A Simple and One-pot Synthesis of Tetrahydrobenzo[b]pyrans and Spirooxindoles Catalyzed by H-Fe3O4@DA-SO3H as an Efficient, Light and Reusable Nanocatalyst.
One of the principles of green chemistry is using inexpensive reagents and catalysts to design green route for synthesis of organic compounds. Recently magnetic nanoparticles have provided a considerable merits. In this study, hollow Fe3O4@Dopamine-SO3H has been successfully applied for the green synthesis of tetrahydrobenzo[b]pyrans and spirooxindoles via one-pot multi-component reaction. Chemical reagents were purchased from Merck and Aldrich. Melting points were determined using an Electrothermal 9100. Fourier transform infrared and NMR spectra were recorded with a Shimadzu 8400 spectrometer and Bruker spectrometer, respectively. The reaction between benzaldehyde, malononitrile and dimedone was selected as the model for synthesis of tetrahydrobenzo[b]pyran. The obtained results showed that the best amount of catalyst is 0.01 g and the reaction has occurred in solvent free condition at 70°C. The results showed that both electron-withdrawing and electron-donating substituents have an acceptable yield in the reaction. After that the scope of this method was evaluated in one-pot synthesis of spirooxindole derivatives through three-component reaction of isatin derivatives, malononitrile or ethyl cyanoacetate and 1,3-cycllic diketone. The optimum condition was 0.01 g catalyst using H2O under reflux condition. Then other derivatives produced in excellent yields during short reaction times. Tetrahydrobenzo[b]pyran and spirooxindole derivatives in the presence of this catalyst were synthesized. The ease of preparation and handling of the catalyst and operational simplicity are some of the main advantages of this work. In addition, the catalyst could be recycled and reused at least six times without notable reduction in its catalytic activity.


Case Study: Nutrition Planning and Intake for Marathon des Sables-A Series of Five Runners.
This case study describes the nutrition plans, intakes and experiences of five ultra-marathon runners who completed the Marathon des Sables in 2011 and 2013; age 37 (28-43) y, height 184 (180-190) cm, body mass 77.5 (71-85.5) kg, marathon personal best 3:08 (2:40-3:32). MdS is a 7-day, six-stage ultra-running stage race held in the Sahara Desert (total distance of timed stages 1-5 was 233.2 km in 2011, 223.4 km in 2013). Competitors are required to carry all equipment and food (except water) for the race duration, a minimum of 8,360 kJ/day and total pack weight of 6.5-15 kg. Total food mass carried was 4.2 (3.8-4.7) kg or 0.7 (0.5-1.1) kg/day. Planned energy (13,550 (10,323-18,142) kJ/day), protein (1.3 (0.8-1.8) g/kg/day), and carbohydrate (6.2 (4.3-9.2) g/kg/day) intakes on the fully self-sufficient days were slightly below guideline recommendations, due to the need to balance nutritional needs with food mass to be carried. Energy density was 1,636 (1,475-1,814) kJ/100g. 98.5% of the planned food was consumed. Fluid consumption was ad libitum with no symptoms or medical treatment required for dehydration or hyponatremia. During-stage carbohydrate intake was 42 (20-64) g/hour. Key issues encountered by runners included difficulty consuming foods due to dry mouth, and unpalatability of sweet foods (energy gels, sports drinks) when heated in the sun. Final classification of the runners ranged from 11th to 175th of 970 finishers in 2013, and 132nd of 805 in 2011. The described pattern of intake and macronutrient quantities were positively appraised by the five runners.


Dose-dependent dual role of PIT-1 (POU1F1) in somatolactotroph cell proliferation and apoptosis.
To test the role of wtPIT-1 (PITWT) or PIT-1 (R271W) (PIT271) in somatolactotroph cells, we established, using inducible lentiviral vectors, sublines of GH4C1 somatotroph cells that allow the blockade of the expression of endogenous PIT-1 and/or the expression of PITWT or PIT271, a dominant negative mutant of PIT-1 responsible for Combined Pituitary Hormone Deficiency in patients. Blocking expression of endogenous PIT-1 induced a marked decrease of cell proliferation. Overexpressing PITWT twofold led also to a dose-dependent decrease of cell proliferation that was accompanied by cell death. Expression of PIT271 induced a strong dose-dependent decrease of cell proliferation accompanied by a very pronounced cell death. These actions of PIT271 are independent of its interaction/competition with endogenous PIT-1, as they were unchanged when expression of endogenous PIT-1 was blocked. All these actions are specific for somatolactotroph cells, and could not be observed in heterologous cells. Cell death induced by PITWT or by PIT271 was accompanied by DNA fragmentation, but was not inhibited by inhibitors of caspases, autophagy or necrosis, suggesting that this cell death is a caspase-independent apoptosis. Altogether, our results indicate that under normal conditions PIT-1 is important for the maintenance of cell proliferation, while when expressed at supra-normal levels it induces cell death. Through this dual action, PIT-1 may play a role in the expansion/regression cycles of pituitary lactotroph population during and after lactation. Our results also demonstrate that the so-called "dominant-negative" action of PIT271 is independent of its competition with PIT-1 or a blockade of the actions of the latter, and are actions specific to this mutant variant of PIT-1.


A Molecular Window into the Biology and Epidemiology of Pneumocystis spp.
Pneumocystis, a unique atypical fungus with an elusive lifestyle, has had an important medical history. It came to prominence as an opportunistic pathogen that not only can cause life-threatening pneumonia in patients with HIV infection and other immunodeficiencies but also can colonize the lungs of healthy individuals from a very early age. The genus Pneumocystis includes a group of closely related but heterogeneous organisms that have a worldwide distribution, have been detected in multiple mammalian species, are highly host species specific, inhabit the lungs almost exclusively, and have never convincingly been cultured in vitro, making Pneumocystis a fascinating but difficult-to-study organism. Improved molecular biologic methodologies have opened a new window into the biology and epidemiology of Pneumocystis. Advances include an improved taxonomic classification, identification of an extremely reduced genome and concomitant inability to metabolize and grow independent of the host lungs, insights into its transmission mode, recognition of its widespread colonization in both immunocompetent and immunodeficient hosts, and utilization of strain variation to study drug resistance, epidemiology, and outbreaks of infection among transplant patients. This review summarizes these advances and also identifies some major questions and challenges that need to be addressed to better understand Pneumocystis biology and its relevance to clinical care.


Stories from the frontlines: decolonising social contracts for disasters.
Disasters are framed as political moments when states are unable to provide security to their citizens, causing disruption and a possible 'break' in the state-citizen social contract. Evidence from the frontlines of insurgency and secessionist movements in southern Philippines suggests that social contracts do not 'break' in this manner, despite widespread suffering during a complex event. This paper presents new perspectives on social contracts after disasters, in conflict-affected regions. Using ethnographic data from two case studies in the Philippines, it argues that disasters in conflict-affected areas do not manifest a 'break' in social contracts in ways that result in 'state failure' and 'insurgent capture'. Instead, it shows that the state-citizen contract is a dynamic contestation of state responsibilities, while also being malleably resilient. The inequalities and anxieties prevalent in social contracts are reproduced in the highly differentiated experiences of 'disaster citizenship' for people living amidst conflict.


All-payer ratesetting: down but not out.
In the United States, when the cost-containment paradigm shifted from regulation to competition, all-payer hospital ratesetting went out of favor. After reviewing the published literature and supplementing the existing literature with more current information, the author concludes that all-payer ratesetting is able to meet its multiple objectives of cost containment, reduction of the amount of cost shifting, improvement of access to the uninsured, and increased productivity. At the same time, all-payer ratesetting has not stifled the diffusion of competitive health care systems or new technology, and any impact on length of stay, admissions, and quality of care is small, if it exists at all.


Dynamic stiffness and transmissibility of commercially available wheelchair cushions using a laboratory test method.
Evidence suggests that wheelchair (WC) users are exposed to unhealthy levels of vibration during WC use. Health risks associated with vibration exposure include vertebral disc degeneration and back pain, which may consequently decrease the function and independence of WC users. Some evidence suggests that the cushions used in WCs may amplify vibrations, although conclusive evidence has not been presented in the literature. This study evaluated and compared the transmissibility of commercially available WC cushions with two laboratory test methods: (1) direct measurement of transmissibility while human subjects propelled a WC over a road course with different cushions and (2) characterization of cushions with a material testing system (MTS) combined with mathematical models of the apparent mass of the human body. Results showed that although dynamic characterization of WC cushions is possible with an MTS, the results did not correlate well with the transmissibility obtained in the WC road course. Significant differences were found for transmissibility among the cushions tested, with the air-based cushions having lower transmissibility than the foam- or gel-based cushions.


Air pollution and daily admissions for chronic obstructive pulmonary disease in 6 European cities: results from the APHEA project.
We investigated the short-term effects of air pollution on hospital admissions for chronic obstructive pulmonary disease (COPD) in Europe. As part of a European project (Air Pollution and Health, a European Approach (APHEA)), we analysed data from the cities of Amsterdam, Barcelona, London, Milan, Paris and Rotterdam, using a standardized approach to data eligibility and statistical analysis. Relative risks for daily COPD admissions were obtained using Poisson regression, controlling for: seasonal and other cycles; influenza epidemics; day of the week; temperature; humidity and autocorrelation. Summary effects for each pollutant were estimated as the mean of each city's regression coefficients weighted by the inverse of the variance, allowing for additional between-cities variance, as necessary. For all ages, the relative risks (95% confidence limits (95% CL)) for a 50 microg x m(-3) increase in daily mean level of pollutant (lagged 1-3 days) were (95% CL): sulphur dioxide 1.02 (0.98, 1.06); black smoke 1.04 (1.01, 1.06); total suspended particulates 1.02 (1.00, 1.05), nitrogen dioxide 1.02 (1.00, 1.05) and ozone (8 h) 1.04 (1.02, 1.07). The results confirm that air pollution is associated with daily admissions for chronic obstructive pulmonary disease in European cities with widely varying climates. The results for particles and ozone are broadly consistent with those from North America, though the coefficients for particles are substantially smaller. Overall, the evidence points to a causal relationship but the mechanisms of action, exposure response relationships and pollutant interactions remain unclear.


Near-infrared excited ultraviolet emitting upconverting phosphors as an internal light source in dry chemistry test strips for glucose sensing.
Upconverting phosphors are inorganic crystals with interesting optical properties, including the ability to convert infrared radiation to emission at shorter wavelengths. In this paper we present the utilization of nanosized β-NaYF4:Yb(3+),Tm(3+), synthesized in the presence of K(+), emitting at 365 nm under 980 nm excitation as an internal light source in glucose sensing dry chemistry test strips. The feasibility of the nanoparticles as an internal UV light source was compared to the use of an external broadband lamp. The results obtained from glucose measurements using UCNPs were in agreement with the traditional method based on measuring reflectance using an external UV light source. In addition the multiple emission peaks of UCNPs offered the possibility of using them as a control signal to account for various sources of error arising in the assay. The high penetration depth of the NIR-excitation made it also possible to excite the UCNPs through a layer of whole blood, giving more freedom to the design of the optical setup.


The advanced practice nursing role in a high-risk breast cancer clinic.
To describe the role of an oncology nurse practitioner in a breast cancer prevention clinic. Published articles, abstracts, and book chapters and personal experience. Validated risk assessment models and genetic screening can be used to assess an individual's risk for breast cancer. Lifestyle changes and medical interventions can reduce that risk. Interventions for primary prevention of breast cancer soon may become one of the most effective means of reducing the incidence, morbidity, and mortality of breast cancer. Advanced practice nurses in the oncology setting are ideal healthcare providers to assess patients' risk of breast cancer, determine physical findings that can influence that risk, provide risk education, synthesize existing data, and make recommendations for surveillance, pharmacotherapy, lifestyle changes, and genetic counseling and testing. Limitations in the existing data in cancer prevention provide excellent opportunities for nursing research.


Full-field interferometric confocal microscopy using a VCSEL array.
We present an interferometric confocal microscope using an array of 1200 vertical cavity surface emitting lasers (VCSELs) coupled to a multimode fiber. Spatial coherence gating provides ~18,000 continuous virtual pinholes, allowing an entire en face plane to be imaged in a snapshot. This approach maintains the same optical sectioning as a scanning confocal microscope without moving parts, while the high power of the VCSEL array (∼5 mW per laser) enables high-speed image acquisition with integration times as short as 100 μs. Interferometric detection also recovers the phase of the image, enabling quantitative phase measurements and improving the contrast when imaging phase objects.


Tafenoquine exposure assessment, safety, and relapse prevention efficacy in children with Plasmodium vivax malaria: open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 trial.
Single-dose tafenoquine 300 mg is approved for Plasmodium vivax malaria relapse prevention in patients at least 16 years old. We aimed to determine appropriate oral tafenoquine paediatric dosing regimens, including a dispersible formulation, and evaluated tafenoquine efficacy and safety in children infected with P vivax. This open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 study enrolled children (2-15 years) who weighed 5 kg or more, with glucose-6-phosphate dehydrogenase activity more than 70% of the local population median, and P vivax malaria infection, from three community health centres in Vietnam and one in Colombia. Patients received 3-day chloroquine plus oral single-dose tafenoquine as dispersible tablets (50 mg) or film-coated tablets (150 mg). Dosing groups were assigned by body weight, predicted to achieve similar median exposures as the approved 300 mg dose for adults: patients who weighed 5 kg or more to 10 kg received 50 mg, those who weighed more than 10 to 20 kg received 100 or 150 mg, those who weighed more than 20 to 35 kg received 200 mg, and patients who weighed more than 35 kg received 300 mg. Population pharmacokinetic analysis was done to develop a paediatric population pharmacokinetic model. The primary outcome was the tafenoquine area under the concentration-time curve extrapolated to infinity (AUC[0-∞]) by patient body weight in the pharmacokinetic population (all patients who received tafenoquine with at least one valid pharmacokinetic sample) estimated from a paediatric population pharmacokinetic model. A key prespecified secondary outcome was 4-month recurrence-free efficacy. This trial is registered with ClinicalTrials.gov, NCT02563496. Between Feb 6, 2017, and Feb 17, 2020, 60 patients were enrolled into the study: 14 (23%) received tafenoquine 100 mg, five (8%) 150 mg, 22 (36%) 200 mg, and 19 (32%) 300 mg. The paediatric population pharmacokinetic model predicted adequate tafenoquine exposure at all doses. The predicted median AUC(0-∞) was 73·8 (90% prediction interval [PI] 46·9-117·0) μg × h/mL with the 50 mg dose for patients who weighed 5 kg or more to 10 kg, 87·5 (55·4-139·0) μg × h/mL with the 100 mg dose for body weight more than 10 to 20 kg, 110·7 (70·9-174·0) μg × h/mL with the 200 mg dose for body weight more than 20 to 35 kg, and 85·7 (50·6-151·0) μg × h/mL with the 300 mg dose for body weight more than 35 kg. 4-month recurrence-free efficacy was 94·7% (95% CI 84·6-98·3). Adverse events were consistent with previous studies, except for the seven (12%) of 60 patients who had post-dose vomiting or spitting with the 50 mg dispersed tablet. Following mitigation strategies, there were no additional occurrences of this adverse event. There were no deaths during the study. For the prevention of P vivax relapse in children, single-dose tafenoquine, including a dispersible formulation, had exposure, safety, and efficacy consistent with observations in adolescents and adults, notwithstanding post-dose vomiting. GlaxoSmithKline and Medicines for Malaria Venture. For the Vietnamese and Spanish translations of the abstract see Supplementary Materials section.


The pharmacology of an insect ganglion: actions of carbamylcholine and acetylcholine.
1. Methods for presenting dose-response data for the ganglionic actions of cholinergic agonists (e.g. carbamylcholine) are compared, using the mannitol-gap technique for electrophysiological recording of synaptic events at the cercal nerve, giant fibre synapse of the sixth abdominal ganglion of the cockroach Periplaneta americana. 2. At concentrations around 10(-5)M, carbamylcholine has no effect on ganglionic polarization but potentiates the monosynaptic EPSP. At 10(-4)M and higher concentrations, ganglionic depolarization is accompanied by a reduction of EPSP. 3. Pretreatment with eserine (10(-6) M) considerably shifts the dose-response curve for acetylcholine so that synaptic transmission is consistently sensitive to 10(-6) M acetylcholine.


Anaemia and Plasmodium falciparum infections among young children in an holoendemic area, Bagamoyo, Tanzania.
Although the aetiology of anaemia in tropical areas is multifactorial, Plasmodium falciparum malaria is commonly associated with anaemia in children living in holoendemic malaria areas. Such an association was examined in a population based study of 338 children 6 to 40 months of age living in the Bagamoyo area of Tanzania. Stepwise regression analysis showed that fever and parasitaemia were effective in predicting anaemia and that the anaemic condition was age dependent. The majority of the children were iron deficient, followed by normochromic macrocytic anaemias. There was strong evidence in this age group that the anaemia was associated with malaria and not geohelminth infection. The importance of malaria and anaemia as a cause of childhood morbidity in Africa is discussed. This condition has taken on new significance with the realization that blood transfusions commonly used to treat severe anaemia are a major vehicle for Human Immunodeficiency Virus (HIV) transmission.


[Psychometric properties of the spanish version of the "Barriers to Being Active Quiz" among university students in Colombia].
The Barriers to Being Active Quiz (BBAQ) measures seven barriers to being physically active. The test was translated into Spanish by the team that developed its original English version, but it lacks of the validity assessment studies. The aim of this study was to evaluate the psychometric properties of BBAQ (21 items version), focusing on the reliability and validity. A total of 2634 (1462 female and 1172 male; age 18-30 years) university students completed the BBAQ-21 items questionnaire. Cronbach alpha was calculated to assess the internal consistency. Intraclass correlation coefficients (ICC) and degree of agreement were calculated to assess the test-retest reliability, with a period of 7 days between both administrations, as a measure of reproducibility. An exploratory factor analysis (EFA) and confirmatory (CFA) were done to analyze the validity of BBAQ-21 items. The Cronbach alpha coefficient of BBAQ-21 showed between 0,812 and 0,844 and ICC ranged between 0,46 and 0,87. The degree of agreement for all individual items ranged from 45% to 80%. The EFA showed a 4-factor solution that explained 52,90% of the variance and CFA showed moderate factor loadings. Results support the use of this questionnaire with populations of university students, considering its reliability and validity. BBAQ-21 is available to assess the barriers to physical activity in Latin America.


On the construction of experimental designs for a given task by jointly optimizing several quality criteria: Pareto-optimal experimental designs.
Experimental designs for a given task should be selected on the base of the problem being solved and of some criteria that measure their quality. There are several such criteria because there are several aspects to be taken into account when making a choice. The most used criteria are probably the so-called alphabetical optimality criteria (for example, the A-, E-, and D-criteria related to the joint estimation of the coefficients, or the I- and G-criteria related to the prediction variance). Selecting a proper design to solve a problem implies finding a balance among these several criteria that measure the performance of the design in different aspects. Technically this is a problem of multi-criteria optimization, which can be tackled from different views. The approach presented here addresses the problem in its real vector nature, so that ad hoc experimental designs are generated with an algorithm based on evolutionary algorithms to find the Pareto-optimal front. There is not theoretical limit to the number of criteria that can be studied and, contrary to other approaches, no just one experimental design is computed but a set of experimental designs all of them with the property of being Pareto-optimal in the criteria needed by the user. Besides, the use of an evolutionary algorithm makes it possible to search in both continuous and discrete domains and avoid the need of having a set of candidate points, usual in exchange algorithms.


Simulations of simple artificial genetic networks reveal features in the use of Relevance Networks.
Recent research on large scale microarray analysis has explored the use of Relevance Networks to find networks of genes that are associated to each other in gene expression data. In this work, we compare Relevance Networks with other types of clustering methods to test some of the stated advantages of this method. The dataset we used consists of artificial time series of Boolean gene expression values, with the aim of mimicking microarray data, generated from simple artificial genetic networks. By using this dataset, we could not confirm that Relevance Networks based on mutual information perform better than Relevance Networks based on Pearson correlation, partitional clustering or hierarchical clustering, since the results from all methods were very similar. However, all three methods successfully revealed the subsets of co-expressed genes, which is a valuable step in identifying co-regulation.


Slow sedimentation and deformability of charged lipid vesicles.
The study of vesicles in suspension is important to understand the complicated dynamics exhibited by cells in in vivo and in vitro. We developed a computer simulation based on the boundary-integral method to model the three dimensional gravity-driven sedimentation of charged vesicles towards a flat surface. The membrane mechanical behavior was modeled using the Helfrich Hamiltonian and near incompressibility of the membrane was enforced via a model which accounts for the thermal fluctuations of the membrane. The simulations were verified and compared to experimental data obtained using suspended vesicles labelled with a fluorescent probe, which allows visualization using fluorescence microscopy and confers the membrane with a negative surface charge. The electrostatic interaction between the vesicle and the surface was modeled using the linear Derjaguin approximation for a low ionic concentration solution. The sedimentation rate as a function of the distance of the vesicle to the surface was determined both experimentally and from the computer simulations. The gap between the vesicle and the surface, as well as the shape of the vesicle at equilibrium were also studied. It was determined that inclusion of the electrostatic interaction is fundamental to accurately predict the sedimentation rate as the vesicle approaches the surface and the size of the gap at equilibrium, we also observed that the presence of charge in the membrane increases its rigidity.


Reliability and validity of a maternal food frequency questionnaire designed to estimate consumption of common food allergens.
Maternal food intake during pregnancy may influence the development of food hypersensitivity (FHS) in the child. A food frequency questionnaire estimating the frequency with which some of the mains food allergens are consumed was designed and validated. Pregnant women were recruited at the ante-natal clinic of St. Mary's Hospital, Isle of Wight, UK. A food frequency questionnaire was developed and validated by comparing responses to information recorded in 7 days food diaries. The reliability of the food frequency questionnaire was evaluated by asking women to complete the questionnaire on two separate occasions at 30 and 36 weeks gestation. Fifty-seven women completed the validity study and 91 women completed the reliability study. For both validity and reliability, questions with dichotomous response categories showed the highest level of agreement. Frequency of intake of foods commonly "hidden" in foods produced the lowest validity and reliability scores. In the validity study responses to the food frequency questionnaire identically matched information recorded in the food diaries 80% of the time, on average. In the reliability study, responses were identical on both questionnaires 85% of the time on average. In this study a food frequency questionnaire estimating the frequency with which some of the main food allergens are consumed during pregnancy was designed and validated. This food frequency questionnaire could be used in future studies to assess the role of maternal food intake in the development of FHS in the infant.


Microarray-based ultra-high resolution discovery of genomic deletion mutations.
Oligonucleotide microarray-based comparative genomic hybridization (CGH) offers an attractive possible route for the rapid and cost-effective genome-wide discovery of deletion mutations. CGH typically involves comparison of the hybridization intensities of genomic DNA samples with microarray chip representations of entire genomes, and has widespread potential application in experimental research and medical diagnostics. However, the power to detect small deletions is low. Here we use a graduated series of Arabidopsis thaliana genomic deletion mutations (of sizes ranging from 4 bp to ~5 kb) to optimize CGH-based genomic deletion detection. We show that the power to detect smaller deletions (4, 28 and 104 bp) depends upon oligonucleotide density (essentially the number of genome-representative oligonucleotides on the microarray chip), and determine the oligonucleotide spacings necessary to guarantee detection of deletions of specified size. Our findings will enhance a wide range of research and clinical applications, and in particular will aid in the discovery of genomic deletions in the absence of a priori knowledge of their existence.


Italian Nivolumab Expanded Access Program in Nonsquamous Non-Small Cell Lung Cancer Patients: Results in Never-Smokers and EGFR-Mutant Patients.
Nivolumab is the first checkpoint inhibitor approved for the treatment of nonsquamous NSCLC. We report results from the nivolumab Italian expanded access program focusing on never-smokers and patients with EGFR-mutant nonsqamous NSCLC. Nivolumab (3 mg/kg intravenously every 2 weeks) was administered upon physicians' request to patients who had relapsed after one or more prior systemic treatments for stage IIIB/IV nonsquamous NSCLC. Efficacy and safety were evaluated in patients who received at least one dose of nivolumab. Of 1588 patients with nonsquamous NSCLC, 305 (19.2%) were never-smokers. EGFR status was available for 1395 patients. Of the 102 patients (6.4%) with EGFR mutation-positive tumors, 51 (50%) were never-smokers. The objective response rate was significantly higher in patients with wild-type EGFR than patients with EGFR-mutant tumors (19.6% versus 8.8% [p = 0.007]), in former and current smokers than in never-smokers (21.5% versus 9.2% [p = 0.0001]), and in never-smokers with wild-type EGFR than in never-smokers with mutant EGFR (11.0% versus 1.9% [p = 0.04]). There was no significant difference in objective response rate between smokers with wild-type EGFR and smokers with mutant EGFR (22.0% versus 20.6%). There was no statistically significant difference in median progression-free survival or in median overall survival. The median overall survival times were 11 months in patients with EGFR wild-type tumors versus 8.3 months in patients with EGFR-mutant tumors, 11.6 months in smokers versus 10.0 months in never-smokers, 11.0 months in never-smokers with EGFR wild-type tumors versus 5.6 months in never-smokers with EGFR-mutant tumors, and 14.1 months in smokers with EGFR-mutant tumors versus 11.3 months in smokers with EGFR wild-type tumors. The data on the Italian expanded access program in populations with nonsquamous NSCLC suggest that subgroups of patients could benefit differently from nivolumab according to their EGFR mutational status and smoking habits. These results warrant further investigation.


The cost of cancer.
In the last 30 years medical science has developed an array of new technologies such as cell cytology, radio-isotopic scanning, soft tissue X-rays (mammography and computerized tomography), etc., which have potential for the early detection of cancer, and when coupled with current or future therapeutic techniques may lead to improved rates of cure or prolonged survival of patients with cancer. Whenever preliminary evidence of efficacy is developed, considerable public pressure mounts both within and outside the medical community to implement screening programs on a widespread basis. Advances in screening and treatment, however, are coming at a time when there is serious nationwide concern over the total amount now being spent for health care in the nation and the rate of inflation that has occurred almost every year. In the medical literature, the little existing identification of the costs and economic benefits of screening (and of disease control programs in general) is often presented in a fairly simplistic fashion. Yet, just as many of the biologic issues in cancer screening are complex, so too are the economic ones. This paper will begin to identify: 1. the economic approaches to evaluating screening, 2. the problems in specifying costs, 3. the issues involved in selecting benefit measures, and 4. how these interact in the formulation of screening policies. In addressing these issues, new data on cost of cancer treatment, based on the third National Cancer Survey, will be presented. These data include hospital and nonhospital costs, disaggregated by source, cancer site and stage.


A measure of severe psychological abuse normed on a nationally representative sample of adults.
A psychological abuse scale representing truly egregious psychological actions that could occur between adult intimate partners was constructed. To insure that the component behaviors would be viewed as highly problematic, the likely malignant intent of the actions was included in item descriptions. Fourteen categories of psychological abuse were devised as relatively independent forms of destructive behaviors, and, within each category, 3 items were devised to represent increasingly severe psychological actions. A nationally representative sample of adults (N = 614) responding to an online survey rated the perceived severity of the 42 aversive behaviors. Reliability and validity indicators, along with descriptive data, are presented. The ratings of the sample basically established the items as egregious in nature, the categories as distinct from each other, and the items within categories as varying in expected directions in terms of severity. Except for gender, demographics had little effect on participants' ratings. Social desirability and dimensions of attachment showed weak relationships with participants' ratings.


Effectiveness of a Breathing Training Program on Quality of Life in Patients with Predialysis Chronic Kidney Disease: A Randomized Controlled Trial.
Chronic kidney disease (CKD) patients have suboptimal quality of life (QOL). Various studies/researches have revealed that breathing exercises have a positive and favorable impact on different systems of the body. This study aims to assess the effect of a breathing training program on QOL in patients with predialysis CKD. The study was a single-center study conducted at PGIMER, Chandigarh. Randomized controlled trial. Sixty individuals were enrolled and randomized using lottery method. QOL was assessed or evaluated by Kidney Disease and QOL questionnaire (KDQOL™-36). Breathing exercises were taught to the intervention group. Patients included in control group continued with the routine care. Assessment of QOL was done after 4 weeks in both the groups. Change in KDQOL™-36 scores showed significant difference between control and the intervention group. The mean scores of control group in the subscale effects of kidney disease, SF-12 Physical functioning (Physical Health Composite) and SF-12 Mental functioning (Mental Health Composite) were 84.79, 39.16 and 37.40, respectively, whereas in intervention group, the respective mean scores were 91.88, 43.92, and 44.16. The difference was statistically significant (P = 0.04, P = 0.01, and P = 0.003, respectively). Breathing training program improves QOL in patients with predialysis CKD.


Beliefs about lying and spreading of dishonesty: undetected lies and their constructive and destructive social dynamics in dice experiments.
Field experiments have shown that observing other people littering, stealing or lying can trigger own misconduct, leading to a decay of social order. However, a large extent of norm violations goes undetected. Hence, the direction of the dynamics crucially depends on actors' beliefs regarding undetected transgressions. Because undetected transgressions are hardly measureable in the field, a laboratory experiment was developed, where the complete prevalence of norm violations, subjective beliefs about them, and their behavioral dynamics is measurable. In the experiment, subjects could lie about their monetary payoffs, estimate the extent of liars in their group and make subsequent lies contingent on information about other people's lies. Results show that informed people who underestimate others' lying increase own lying more than twice and those who overestimate, decrease it by more than half compared to people without information about others' lies. This substantial interaction puts previous results into perspective, showing that information about others' transgressions can trigger dynamics in both directions: the spreading of normative decay and restoring of norm adherence.


Cerebral palsy and neonatal death in term singletons born small for gestational age.
To investigate the probable timing of events leading to cerebral palsy (CP) in singletons born small for gestational age (SGA) at term, taking neonatal death into consideration. In this registry-based cohort study, data on 400 488 singletons born during 1996-2003 were abstracted from the Medical Birth and the CP registries of Norway. Among 36 604 SGA children (birth weight <10th percentile), 104 died in the neonatal period and 69 developed CP. Apgar scores at 5 minutes, risk factors, MRI findings, and CP subtypes were used to assess the timing of events leading to CP or neonatal death. Intrapartum origin of CP was considered in 5 SGA children (7%; 95% confidence interval: 3-16) in comparison with 31 of 263 (12%; 95% confidence interval: 8-16) non-SGA children (P = .28). The proportions of children who died in the neonatal period after a probable intrapartum event did not differ between the groups when children with congenital malformations were excluded. Probable antenatal events leading to CP and neonatal death were more common among SGA than non-SGA children (P < .001). In ~90% of children born SGA the event leading to CP is of probable antenatal origin. The low proportion of SGA children with CP after a probable intrapartum event was not outweighed by a higher neonatal mortality rate when congenital malformations were excluded. The higher risk of CP among SGA than among non-SGA children is probably due to a higher prevalence of antenatal risk factors.


Optimizing single mode robustness of the distributed modal filtering rod fiber amplifier.
High-power fiber amplifiers for pulsed applications require large mode area (LMA) fibers having high pump absorption and near diffraction limited output. Photonic crystal fibers allow realization of short LMA fiber amplifiers having high pump absorption through a pump cladding that is decoupled from the outer fiber diameter. However, achieving ultra low NA for single mode (SM) guidance is challenging, thus different design strategies must be applied. The distributed modal filtering (DMF) design enables SM guidance in ultra low NA fibers with very large cores, where large preform tolerances can be compensated during the fiber draw. Design optimization of the SM bandwidth of the DMF rod fiber is presented. Analysis of band gap properties results in a fourfold increase of the SM bandwidth compared to previous results, achieved by utilizing the first band of cladding modes, which can cover a large fraction of the Yb emission band including wavelengths of 1030 nm and 1064 nm. Design parameters tolerating refractive index fabrication uncertainties of ± 10⁻⁴ are targeted to yield stable SM bandwidths.


Thyroidectomy decreases snoring and sleep apnea symptoms.
Patients with goiter often complain of compressive symptoms, which may contribute to symptoms of obstructive sleep apnea (OSA). However, the impact of thyroid enlargement on these symptoms is not clear. Therefore, we sought to evaluate whether symptoms of sleep apnea resolved after thyroidectomy by using a validated questionnaire. The Berlin Questionnaire, a validated sleep apnea assessment tool, was provided to patients at a single academic institution before and after thyroidectomy. Patients who admitted to symptoms of snoring were asked to complete the questionnaire before and 8 weeks after surgery to assess for improvement in symptoms. The questionnaire uses 3 categories of questions to determine risk of sleep apnea. Two symptom categories must be positive for a patient to be considered high risk for sleep apnea. Forty-five patients completed both pre- and postoperative questionnaires. The average age of patients completing the questionnaire was 53±2 years, and 78% of patients were female. Average body mass index was 33.3±1.4 kg/m(2). Based on their preoperative questionnaire score, 71% of patients were considered to be high risk for OSA, and this decreased to 51% after surgery (p=0.002). Overall scores significantly improved after surgery (mean 2.0 vs. 1.6, p<0.0001). Specifically, patients noted a significant decrease in snoring frequency after surgery (p=0.002), as well as a significant decrease in whether or not their snoring bothered others (p=0.004). The frequency of nodding off during the day also significantly decreased after surgery (p=0.02). Among patients with ≥25% improvement compared with those with <25% improvement in scores, the only significant difference found was a higher preoperative thyrotropin among patients with <25% improvement (p=0.03). No significant difference was found between age, gender, presence of compressive symptoms, gland weight at resection, presence of thyroiditis, or the largest dimension of the gland at resection. Thyroid surgery appears to significantly improve symptoms of OSA in patients who screened positive for symptoms before surgery. Evaluation of patients with OSA should include evaluation of thyroid disease, as symptoms of sleep apnea may improve with thyroidectomy.


Copper reduction by the octapeptide repeat region of prion protein: pH dependence and implications in cellular copper uptake.
The physiological function of the prion protein (PrP) remains enigmatic despite its established involvement in the pathogenesis of spongiform encephalopathies. PrP is a glycolipid-anchored membrane protein, which constitutively recycles between the cell surface and an endosomal compartment. The N-terminal region of PrP contains a four tandem repeat (OP4) of the octapeptide PHGGGWGQ (OP) that binds and reduces Cu(II) ions. We have examined the kinetic properties of the OP4-mediated Cu(II) reduction and found that OP4 exhibits the highest reduction activity around pH 6.5, close to the pH in early endosomes. All four OP units and at least one tryptophan side chain are essential for Cu(II) reduction. The reaction is described by an uncompetitive substrate inhibition mechanism involving a 1:1 Cu(II)-OP4 active intermediate. Structural analysis by Raman spectroscopy has revealed that the Cu(II) ion is coordinated by four histidine Ntau atoms in the active intermediate and the feasibility of formation of this intermediate correlates with the Cu(II) reduction over a pH range from 5.0 to 8.2. Molecular mechanics calculations suggest that two tryptophan residues of OP4 are located near the Cu(II) site, being consistent with the importance of redox-active tryptophan in the Cu(II) reduction. PrP has been proposed to capture Cu(II) ions in the extracellular space and release them in the endosome. The results of this study strongly suggest that PrP also plays a role in the reduction of captured Cu(II) ions prior to their transfer to Cu(I)-specific intracellular copper trafficking proteins.


Tumor location is not an independent prognostic factor in early stage non-small cell lung cancer.
Conventional thoracic surgical teaching suggests a worse outcome for lower lobe lung cancers. It is unclear whether this is due to stage migration or whether lobar location is an independent negative prognostic factor. We performed a retrospective review of our institutional database of patients undergoing resection for pathologic stage I or stage II lung cancer between Jan 2000 and December 2006. Survival analysis was used to compare outcomes in various groups using the log-rank test. Logistic regression analysis was used to compare the primary dependent variables; age, size, and location of tumor (both laterality and lobe), histology (adenocarcinoma, squamous, large cell, or neuroendocrine and others) and type of resection (wedge, lobectomy or segmentectomy, and pneumonectomy). A total of 841 patients met the inclusion criteria. The mean age of patients was 64.9 years, mean tumor size 3.3 cm, and, 144 patients had N1 disease. The three-year and five-year survivals for stage I tumors were 346 of 478 (72.4%) and 277 of 497 (55.7%), respectively. There was no difference in survival based upon lobar location. The three-year and five-year survivals for stage II tumors were 81 of 175 (46.3%) and 39 of 150 (26%), respectively, and lobar location did not influence survival. Logistic regression analysis showed that for stage I tumors increasing age and having undergone a pneumonectomy were associated with worse survival, and for stage II tumors increasing age and adenocarcinoma histology were associated with worse survival. Tumor location within the lung does not predict survival in pathologic stage I/II non-small cell lung carcinoma. Increasing age, adenocarcinoma histology, and pneumonectomy as the resection may lead to worse long-term survival.


Interference of surface waves in a metallic nanoslit.
We investigate the interference of the surface plasmon polariton (SPP) with an incident beam on a metallic slit using the FDTD. We find that the bulk waves radiated at the slit edge by scattering of the SPP leak into the slit and induce accumulated charges within the skin depth, which excite new SPPs on the slit side-walls. The SPP on the top surface of aperture is coupled into the slit and induces the 2D asymmetric field distributions, including the horizontal and vertical Fabry-Perot multi-reflection resonator modes. We show that the addition of these modes with the slit waveguide modes induced by a normally incident beam is the interference between the SPP and the incident beam, which enhances or suppresses the slit transmission, depending on their relative phase.


Commodity risk assessment of Berberis thunbergii potted plants from Turkey.
The European Commission requested the EFSA Panel on Plant Health to prepare and deliver risk assessments for commodities listed in the Commission Implementing Regulation (EU) 2018/2019 as 'High-risk plants, plant products and other objects'. This Scientific Opinion covers plant health risks posed by potted plants (2-3 years old) of Berberis thunbergii produced in nurseries and imported into the EU from Turkey, taking into account the available scientific information, including the technical information provided by the NPPO of Turkey. The relevance of any pest for this Opinion was based on evidence following defined criteria. Two species, the EU-quarantine pest Bemisia tabaci and the non-regulated pest Malacosoma parallela, fulfilled the relevant criteria and were selected for further evaluation. For these pests, the risk mitigation measures proposed in the technical dossier from Turkey were evaluated taking into account the possible limiting factors. For these pests, an expert judgement is given on the likelihood of pest freedom taking into consideration the risk mitigation measures acting on the pest, including uncertainties associated with the assessment. The estimated degree of pest freedom varies among the pests evaluated, with B. tabaci being the pest most frequently expected on the imported plants. The Expert Knowledge Elicitation indicated, with 95% certainty, that between 9,928 and 10,000 plants per 10,000 would be free of B. tabaci. The role of Berberis thunbergii as possible host of Puccinia spp. is discussed in the body of the opinion.


Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: A case-cohort study and murine model of acute particulate exposure.
World Trade Center-particulate matter(WTC-PM) exposure and metabolic-risk are associated with WTC-Lung Injury(WTC-LI). The receptor for advanced glycation end-products (RAGE) is most highly expressed in the lung, mediates metabolic risk, and single-nucleotide polymorphisms at the AGER-locus predict forced expiratory volume(FEV). Our objectives were to test the hypotheses that RAGE is a biomarker of WTC-LI in the FDNY-cohort and that loss of RAGE in a murine model would protect against acute PM-induced lung disease. We know from previous work that early intense exposure at the time of the WTC collapse was most predictive of WTC-LI therefore we utilized a murine model of intense acute PM-exposure to determine if loss of RAGE is protective and to identify signaling/cytokine intermediates. This study builds on a continuing effort to identify serum biomarkers that predict the development of WTC-LI. A case-cohort design was used to analyze a focused cohort of male never-smokers with normal pre-9/11 lung function. Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with soluble RAGE (sRAGE)≥97pg/mL, CRP≥2.4mg/L, and MMP-9≤397ng/mL, respectively, assessed in a multivariate logistic regression model (ROCAUC of 0.72). Wild type(WT) and RAGE-deficient(Ager-/-) mice were exposed to PM or PBS-control by oropharyngeal aspiration. Lung function, airway hyperreactivity, bronchoalveolar lavage, histology, transcription factors and plasma/BAL cytokines were quantified. WT-PM mice had decreased FEV and compliance, and increased airway resistance and methacholine reactivity after 24-hours. Decreased IFN-γ and increased LPA were observed in WT-PM mice; similar findings have been reported for firefighters who eventually develop WTC-LI. In the murine model, lack of RAGE was protective from loss of lung function and airway hyperreactivity and was associated with modulation of MAP kinases. We conclude that in a multivariate adjusted model increased sRAGE is associated with WTC-LI. In our murine model, absence of RAGE mitigated acute deleterious effects of PM and may be a biologically plausible mediator of PM-related lung disease.


"Illusions of normality": a methodological critique of category-specific naming.
Category-specific disorders are perhaps the archetypal example of domain-specificity--being typically defined by the presence of dissociations between living and nonliving naming ability in people following neurological damage. The methods adopted to quantify naming across categories are therefore pivotal since they provide the criterion for defining whether patients have a category effect and necessarily influence the subsequent direction and the interpretation of testing. This paper highlights a series of methodological concerns relating to how we measure and define category (or any) dissociations. These include the common failure to include control data or the use of control data that is inappropriate e.g. at ceiling, unmatched. A review of past cases shows that the overwhelming majority suffers from these problems and therefore challenges conclusions about the purported empirical demonstrations of dissociations and double dissociations in the category specific literature. This is not a refutation of category deficits, but skepticism about the current existence of any convincing empirical demonstrations of category specific double dissociations. As a potential solution, certain minimal criteria are proposed that might aid with the attempt to document category effects that are more methodologically convincing.


Graphene oxide-stabilized perfluorocarbon emulsions for controlled oxygen delivery.
Perfluorocarbon (PFC) emulsions are capable of absorbing large quantities of oxygen. They are widely used as blood alternates for quick oxygenation of tissues. However, they are unsuitable for applications where sustained oxygen supply is desired over an extended period of time. Here, we have designed a new PFC oxygen delivery system that combines perfluorodecalin with graphene oxide (GO), where GO acts both as an emulsifier and a stabilizing agent. The resulting emulsions (PFC@GO) release oxygen at least one order of magnitude slower than emulsions prepared with other common surfactants. The release rate can be controlled by varying the thickness of the GO layer. Controlled release of oxygen make these emulsions excellent oxygen carriers for applications where sustained oxygen delivery is required e.g. in tissue regeneration and vascular wound healing.


Perspectives on the use of stem cells for autism treatment.
Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders. ASDs are clinically defined by deficits in communication, social skills, and repetitive and/or restrictive interests and behaviours. With the prevalence rates for ASDs rapidly increasing, the need for effective therapies for autism is a priority for biomedical research. Currently available medications do not target the core symptoms, can have markedly adverse side-effects, and are mainly palliative for negative behaviours. The development of molecular and regenerative interventions is progressing rapidly, and medicine holds great expectations for stem cell therapies. Cells could be designed to target the observed molecular mechanisms of ASDs, that is, abnormal neurotransmitter regulation, activated microglia, mitochondrial dysfunction, blood-brain barrier disruptions, and chronic intestinal inflammation. Presently, the paracrine, secretome, and immunomodulatory effects of stem cells would appear to be the likely mechanisms of application for ASD therapeutics. This review will focus on the potential use of the various types of stem cells: embryonic, induced pluripotential, fetal, and adult stem cells as targets for ASD therapeutics.


Characteristics and outcome of patients with acute myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction chemotherapy.
Pretreatment characteristics and outcome of patients treated with induction regimens containing high-dose ara-C (HiDAC) at M. D. Anderson Cancer Center refractory to 1 cycle of induction were compared with similar patients achieving a complete response (CR). Among 1597 patients treated with HiDAC-based induction from 1995 to 2009, 285 were refractory to 1 cycle. Median age was 59 years (range, 18-85 years). Induction regimens included HiDAC with anthracyclines (n = 181; 64%) or HiDAC with nonanthracycline chemotherapy (n = 104; 36%). Refractory patients were older (median age, 59 vs 56 years; P < .001), more likely with unfavorable cytogenetics (P < .001) and antecedent hematologic disorder (P < .001), and had a higher presentation white blood cell count (P = .04), but not a higher incidence of FLT3 mutations (P = .85), than those achieving CR. Forty-three patients (22%) responded to salvage (35 CR and 8 CR without platelet recovery). With a median follow-up of 72 months (range, 27-118 months) in responders, 11 are alive. Nineteen patients (7%) were alive and in CR for at least 6 months, including 9 who underwent allogeneic stem cell transplantation. On multivariate analysis, severe thrombocytopenia, leukocytosis, increasing marrow blast percentage, unfavorable cytogenetics, and salvage not including allogeneic stem cell transplantation were associated with a worse survival. Alternative strategies are needed for these patients.


Using GPUs to accelerate computational diffusion MRI: From microstructure estimation to tractography and connectomes.
The great potential of computational diffusion MRI (dMRI) relies on indirect inference of tissue microstructure and brain connections, since modelling and tractography frameworks map diffusion measurements to neuroanatomical features. This mapping however can be computationally highly expensive, particularly given the trend of increasing dataset sizes and the complexity in biophysical modelling. Limitations on computing resources can restrict data exploration and methodology development. A step forward is to take advantage of the computational power offered by recent parallel computing architectures, especially Graphics Processing Units (GPUs). GPUs are massive parallel processors that offer trillions of floating point operations per second, and have made possible the solution of computationally-intensive scientific problems that were intractable before. However, they are not inherently suited for all problems. Here, we present two different frameworks for accelerating dMRI computations using GPUs that cover the most typical dMRI applications: a framework for performing biophysical modelling and microstructure estimation, and a second framework for performing tractography and long-range connectivity estimation. The former provides a front-end and automatically generates a GPU executable file from a user-specified biophysical model, allowing accelerated non-linear model fitting in both deterministic and stochastic ways (Bayesian inference). The latter performs probabilistic tractography, can generate whole-brain connectomes and supports new functionality for imposing anatomical constraints, such as inherent consideration of surface meshes (GIFTI files) along with volumetric images. We validate the frameworks against well-established CPU-based implementations and we show that despite the very different challenges for parallelising these problems, a single GPU achieves better performance than 200 CPU cores thanks to our parallel designs.


Structural classification of neutralizing antibodies against the SARS-CoV-2 spike receptor-binding domain suggests vaccine and therapeutic strategies.
The COVID-19 pandemic presents an urgent health crisis. Human neutralizing antibodies (hNAbs) that target the host ACE2 receptor-binding domain (RBD) of the SARS-CoV-2 spike1-5 show therapeutic promise and are being evaluated clincally6-8. To determine structural correlates of SARS-CoV-2 neutralization, we solved 8 new structures of distinct COVID-19 hNAbs5 in complex with SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed classification into categories: (1) VH3-53 hNAbs with short CDRH3s that block ACE2 and bind only to "up" RBDs, (2) ACE2-blocking hNAbs that bind both "up" and "down" RBDs and can contact adjacent RBDs, (3) hNAbs that bind outside the ACE2 site and recognize "up" and "down" RBDs, and (4) Previously-described antibodies that do not block ACE2 and bind only "up" RBDs9. Class 2 comprised four hNAbs whose epitopes bridged RBDs, including a VH3-53 hNAb that used a long CDRH3 with a hydrophobic tip to bridge between adjacent "down" RBDs, thereby locking spike into a closed conformation. Epitope/paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally-occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects, suggesting combinations for clinical use, and providing insight into immune responses against SARS-CoV-2.


Interdevice variability in percent fat estimates using the BOD POD.
To evaluate interdevice reliability in body density (Db) and percent body fat (%BF) using air-displacement plethysmography, the BOD POD (BP) body composition system. Duplicate body composition tests were performed in immediate succession on 50 adults (26 M, 24 F; 21-53 y) using two BP units located in the same body composition laboratory. Mean Db and %BF between BP1 and BP2 did not differ significantly for men (DeltaDb = 0.0003+/-0.0008 g/ml, P = 0.632; Delta%BF = 0.1+/-1.3, P = 0.665), while for women, there were small but significant differences in Db and %BF between BP1 and BP2 (DeltaDb = 0.0018+/-0.0003 g/ml, P = 0.001; Delta%BF = 0.8+/-1.1, P = 0.001). The regression between %BF by BP1 and BP2 did not deviate significantly from the line of identity for both men and women (R2 = 0.95, standard error of estimate (s.e.e.) = 1.23 %BF for men; R2 = 0.97, s.e.e = 1.13 %BF for women). Individual variations in %BF estimates between the two BP units were within acceptable ranges (95% limits of agreement = -2.5-2.7 %BF for men; -1.4-3.0 %BF for women), and there was no trend in individual differences as %BF varied (r = -0.19, P = 0.359 for men; r = 0.09, P = 0.677 for women). Other subject characteristics, including age, body mass, height, and body mass index, did not significantly contribute to the differences in %BF estimates by the two BP units. No clinically significant differences in Db and %BF estimates exist between the BP units, and the interdevice variability of the BP has minimal impact on %BF estimates. Further, test-to-test reliability between BP units appears to be as good as within one unit.


Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial.
IMPORTANCE We developed a novel strategy for treatment of Leber hereditary optic neuropathy (LHON) caused by a mutation in the nicotinamide adenine dinucleotide dehydrogenase subunit IV (ND4) mitochondrial gene. OBJECTIVE To demonstrate the safety and effects of the gene therapy vector to be used in a proposed gene therapy clinical trial. DESIGN AND SETTING In a series of laboratory experiments, we modified the mitochondrial ND4 subunit of complex I in the nuclear genetic code for import into mitochondria. The protein was targeted into the organelle by agency of a targeting sequence (allotopic expression). The gene was packaged into adeno-associated viral vectors and then vitreally injected into rodent, nonhuman primate, and ex vivo human eyes that underwent testing for expression and integration by immunohistochemical analysis and blue native polyacrylamide gel electrophoresis. During serial follow-up, the animal eyes underwent fundus photography, optical coherence tomography, and multifocal or pattern electroretinography. We tested for rescue of visual loss in rodent eyes also injected with a mutant G11778A ND4 homologue responsible for most cases of LHON. EXPOSURE Ocular infection with recombinant adeno-associated viral vectors containing a wild-type allotopic human ND4 gene. MAIN OUTCOMES AND MEASURES Expression of human ND4 and rescue of optic neuropathy induced by mutant human ND4. RESULTS We found human ND4 expressed in almost all mouse retinal ganglion cells by 1 week after injection and ND4 integrated into the mouse complex I. In rodent eyes also injected with a mutant allotopic ND4, wild-type allotopic ND4 prevented defective adenosine triphosphate synthesis, suppressed visual loss, reduced apoptosis of retinal ganglion cells, and prevented demise of axons in the optic nerve. Injection of ND4 in the ex vivo human eye resulted in expression in most retinal ganglion cells. Primates undergoing vitreal injection with the ND4 test article and followed up for 3 months had no serious adverse reactions. CONCLUSIONS AND RELEVANCE Expression of our allotopic ND4 vector in the ex vivo human eye, safety of the test article, rescue of the LHON mouse model, and the severe irreversible loss of visual function in LHON support clinical testing with mutated G11778A mitochondrial DNA in our patients.


Applying landscape metrics to species distribution model predictions to characterize internal range structure and associated changes.
Distributional shifts in species ranges provide critical evidence of ecological responses to climate change. Assessments of climate-driven changes typically focus on broad-scale range shifts (e.g. poleward or upward), with ecological consequences at regional and local scales commonly overlooked. While these changes are informative for species presenting continuous geographic ranges, many species have discontinuous distributions-both natural (e.g. mountain or coastal species) or human-induced (e.g. species inhabiting fragmented landscapes)-where within-range changes can be significant. Here, we use an ecosystem engineer species (Sabellaria alveolata) with a naturally fragmented distribution as a case study to assess climate-driven changes in within-range occupancy across its entire global distribution. To this end, we applied landscape ecology metrics to outputs from species distribution modelling (SDM) in a novel unified framework. SDM predicted a 27.5% overall increase in the area of potentially suitable habitat under RCP 4.5 by 2050, which taken in isolation would have led to the classification of the species as a climate change winner. SDM further revealed that the latitudinal range is predicted to shrink because of decreased habitat suitability in the equatorward part of the range, not compensated by a poleward expansion. The use of landscape ecology metrics provided additional insights by identifying regions that are predicted to become increasingly fragmented in the future, potentially increasing extirpation risk by jeopardising metapopulation dynamics. This increased range fragmentation could have dramatic consequences for ecosystem structure and functioning. Importantly, the proposed framework-which brings together SDM and landscape metrics-can be widely used to study currently overlooked climate-driven changes in species internal range structure, without requiring detailed empirical knowledge of the modelled species. This approach represents an important advancement beyond predictive envelope approaches and could reveal itself as paramount for managers whose spatial scale of action usually ranges from local to regional.


The sensitive hare: sublethal effects of predator stress on reproduction in snowshoe hares.
1. Prey responses to high predation risk can be morphological or behavioural and ultimately come at the cost of survival, growth, body condition, or reproduction. These sub-lethal predator effects have been shown to be mediated by physiological stress. We tested the hypothesis that elevated glucocorticoid concentrations directly cause a decline in reproduction in individual free-ranging female snowshoe hares, Lepus americanus. We measured the cortisol concentration from each dam (using a faecal analysis enzyme immunoassay) and her reproductive output (litter size, offspring birth mass, offspring right hind foot (RHF) length) 30 h after birth. 2. In a natural monitoring study, we monitored hares during the first and second litter from the population peak (2006) to the second year of the decline (2008). We found that faecal cortisol metabolite (FCM) concentration in dams decreased 52% from the first to the second litter. From the first to the second litter, litter size increased 122%, offspring body mass increased 130%, and offspring RHF length increased 112%. Dam FCM concentrations were inversely related to litter size (r(2) = 0.19), to offspring birth mass (r(2) = 0.32), and to offspring RHF length (r(2) = 0.64). 3. In an experimental manipulation, we assigned wild-caught, pregnant hares to a control and a stressed group and held them in pens. Hares in the stressed group were exposed to a dog 1-2 min every other day before parturition to simulate high predation risk. At parturition, unsuccessful-stressed dams (those that failed to give birth to live young) and stressed dams had 837% and 214%, respectively, higher FCM concentrations than control dams. Of those females that gave birth, litter size was similar between control and stressed dams. However, offspring from stressed dams were 37% lighter and 16% smaller than offspring from control dams. Increasing FCM concentration in dams caused the decline of offspring body mass (r(2) = 0.57) and RHF (r(2) = 0.52). 4. This is the first study in a free-ranging population of mammals to show that elevated, predator-induced, glucocorticoid concentrations in individual dams caused a decline in their reproductive output measured both by number and quality of offspring. Thus, we provide evidence that any stressor, not just predation, which increases glucocorticoid concentrations will result in a decrease in reproductive output.


Genome bioinformatic analysis of nonsynonymous SNPs.
Genome-wide association studies of common diseases for common, low penetrance causal variants are underway. A proportion of these will alter protein sequences, the most common of which is the non-synonymous single nucleotide polymorphism (nsSNP). It would be an advantage if the functional effects of an nsSNP on protein structure and function could be predicted, both for the final identification process of a causal variant in a disease-associated chromosome region, and in further functional analyses of the nsSNP and its disease-associated protein. In the present report we have compared and contrasted structure- and sequence-based methods of prediction to over 5500 genes carrying nearly 24,000 nsSNPs, by employing an automatic comparative modelling procedure to build models for the genes. The nsSNP information came from two sources, the OMIM database which are rare (minor allele frequency, MAF, < 0.01) and are known to cause penetrant, monogenic diseases. Secondly, nsSNP information came from dbSNP125, for which the vast majority of nsSNPs, mostly MAF > 0.05, have no known link to a disease. For over 40% of the nsSNPs, structure-based methods predicted which of these sequence changes are likely to either disrupt the structure of the protein or interfere with the function or interactions of the protein. For the remaining 60%, we generated sequence-based predictions. We show that, in general, the prediction tools are able distinguish disease causing mutations from those mutations which are thought to have a neutral affect. We give examples of mutations in genes that are predicted to be deleterious and may have a role in disease. Contrary to previous reports, we also show that rare mutations are consistently predicted to be deleterious as often as commonly occurring nsSNPs.


Antimicrobial effects of calcium hydroxide, chlorhexidine, and propolis on Enterococcus faecalis and Candida albicans.
To evaluate the efficacy of calcium hydroxide (Ca[OH]2 ), 2% chlorhexidine (CHX) gel, and propolis against both Enterococcus faecalis (E. faecalis) and Candida albicans (C. albicans) using infected dentine models at two different depths (100 and 200 μm) after 14 days of application. A total of 120 roots of extracted single-rooted human teeth were chemo-mechanically prepared and sterilized. Sixty roots were infected with E. faecalis, and the remaining 60 with C. albicans. Each group was divided into four subgroups (n = 15) to apply intracanal medicaments, namely saline solution (negative control), Ca(OH)2 , CHX, and propolis during the 14 days. Dentine shavings were collected and cultivated. Colony-forming units (c.f.u.) were registered. Statistical analysis was done using the Kruskal-Wallis test, followed by Dunn's/Bonferroni multiple comparison test (P < 0.05). All experimental agents significantly reduced E. faecalis c.f.u. There was no significant difference between CHX and propolis reducing E. faecalis c.f.u. at 100 and 200 μm. Only CHX had a statistically-significant antifungal efficacy in the C. albicans group at the two depths assessed. CHX was the most potent medicament against both E. faecalis and C. albicans, and Ca(OH)2 was the least. Both CHX and propolis were the most effective against E. faecalis, whereas only CHX had the highest antifungal activity on C. albicans in dentine of extracted teeth.


A review of the mechanisms by which attentional feedback shapes visual selectivity.
The glut of information available for the brain to process at any given moment necessitates an efficient attentional system that can 'pick and choose' what information receives prioritized processing. A growing body of work, spanning numerous methodologies and species, reveals that one powerful way in which attending to an item separates the wheat from the chaff is by altering a basic response property in the brain: neuronal selectivity. Selectivity is a cornerstone response property, largely dictating our ability to represent and interact with the environment. Although it is likely that selectivity is altered throughout many brain areas, here we focus on how directing attention to an item affects selectivity in the visual system, where this response property is generally more well characterized. First, we review the neural architecture supporting selectivity, and then discuss the various changes that could occur in selectivity for an attended item. In a survey of the literature, spanning neurophysiology, neuroimaging and psychophysics, we reveal that there is general convergence regarding the manner with which selectivity is shaped by attentional feedback. In a nutshell, the literature suggests that the type of changes in selectivity that manifest appears to depend on the type of attention being deployed: whereas directing spatial attention towards an item only alters spatial selectivity, directing feature-based attention can alter the selectivity of attended features.


Evaluation of Hand-to-Hand Bioelectrical Impedance Analysis for Estimating Percent Body Fat in Young Adults.
Purposes were to (a) to examine the validity and precision of a hand-to-hand bioelectrical impedance analyzer (HBIA) and (b) to determine the effect of an acute sub-maximal aerobic exercise bout on HBIA percent body fat (%BF) measures. Forty-one young adults (21 women; 20 men) visited the laboratory for body composition assessment on two separate occasions. During the control session, %BF was assessed by HBIA twice, before and immediately after 30 min of rest, and once by air-displacement plethysmography (ADP), using the BOD POD, which was considered the criterion method for comparison. During the exercise session, HBIA %BF measurements were determined prior-to and immediately after 30 minutes of moderate-intensity treadmill exercise. HBIA significantly underestimated %BF in the total sample (mean difference (MD) = 1.4 ± 4.3%) and, when examined by gender, in the women (MD = 2.4 ± 4.1%). The standard errors of estimate (range 4.1-4.3%) also exceeded the recommended range for accuracy (<3.5%). Following exercise, there was minimal, but statistically significant reduction in HBIA-measured %BF pre- to post-exercise for the total sample (19.6 ± 6.0 vs. 19.3 ± 6.0%; p = 0.011). HBIA underestimated %BF when compared to ADP and the individual prediction error exceeded current recommendations when assessing young adults. In addition, performing sub-maximal aerobic exercise prior to the assessment decreased the %BF estimate. When one factors the exercise-induced alterations with the currently observed tendency for HBIA to underestimate %BF, it is apparent that exercise may further reduce the accuracy of this method.


Incidence of chronic groin pain following open mesh inguinal hernia repair, and effect of elective division of the ilioinguinal nerve: meta-analysis of randomized controlled trials.
Chronic post-operative groin pain is a substantial complication following open mesh inguinal hernia repair. The exact cause of this pain is still unclear, but entrapment or trauma of the ilioinguinal nerve may have a role to play. Elective division of this nerve during hernia repair has been proposed in an attempt to reduce the incidence of chronic groin pain. We performed a meta-analysis of nine randomized controlled trials comparing preservation versus elective division of the ilioinguinal nerve during this operation. A substantial proportion of patients having open mesh inguinal hernia repair experience chronic groin pain when the ilioinguinal nerve is preserved (estimated rate of 9.4% at 6 months and 4.8% at 1 year). Elective division of the nerve resulted in a significant reduction of groin pain at 6-months post-surgery (RR 0.47, p = 0.02), including moderate/severe pain (RR 0.57, p = 0.01). However, division of the nerve also resulted in an increase of subjective groin numbness at this time point (RR 1.55, p = 0.06). At 12-month post-surgery, the beneficial effect of nerve division on chronic pain was reduced, with no significant difference in the rates of overall groin pain (RR 0.69, p = 0.38), or of moderate-to-severe groin pain (RR 0.99, p = 0.98) between the two groups. The prevalence of groin numbness was also similar between the two groups at 12-month post-surgery (RR 0.79, p = 0.48). Routine elective division of the ilioinguinal nerve during open mesh inguinal hernia repair does not significantly reduce chronic groin pain beyond 6 months, and may result in increased rates of groin numbness, especially in the first 6-months post-surgery.


Blood platelet formation in vitro. The role of the cytoskeleton in megakaryocyte fragmentation.
We have developed a unique in vitro model that promotes differentiation of megakaryocytes into platelets. When megakaryocytes isolated from guinea pig bone marrow were cultured on hydrated rat tail collagen gels, cells spontaneously formed elongated, beaded processes that fragmented to yield cytoplasmic pieces with the same size and internal composition as individual platelets. Addition of nocodazole at the initiation of cultures blocked process formation, while addition of nocodazole to cells with previously established processes resulted in their retraction. The addition of taxol to cultures resulted in abnormally thick processes that were tightly adherent to the underlying substratum, and did not bead or fragment. Cytochalasin D accelerated process formation and fragmentation of megakaryocytes cultured on collagen gels by twofold. On the basis of these results, we propose a model for platelet formation in culture that involves the following steps: adherence of megakaryocytes to the underlying extracellular matrix; dilation of the demarcation membrane system and breakdown of the actin-rich peripheral zone; microtubule-based extension of pseudopodia, which are no longer adherent to the substratum; and fragmentation into platelets by the coalescence and fusion of demarcation membrane vesicles with the plasma membrane. We feel that this distinctive culture system closely approximates thrombocytopoiesis in vivo, thus allowing detailed elucidation of this important process.


Health behaviors of native Hawaiian and Pacific Islander adults in California.
Smoking, diet and physical activity are associated with chronic diseases, but representative prevalence data on these behaviors for Native Hawaiian and Pacific Islander (NHPI) adults are scarce. Data from the 2005 California Health Interview Survey were analyzed for self-identified NHPI and non-Hispanic white (NHW) adults. Ethnic and NHPI gender differences were examined for socio-demographic variables, obesity and health behaviors. Compared to NHW, NHPI displayed higher prevalence of obesity (p<0.001), smoking (p<0.05) and consumption of unhealthy foods and beverages (p<0.05). NHPI males were more likely than females to smoke (p<0.001). NHPI adults appear to be at higher risk for chronic disease than NHW due to obesity, smoking and intake of unhealthy foods and beverages. Culturally-specific health promotion interventions are needed to reduce risks among the underrepresented NHPI population.


In vitro fermentation of raffinose by the human gut bacteria.
Raffinose has become a major focus of research interest and recent studies have shown that besides beneficial bifidobacteria and lactobacilli, Escherichia coli, Enterococcus faecium and Streptococcus pneumoniae can also utilize raffinose and raffinose might lead to flatulence in some hosts. Therefore, it is required to find out the raffinose-metabolizing bacteria in the gut and the bacteria responsible for the flatulence. The BLASTP search results showed that the homologous proteins of glycosidases related to raffinose utilization are widely distributed in 196 of the 528 gut bacterial strains. Fifty-nine bacterial strains belonging to nine species of five genera were isolated from human feces and were found to be capable of utilizing raffinose; of these species, Enterococcus avium and Streptococcus salivarius were reported for the first time. High-performance liquid chromatography (HPLC) analysis of the supernatants of the nine species revealed that the bacteria could utilize raffinose in different manners. Glucose and melibiose were detected in the supernatants of Enterococcus avium E5 and Streptococcus salivarius B5, respectively. However, no resulting saccharides of raffinose degradation were detected in the supernatants of other seven strains, indicating that they had different raffinose utilization types from Enterococcus avium E5 and Streptococcus salivarius B5. Gas was produced with raffinose utilization by Escherichia coli, Enterococcus faecium, Streptococcus macedonicus, Streptococcus pasteurianus and Enterococcus avium. Thus, more attention should be paid to the raffinose-utilizing bacteria besides bifidobacteria and further studies are required to reveal the mechanisms of raffinose utilization to clarify the relationship between raffinose and gut bacteria.


Sterility and microbiological assessment of reused single-use cardiac electrophysiology catheters.
To assess the performance and limitations of a reprocessing protocol for nonlumen electrophysiology catheters by testing the sterility of reprocessed devices and defining the maximum number of reprocessing cycles sustainable by the device in hygienically safe conditions. Simulated use, reprocessing, and testing of the catheters. Microbiology and virology department of a public health diagnostic laboratory. Seventy-three catheters were collected after clinical use on patients. The first group of devices was tested for sterility after 1 cycle of reprocessing. By the repetition of simulated use (blood inoculated with bacteria) and reprocessing (decontamination, cleaning, and hydrogen peroxide gas plasma sterilization), we obtained 39 sample devices reprocessed 2 times, 26 reprocessed 3 times, 28 reprocessed 4 times, 36 reprocessed 5 times, and 22 reprocessed 6 times. Devices were cultured for 28 days in trypticase soy broth. We tested 208 catheters with 6 cycles of reprocessing and 4 inoculated bacteria species. No devices tested positive for the inoculated strains until the fourth cycle of reprocessing. One of 35 catheters showed the growth of the inoculated strain Bacillus subtilis after 5 cycles of reprocessing, and 1 of 22 catheters showed growth of this organism 6 cycles. After the second reprocessing, 7 of 36 devices showed growth of gram-negative bacteria other than the strain inoculated. Reprocessing according to the reprocessing protocol was insufficient to guarantee device sterility after 5 reuses. Cleaning with enzymatic solution revealed good cleaning properties with efficient bioburden reduction. Storage intervals of longer than 24 hours during reprocessing should be avoided to limit contamination or bacterial overgrowth. Technical considerations suggest the introduction of reprocessing procedures only in hospitals with considerable workloads.


The MtrAB two-component system controls antibiotic production in Streptomyces coelicolor A3(2).
MtrAB is a highly conserved two-component system implicated in the regulation of cell division in the Actinobacteria. It coordinates DNA replication with cell division in the unicellular Mycobacterium tuberculosis and links antibiotic production to sporulation in the filamentous Streptomyces venezuelae. Chloramphenicol biosynthesis is directly regulated by MtrA in S. venezuelae and deletion of mtrB constitutively activates MtrA and results in constitutive over-production of chloramphenicol. Here we report that in Streptomyces coelicolor, MtrA binds to sites upstream of developmental genes and the genes encoding ActII-1, ActII-4 and RedZ, which are cluster-situated regulators of the antibiotics actinorhodin (Act) and undecylprodigiosin (Red). Consistent with this, deletion of mtrB switches on the production of Act, Red and streptorubin B, a product of the Red pathway. Thus, we propose that MtrA is a key regulator that links antibiotic production to development and can be used to upregulate antibiotic production in distantly related streptomycetes.


Perception of gastroesophageal reflux disease in urban population in Pakistan.
To determine the frequency and health care seeking behavior of patients with gastroesophageal reflux symptoms using American College of Gastroenterology (ACG) questionnaire for gastroesophageal reflux disease (GERD). Cross-sectional study. Section of Gastroenterology, Department of Medicine, The Aga Khan University Hospital, Karachi, from April 2002 to November 2003. A total of 1267 persons above 15 years of age were interviewed using a modified questionnaire for GERD from the American College of Gastroenterology (ACG), which previously validated in our section as a screening tool in an urban population in Pakistan. Nine hundred and sixty-three individuals responded to the questionnaire. Mean age of the surveyed sample was 24+/-9.3 years. Using the ACG criteria, the overall frequency of gastroesophageal reflux symptoms was 24% (228/963) with 58% (133/228) males and 42% (95/228) females. Symptoms experienced frequently were reflux from the stomach, 58% (133/228), with a bitter, acid taste in the mouth. Seventy-four percent (169/228) experienced this postprandially. Symptoms were associated with spicy fried food in 71% (161/228). Sixty-seven percent (152/228) did not seek health care advice, 32% (74/228) practiced self-medications and 33% (76/228) consulted a physician. Gastroesophageal reflux is a common problem in the urban population of Pakistan.


Regeneration of mammalian cochlear and vestibular hair cells through Hes1/Hes5 modulation with siRNA.
The Notch pathway is a cell signaling pathway determining initial specification and subsequent cell fate in the inner ear. Previous studies have suggested that new hair cells (HCs) can be regenerated in the inner ear by manipulating the Notch pathway. In the present study, delivery of siRNA to Hes1 and Hes5 using a transfection reagent or siRNA to Hes1 encapsulated within poly(lactide-co-glycolide acid) (PLGA) nanoparticles increased HC numbers in non-toxin treated organotypic cultures of cochleae and maculae of postnatal day 3 mouse pups. An increase in HCs was also observed in cultured cochleae and maculae of mouse pups pre-conditioned with a HC toxin (4-hydroxy-2-nonenal or neomycin) and then treated with the various siRNA formulations. Treating cochleae with siRNA to Hes1 associated with a transfection reagent or siRNA to Hes1 delivered by PLGA nanoparticles decreased Hes1 mRNA and up-regulated Atoh1 mRNA expression allowing supporting cells (SCs) to acquire a HC fate. Experiments using cochleae and maculae of p27(kip1)/-GFP transgenic mouse pups demonstrated that newly generated HCs trans-differentiated from SCs. Furthermore, PLGA nanoparticles are non-toxic to inner ear tissue, readily taken up by cells within the tissue of interest, and present a synthetic delivery system that is a safe alternative to viral vectors. These results indicate that when delivered using a suitable vehicle, Hes siRNAs are potential therapeutic molecules that may have the capacity to regenerate new HCs in the inner ear and possibly restore human hearing and balance function.


A narrative review of the success of intramuscular gluteal injections and its impact in psychiatry.
There are 12 billion injections given worldwide every year. For many injections, the intramuscular route is favoured over the subcutaneous route due to the increased vascularity of muscle tissue and the corresponding increase in the bioavailability of drugs when administered intramuscularly. This paper is a review of the variables that affect the success of intramuscular injections and the implications that these success rates have in psychiatry and general medicine. Studies have shown that the success rates of intended intramuscular injections vary between 32 and 52%, with the rest potentially resulting in inadvertent subcutaneous drug deposition. These rates are found to be even lower for certain at-risk populations, such as obese patients and those on antipsychotic medications. The variables associated with an increased risk of injection failure include female sex, obesity, site of injection, and subcutaneous fat depth. New guidelines and methods are needed in order to address this challenge and ensure that patients receive optimum care. Looking forward, the best way to improve the delivery of intramuscular injections worldwide is to develop uniform algorithms or innovative medical devices to confirm or guarantee successful delivery at the bedside.


Looking for intoolligence: A unified framework for the cognitive study of human tool use and technology.
Humans have considerably modified their environment by making and building a number of tools, technologies, and constructions. This unique ability compared to other animals is the focus of researchers in different fields of psychology. However, there is confusion about the definitions proposed, generating difficulties in making connections between those different fields. This article presents the first unified framework (i.e., intoolligence) aiming to overcome these issues by focusing on the cognitive processes involved in the different forms taken by human tool use and technology, rather than on the overt behavior. To lay the foundation for intoolligence, we first address a series of epistemological misconceptions, which are the root cause for the current confusion. Particularly, we discuss the limitations of the widespread idea that tool use relies on specific cognitive skills, centered on the manipulative aspect of tool use. We develop, based on this analysis, details concerning our framework, which is based on the key principle that making and using are 2 independent cognitive steps. This distinction allows us to redefine tool use by breaking it down into 3 modes: assistive tool use, arbitrary tool use, and free tool use. This article opens a new chapter on the topic of human tool use and technology. (PsycINFO Database Record


The impact of climate change on the world's marine ecosystems.
Marine ecosystems are centrally important to the biology of the planet, yet a comprehensive understanding of how anthropogenic climate change is affecting them has been poorly developed. Recent studies indicate that rapidly rising greenhouse gas concentrations are driving ocean systems toward conditions not seen for millions of years, with an associated risk of fundamental and irreversible ecological transformation. The impacts of anthropogenic climate change so far include decreased ocean productivity, altered food web dynamics, reduced abundance of habitat-forming species, shifting species distributions, and a greater incidence of disease. Although there is considerable uncertainty about the spatial and temporal details, climate change is clearly and fundamentally altering ocean ecosystems. Further change will continue to create enormous challenges and costs for societies worldwide, particularly those in developing countries.


Occupational mobility and automation: a data-driven network model.
The potential impact of automation on the labour market is a topic that has generated significant interest and concern amongst scholars, policymakers and the broader public. A number of studies have estimated occupation-specific risk profiles by examining how suitable associated skills and tasks are for automation. However, little work has sought to take a more holistic view on the process of labour reallocation and how employment prospects are impacted as displaced workers transition into new jobs. In this article, we develop a data-driven model to analyse how workers move through an empirically derived occupational mobility network in response to automation scenarios. At a macro level, our model reproduces the Beveridge curve, a key stylized fact in the labour market. At a micro level, our model provides occupation-specific estimates of changes in short and long-term unemployment corresponding to specific automation shocks. We find that the network structure plays an important role in determining unemployment levels, with occupations in particular areas of the network having few job transition opportunities. In an automation scenario where low wage occupations are more likely to be automated than high wage occupations, the network effects are also more likely to increase the long-term unemployment of low-wage occupations.


Tuberculosis surveillance in immigrants to Manitoba.
Despite a decrease in the incidence of tuberculosis in Canada over the last decade, the proportion of cases in people not born in Canada has increased. To determine the prevalence of active tuberculosis at the first surveillance clinic visit and the incidence of the disease over a 2-year to 6-year follow-up period, we reviewed the records of all 523 immigrants admitted to Manitoba between 1981 and 1985 who were placed under surveillance. Of the 523, 429 (82%) were seen at least once in the clinic. Among the 429, active tuberculosis was diagnosed at the first visit in 12 (3%) and during the follow-up period in 7 (2%). The relative risk of tuberculosis was 4.5 times higher for immigrants under surveillance than for those not under surveillance. Of the 483 immigrants who were to be seen in Winnipeg 232 (48%) were noncompliant: 94 were not seen at any time, and 138 did not attend for the full follow-up period. Active disease was not reported to have developed in any of the noncompliant subjects. Noncompliers were significantly older than compliers (p less than 0.005), and variations in compliance were noted according to region of origin. Further attempts to improve compliance with surveillance without resorting to punitive measures are indicated.


Polyandrous females found fitter populations.
Multiple mating by females (polyandry) requires an evolutionary explanation, because it carries fitness costs in many species. When mated females disperse alone to a new habitat, their offspring may have no option but to mate with their siblings and incur inbreeding depression. However, some of the offspring of polyandrous females may only be half siblings, reducing inbreeding depression when isolated groups of siblings only have each other as mates. We investigated this putative benefit of polyandry over monandry by initiating multiple genetically isolated populations of Callosobruchus maculatus beetles, each founded by a single female, who received a complete ejaculate from either one or two males. The early generations had comparable fitness, but the F4 and F5 descendants of doubly inseminated females were more numerous and had higher egg-to-adult survival than the descendants of singly inseminated females. This fitness benefit was of similar magnitude whether beetles were reared on their standard food plant, or on a less favourable food source. Our results suggest that polyandrous females produce fitter descendants in inbred founder populations and therefore that polyandry may affect movement ecology and invasion biology.


Cilostazol attenuates murine hepatic ischemia and reperfusion injury via heme oxygenase-dependent activation of mitochondrial biogenesis.
Hepatic ischemia-reperfusion (I/R) can cause hepatocellular injury associated with the inflammatory response and mitochondrial dysfunction. We studied the protective effects of the phosphodiesterase inhibitor cilostazol in hepatic I/R and the roles of mitochondria and the Nrf2/heme oxygenase-1 (HO-1) system. Wild-type, Hmox1(-/-), or Nrf2(-/-) mice were subjected to hepatic I/R in the absence or presence of cilostazol followed by measurements of liver injury. Primary hepatocytes were subjected to cilostazol with the HO-1 inhibitor ZnPP, or Nrf2-specific siRNA, followed by assessment of mitochondrial biogenesis. Preconditioning with cilostazol prior to hepatic I/R protected against hepatocellular injury and mitochondrial dysfunction. Cilostazol reduced the serum levels of alanine aminotransferase, TNF-α, and liver myeloperoxidase content relative to control I/R-treated mice. In primary hepatocytes, cilostazol increased the expression of HO-1, and markers of mitochondrial biogenesis, PGC-1α, NRF-1, and TFAM, induced the mitochondrial proteins COX III and COX IV and increased mtDNA and mitochondria content. Pretreatment of primary hepatocytes with ZnPP inhibited cilostazol-induced PGC-1α, NRF-1, and TFAM mRNA expression and reduced mtDNA and mitochondria content. Genetic silencing of Nrf2 prevented the induction of HO-1 and mitochondrial biogenesis by cilostazol in HepG2 cells. Cilostazol induced hepatic HO-1 production and mitochondrial biogenesis in wild-type mice, but not in Hmox1(-/-) or Nrf2(-/-) mice, and failed to protect against liver injury in Nrf2(-/-) mice. These results suggest that I/R injury can impair hepatic mitochondrial function, which can be reversed by cilostazol treatment. These results also suggest that cilostazol-induced mitochondrial biogenesis was mediated by an Nrf-2- and HO-1-dependent pathway.


Applying single cell multi-omic analyses to understand treatment resistance in pediatric high grade glioma.
Despite improvements in cancer patient outcomes seen in the past decade, tumor resistance to therapy remains a major impediment to achieving durable clinical responses. Intratumoral heterogeneity related to genetic, epigenetic, transcriptomic, proteomic, and metabolic differences between individual cancer cells has emerged as a driver of therapeutic resistance. This cell to cell heterogeneity can be assessed using single cell profiling technologies that enable the identification of tumor cell clones that exhibit similar defining features like specific mutations or patterns of DNA methylation. Single cell profiling of tumors before and after treatment can generate new insights into the cancer cell characteristics that confer therapeutic resistance by identifying intrinsically resistant sub-populations that survive treatment and by describing new cellular features that emerge post-treatment due to tumor cell evolution. Integrative, single cell analytical approaches have already proven advantageous in studies characterizing treatment-resistant clones in cancers where pre- and post-treatment patient samples are readily available, such as leukemia. In contrast, little is known about other cancer subtypes like pediatric high grade glioma, a class of heterogeneous, malignant brain tumors in children that rapidly develop resistance to multiple therapeutic modalities, including chemotherapy, immunotherapy, and radiation. Leveraging single cell multi-omic technologies to analyze naïve and therapy-resistant glioma may lead to the discovery of novel strategies to overcome treatment resistance in brain tumors with dismal clinical outcomes. In this review, we explore the potential for single cell multi-omic analyses to reveal mechanisms of glioma resistance to therapy and discuss opportunities to apply these approaches to improve long-term therapeutic response in pediatric high grade glioma and other brain tumors with limited treatment options.