, appending five or more thymidines, despite having no effect on fluorescence, eliminates this structural degeneracy. To explain this result, we propose that the original spectrally pure cluster is stabilized by a pair of hairpins whose stems can arrange in either a cis or trans orientation. Finally, we quantify the extent to which thymidine appendages of different lengths can be used to fine-tune the electrophoretic mobility of DNA-AgNC.


Investigation of non-community stakeholders regarding community engagement and environmental malodour.
Research into industry-community relationships have focused almost exclusively on the ways in which communities responds to actions from industries. This has led to a paucity of understanding with regards to how community engagement and malodour amelioration practices have been adopted by industry personnel, as well as the attitudes and beliefs of non-community stakeholders in general. In this study, a survey to water industry personnel was distributed to three Australian water utilities in South-Eastern Australia and a semi-structured interview process was carried out with plant managers at six wastewater treatment plants. It was observed that best practice has not yet been established with regards to community engagement and odour amelioration, and that water industry personnel in general had a poor understanding of these concepts. Recommendations for how this situation could be improved, and how non-community stakeholders investigated, are discussed.


The CAZyome of Phytophthora spp.: a comprehensive analysis of the gene complement coding for carbohydrate-active enzymes in species of the genus Phytophthora.
Enzymes involved in carbohydrate metabolism include Carbohydrate esterases (CE), Glycoside hydrolases (GH), Glycosyl transferases (GT), and Polysaccharide lyases (PL), commonly referred to as carbohydrate-active enzymes (CAZymes). The CE, GH, and PL superfamilies are also known as cell wall degrading enzymes (CWDE) due to their role in the disintegration of the plant cell wall by bacterial and fungal pathogens. In Phytophthora infestans, penetration of the plant cells occurs through a specialized hyphal structure called appressorium; however, it is likely that members of the genus Phytophthora also use CWDE for invasive growth because hyphal forces are below the level of tensile strength exhibited by the plant cell wall. Because information regarding the frequency and distribution of CAZyme coding genes in Phytophthora is currently unknown, we have scanned the genomes of P. infestans, P. sojae, and P. ramorum for the presence of CAZyme-coding genes using a homology-based approach and compared the gene collinearity in the three genomes. In addition, we have tested the expression of several genes coding for CE in cultures grown in vitro. We have found that P. infestans, P. sojae and P. ramorum contain a total of 435, 379, and 310 CAZy homologs; in each genome, most homologs belong to the GH superfamily. Most GH and PL homologs code for enzymes that hydrolyze substances present in the pectin layer forming the middle lamella of the plant cells. In addition, a significant number of CE homologs catalyzing the deacetylation of compounds characteristic of the plant cell cuticle were found. In general, a high degree of gene location conservation was observed, as indicated by the presence of sequential orthologous pairs in the three genomes. Such collinearity was frequently observed among members of the GH superfamily. On the other hand, the CE and PL superfamilies showed less collinearity for some of their putative members. Quantitative PCR experiments revealed that all genes are expressed in P. infestans when this pathogen grown in vitro. However, the levels of expression vary considerably and are lower than the expression levels observed for the constitutive control. In conclusion, we have identified a highly complex set of CAZy homologs in the genomes of P. infestans, P. sojae, and P. ramorum, a significant number of which could play roles critical for pathogenicity, by participating in the degradation of the plant cell wall.