Voluntary counseling and testing (VCT) for changing HIV-related risk behavior in developing countries.
Voluntary counseling and testing (VCT) continues to play a critical role in HIV prevention, care and treatment. In recent years, different modalities of VCT have been implemented, including clinic-, mobile- and home-based testing and counseling. This review assesses the effects of all VCT types on HIV-related risk behaviors in low- and middle-income countries. The primary objective of this review is to systematically review the literature examining the efficacy of VCT in changing HIV-related risk behaviors in developing countries across various populations. Five electronic databases - PubMed, Excerpta Medica Database (EMBASE), PsycINFO, Sociological Abstracts, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) - were searched using predetermined key words and phrases. Hand-searching was conducted in four key journals including AIDS, AIDS and Behavior, AIDS Education and Prevention, and AIDS Care; the tables of contents of these four journals during the included time period were individually screened for relevant articles. The reference lists of all articles included in the review were screened to identify any additional studies; this process was iterated until no additional articles were found. To be included in the review, eligible studies had to meet the following inclusion criteria: 1) Take place in a low- or middle-income country as defined by the World Bank, 2) Published in a peer-reviewed journal between January 1, 1990 and July 6, 2010, 3) Involve client-initiated VCT, including pre-test counseling, HIV-testing, and post-test counseling, and 4) Use a pre/post or multi-arm design that compares individuals before and after receiving VCT or individuals who received VCT to those who did not, and 5) Report results pertaining to behavioral, psychological, biological, or social HIV-related outcomes. All citations were initially screened and all relevant citations were independently screened by two reviewers to assess eligibility. For all included studies data were extracted by two team members working independently using a standardized form. Differences were resolved through consensus or discussion with the study coordinator when necessary. Study rigor was assessed using an eight point quality score and through the Cochrane Collaboration's Risk of Bias Assessment Tool. Outcomes comparable across studies, including condom use and number of sex partners, were meta-analyzed using random effects models. With respect to both meta-analyses, data were included from multi-arm studies and from pre/post studies if adequate data were provided. Other outcomes, including HIV-incidence, STI incidence/prevalence, and positive and negative life events were synthesized qualitatively. For meta-analysis, all outcomes were converted to the standard metric of the odds ratio. If an outcome could not be converted to an odds ratio, the study was excluded from analysis. An initial search yielded 2808 citations. After excluding studies failing to meet the inclusion criteria, 19 were deemed eligible for inclusion. Of these studies, two presented duplicate data and were removed. The remaining 17 studies were included in the qualitative synthesis and 8 studies were meta-analyzed. Twelve studies offered clinic-based VCT, 3 were employment-based, 1 involved mobile VCT, and 1 provided home-based VCT. In meta-analysis, the odds of reporting increased number of sexual partners were reduced when comparing participants who received VCT to those who did not, unadjusted random effects pooled OR= 0.69 (95% CI: 0.53-0.90, p=0.007). When stratified by serostatus, these results only remained significant for those who tested HIV-positive. There was an insignificant increase in the odds of condom use/protected sex among participants who received VCT compared to those who did not, unadjusted random effects pooled OR=1.39 (95% CI: 0.97-1.99, p=0.076). When stratified by HIV status, this effect became significant among HIV-positive participants, random effects pooled OR= 3.24 (95% CI: 2.29-4.58, p<0.001). These findings add to growing evidence that VCT can change HIV-related sexual risk behaviors thereby reducing HIV-related risk, and confirming its importance as an HIV prevention strategy. To maximize the effectiveness of VCT, more studies should be conducted to understand which modalities and counseling strategies produce significant reductions in risky behaviors and lead to the greatest uptake of VCT.


Athletic ability assessment: a movement assessment protocol for athletes.
Movement ability is an often-overlooked component of sports science and sports medicine research and needs to be considered alongside the appraisal of physical fitness and performance characteristics. To achieve this, a standardised assessment tool is required. The purpose of this paper is to introduce a new method for assessing movement ability and present results for intra- and inter-rater reliability. National level female football players (n=17) were assessed using a novel movement assessment tool, the Athletic Ability Assessment (AAA). Athletes were assessed according to the scoring criteria by the primary researcher in real-time and via video on two separate occasions to estimate intra-tester reliability. Inter-tester reliability was estimated using the difference between five other testers' video-based scores. The intra-tester minimal detectable change (MDC) for the composite AAA score was 2.9 points (90% confidence limits; 2.3 - 4.2 points) (2.5%; 2.0 - 3.6%) with an intraclass correlation coefficient (ICC) of 0.97 (0.92 - 0.99). Inter-tester MDC for the composite AAA score was 2.8 points (2.5 - 3.3 points) (2.4%; 2.1 - 2.8%) with an ICC 0.96 (0.94 - 0.98) Individual exercise scores for the intra- and inter-tester show a similar range MDC of between 0.4 - 1.1 points and kappa statistic level of agreement between 0.32 -0.77. Results of the reliability analysis suggest high levels of agreement between scorers for total scores and provide reference values for minimal detectable changes using the AAA. The aim of the AAA is to become a reliable movement assessment protocol that addresses specific sporting populations. The reliability of AAA scoring established in this study is the first step in supporting the utilization of the AAA in future research. 2b.


[Study on the epidemic development of COVID-19 in Hubei province by a modified SEIR model].
To establish a SEIR epidemic dynamics model that can be used to evaluate the COVID-19 epidemic, and to predict and evaluate the COVID-19 epidemic in Hubei province using the proposed model. COVID-19 SEIR transmission dynamics model was established, which took transmission ability in latent period and tracking quarantine interventions into consideration. Based on the epidemic data of Hubei province from January 23, 2020 to February 24, 2020, the parameters of the newly established modified SEIR model were fitted. By using Euler integral algorithm to solve the modified SEIR dynamics model, the epidemic situation in Hubei province was analyzed, and the impact of prevention and control measures such as quarantine and centralized treatment on the epidemic development was discussed. The theoretical estimation of the epidemic situation by the modified SEIR epidemic dynamics model is in good agreement with the actual situation in Hubei province. Theoretical analysis showed that prevention and control quarantine and medical follow-up quarantine played an important inhibitory effect on the outbreak of the epidemic.The centralized treatment played a key role in the rapid decline in the number of infected people. In addition, it is suggested that individuals should improve their prevention awareness and take strict self-protection measures to curb the increase in infected people. The modified SEIR model is reliable in the evaluation of COVID-19 epidemic in Hubei province, which provides a theoretical reference for the decision-making of epidemic interventions.


Gag-p6 Tsg101 binding site duplications in maternal-infant HIV infection.
Prevalence and patterns of HIV p6 duplications in HIV-1 mother-to-baby transmission are examined. Resistance genotyping was performed in a multisite U.S. study of antiretroviral resistance in vertical transmission. Sequence data were used in secondary analyses of HIV genetic variation. Two hundred sixty HIV viral RNA samples from HIV-infected pregnant women and their infants were analyzed with a commercial resistance genotyping kit. Chromatograms were examined for variability in the 3' region of gag. From 103 mother-baby sets, 190 samples gave readable p6 sequence. Of 103 mother-baby sets, 20 (19%) showed duplication of between 3 and 12 codons ending at the PTAPP motif of p6. When maternal p6 duplication was present and the p6 sequence was available from both maternal and infant isolates, all (seven of seven) infants had p6 duplications, but two cases showed discordancies between maternal and infant sequences. The prevalence of p6 duplication varied among geographical sites, ranging from 4 of 43 families (9%, Puerto Rico and New York sites) to 16 of 60 families (27%, Massachusetts, Texas, and Illinois). The presence of p6 duplication was not associated with differences in transmission, viral load, or disease progression in the infants, but showed a trend toward association with lower maternal CD4 count. Substantial p6 variation data are generated by resistance genotyping. PTAP duplication is prevalent in this group of HIV-infected women and infants. The duplication is efficiently transmitted from mother to infant, is present at variable prevalence at different geographic sites, and shows no clear association with vertical transmission risks.


A single fast radio burst localized to a massive galaxy at cosmological distance.
Fast radio bursts (FRBs) are brief radio emissions from distant astronomical sources. Some are known to repeat, but most are single bursts. Nonrepeating FRB observations have had insufficient positional accuracy to localize them to an individual host galaxy. We report the interferometric localization of the single-pulse FRB 180924 to a position 4 kiloparsecs from the center of a luminous galaxy at redshift 0.3214. The burst has not been observed to repeat. The properties of the burst and its host are markedly different from those of the only other accurately localized FRB source. The integrated electron column density along the line of sight closely matches models of the intergalactic medium, indicating that some FRBs are clean probes of the baryonic component of the cosmic web.


Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation.
The protein serine-threonine kinase Akt mediates cell survival signaling initiated by various growth-promoting factors such as insulin. Here we report that SEK1 is a target of Akt in intact cells. Insulin inhibited the anisomycin-induced stimulation of both endogenous SEK1 and its substrate c-Jun N-terminal kinase (JNK), but not that of the upstream kinase MEKK1, in 293T cells. The inhibitory action of insulin on SEK1 or JNK1 activation was prevented by the phosphatidylinositol 3-kinase inhibitor LY294002. Expression of a constitutively active form of Akt also inhibited both SEK1 and JNK1 activation, but not that of MEKK1, in transfected 293T cells. Co-immunoprecipitation analysis revealed that endogenous Akt physically interacted with endogenous SEK1 in cells and that this interaction was promoted by insulin. In vitro and in vivo (32)P labeling indicated that Akt phosphorylated SEK1 on serine 78. The SEK1 mutant SEK1(S78A) was resistant to Akt-induced inhibition. Finally, activated Akt inhibited SEK1-mediated apoptosis, and this effect of Akt was prevented by overexpression of SEK(S78A). Taken together, these results suggest that Akt suppresses stress-activated signaling by targeting SEK1.


Telecoupled impacts of livestock trade on non-communicable diseases.
Non-communicable diseases (NCDs)-chronic human health problems such as cardiovascular diseases linked to poor diets-are significant challenges for sustainable development and human health. The international livestock trade increases accessibility to cheap animal products that may expand diet-related NCDs worldwide. However, it is not well understood how the complex interconnections among livestock production, trade, and consumption affect NCD risks around the world. Our global dataset included 33 livestock products (meat, offal, and animal fats) in 156 countries from 1992 to 2011. We employed path analysis to uncover how livestock trade contributes to diet-related NCDs and identify underlying environmental and socioeconomic factors of livestock trade. Then we performed trend analyses to investigate long-term changes in livestock production and trade at a country level. We found that livestock consumption through livestock import increased diet-related NCD risks. This was especially true in developing countries, which in general were not well prepared in terms of policies for NCD risk reduction, and where there was a lack of funding to implement the policies. Population size and income level were the main factors affecting global livestock import activities. Our results suggest that new governance structures to incorporate separate international efforts, improved national policies, and bolstering individual efforts are needed to decrease NCD risks, particularly in developing countries.


Evaluation of health research: measuring costs and socioeconomic effects.
The topic of this work is health research evaluation including basic and clinical medical research, as well as healthcare research. The main objects are to explore possible approaches for valuing research in economic terms and to prepare an analytical model for evaluation of health research using the Swedish context. The study also aims to identify potential effects and their significance, and to provide a basis for discussions about the effects of research investments. The study has reviewed ten articles indicating positive effects, in the form of improved health and economic growth. The study also developed a model applied to Swedish health research. The review indicates that positive effects, in the form of improved health and economic growth, have a value that greatly exceeds the costs of the research investments. The tentative model applied to Swedish health research also indicates predominantly positive returns, but in a lower range than the review would imply. Methodological problems, however, entail major uncertainty in the cited results. Accurate determination of the economic value of research would require significantly better basic data and better knowledge of relationships between research, implementation of new knowledge, and health effects. Information in support of decisions about future allocation of research resources is preferably produced by a combination of general analyses and strategically selected case studies.


Periodontal diseases and HIV infection. A review of the literature.
There have been many references in the literature to HIV-related periodontal diseases, which although poorly substantiated, seem to have established them as part of the expected range of HIV-associated conditions. The original studies have produced conflicting reports which may stem from shortcomings in design. Consequently, the picture remains confused with respect to the classification, epidemiology, microbiology, natural history and management of HIV-related periodontal diseases. Future studies should give greater attention to sampling methods, the use of control groups and defining criteria. This will allow comparison of data between centres and facilitate study of what may be an uncommon disease.


Phase 3 Assessment of the Automated Bone Scan Index as a Prognostic Imaging Biomarker of Overall Survival in Men With Metastatic Castration-Resistant Prostate Cancer: A Secondary Analysis of a Randomized Clinical Trial.
Prostate cancer commonly metastasizes to bone, and bone metastases are associated with pathologic fractures, pain, and reduced survival. Bone disease is routinely visualized using the technetium Tc 99m (99mTc) bone scan; however, the standard interpretation of bone scan data relies on subjective manual assessment of counting metastatic lesion numbers. There is an unmet need for an objective and fully quantitative assessment of bone scan data. To clinically assess in a prospectively defined analysis plan of a clinical trial the automated Bone Scan Index (aBSI) as an independent prognostic determinant of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). This investigation was a prospectively planned analysis of the aBSI in a phase 3 multicenter randomized, double-blind, placebo-controlled clinical trial of tasquinimod (10TASQ10). Men with bone metastatic chemotherapy-naïve CRPC were recruited at 241 sites in 37 countries between March 2011 and August 2015. The statistical analysis plan to clinically evaluate the aBSI was prospectively defined and locked before unmasking of the 10TASQ10 study. The analysis of aBSI was conducted between May 25, 2016, and June 3, 2017. The associations of baseline aBSI with OS, radiographic progression-free survival (rPFS), time to symptomatic progression, and time to opiate use for cancer pain. Of the total 1245 men enrolled, 721 were evaluable for the aBSI. The mean (SD) age (available for 719 men) was 70.6 (8.0) years (age range, 47-90 years). The aBSI population was representative of the total study population based on baseline characteristics. The aBSI (median, 1.07; range, 0-32.60) was significantly associated with OS (hazard ratio [HR], 1.20; 95% CI, 1.14-1.26; P < .001). The median OS by aBSI quartile (lowest to highest) was 34.7, 27.3, 21.7, and 13.3 months, respectively. The discriminative ability of the aBSI (C index, 0.63) in prognosticating OS was significantly higher than that of the manual lesion counting (C index, 0.60) (P = .03). In a multivariable survival model, a higher aBSI remained independently associated with OS (HR, 1.06; 95% CI, 1.01-1.11; P = .03). A higher aBSI was also independently associated with time to symptomatic progression (HR, 1.18; 95% CI, 1.13-1.23; P < .001) and time to opiate use for cancer pain (HR, 1.21; 95% CI, 1.14-1.30; P < .001). To date, this investigation is the largest prospectively analyzed study to validate the aBSI as an independent prognostic imaging biomarker of survival in mCRPC. These data support the prognostic utility of the aBSI as an objective imaging biomarker in the design and eligibility of clinical trials of systemic therapies for patients with mCRPC. ClinicalTrials.gov Identifier: NCT01234311.


Numerical estimation of storage capacity in reflection-type holographic disk memory with three-dimensional speckle-shift multiplexing.
Maximum storage capacity in a reflection-type holographic memory with three-dimensional speckle shift multiplexing is investigated numerically. An explicit expression of storage capacity is derived on the basis of interpage crosstalk noise. We fabricate a simulator to evaluate reflection-type holographic data storage by calculating wave propagation, recording a hologram, and reconstruction by scalar diffraction. We calculate the properties of the resultant diffraction efficiency, that is the noise, at the first null in the speckle-shift multiplexing. Numerical results indicate that the storage capacity is proportional to the numerical aperture to the fourth power and to the volume of the recording medium and is inversely proportional to the wavelength to the third power. Achievable storage capacity is discussed.


Evaluation and management of orthostatic hypotension.
Orthostatic hypotension is defined as a decrease in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg within three minutes of standing when compared with blood pressure from the sitting or supine position. It results from an inadequate physiologic response to postural changes in blood pressure. Orthostatic hypotension may be acute or chronic, as well as symptomatic or asymptomatic. Common symptoms include dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, and headache. Less common symptoms include syncope, dyspnea, chest pain, and neck and shoulder pain. Causes include dehydration or blood loss; disorders of the neurologic, cardiovascular, or endocrine systems; and several classes of medications. Evaluation of suspected orthostatic hypotension begins by identifying reversible causes and underlying associated medical conditions. Head-up tilt-table testing can aid in confirming a diagnosis of suspected orthostatic hypotension when standard orthostatic vital signs are nondiagnostic; it also can aid in assessing treatment response in patients with an autonomic disorder. Goals of treatment involve improving hypotension without excessive supine hypertension, relieving orthostatic symptoms, and improving standing time. Treatment includes correcting reversible causes and discontinuing responsible medications, when possible. Nonpharmacologic treatment should be offered to all patients. For patients who do not respond adequately to nonpharmacologic treatment, fludrocortisone, midodrine, and pyridostigmine are pharmacologic therapies proven to be beneficial.


Evaluation of a method for enhancing interaural level differences at low frequencies.
A method (called binaural enhancement) for enhancing interaural level differences at low frequencies, based on estimates of interaural time differences, was developed and evaluated. Five conditions were compared, all using simulated hearing-aid processing: (1) Linear amplification with frequency-response shaping; (2) binaural enhancement combined with linear amplification and frequency-response shaping; (3) slow-acting four-channel amplitude compression with independent compression at the two ears (AGC4CH); (4) binaural enhancement combined with four-channel compression (BE-AGC4CH); and (5) four-channel compression but with the compression gains synchronized across ears. Ten hearing-impaired listeners were tested, and gains and compression ratios for each listener were set to match targets prescribed by the CAM2 fitting method. Stimuli were presented via headphones, using virtualization methods to simulate listening in a moderately reverberant room. The intelligibility of speech at ±60° azimuth in the presence of competing speech on the opposite side of the head at ±60° azimuth was not affected by the binaural enhancement processing. Sound localization was significantly better for condition BE-AGC4CH than for condition AGC4CH for a sentence, but not for broadband noise, lowpass noise, or lowpass amplitude-modulated noise. The results suggest that the binaural enhancement processing can improve localization for sounds with distinct envelope fluctuations.


Exercise intolerance in Kearns-Sayre syndrome.
Exercise intolerance is a common finding in mitochondrial diseases, including Kearns-Sayre syndrome (KSS), characterised by progressive external ophthalmoplegia, cardiac conduction defects and atypical pigmentary degeneration of the retina. Exercise studies were performed in a 32 year old woman with KSS who had received an atrio-ventricular sequential pacemaker because of continuing breathlessness, having presented with complete heart block requiring a fixed rate demand pacemaker 6 years earlier. Minute ventilation, oxygen consumption, and carbon dioxide production were measured at different workloads on 3 consecutive days by collecting expired air. Compared to controls, after exercise at a subanaerobic workload, heart rate and ventilation were exaggerated relative to both oxygen consumption and carbon dioxide production. The findings are consistent with the hypothesis that, in mitochondrial disorders, impaired oxidative phosphorylation leads to uncoupling of cardiac ouput and ventilation relative to muscle metabolic rate.


Genetic substructure and complex demographic history of South African Bantu speakers.
South Eastern Bantu-speaking (SEB) groups constitute more than 80% of the population in South Africa. Despite clear linguistic and geographic diversity, the genetic differences between these groups have not been systematically investigated. Based on genome-wide data of over 5000 individuals, representing eight major SEB groups, we provide strong evidence for fine-scale population structure that broadly aligns with geographic distribution and is also congruent with linguistic phylogeny (separation of Nguni, Sotho-Tswana and Tsonga speakers). Although differential Khoe-San admixture plays a key role, the structure persists after Khoe-San ancestry-masking. The timing of admixture, levels of sex-biased gene flow and population size dynamics also highlight differences in the demographic histories of individual groups. The comparisons with five Iron Age farmer genomes further support genetic continuity over ~400 years in certain regions of the country. Simulated trait genome-wide association studies further show that the observed population structure could have major implications for biomedical genomics research in South Africa.


Mitochondrial dehydrogenase activity affects adaptation of cardiac oxygen consumption to demand.
The effect of regulation of mitochondrial dehydrogenase activities on the mean response time of mitochondrial oxygen consumption, which characterizes the delay between changes in ATP hydrolysis and changes in oxygen consumption, was investigated in isolated rabbit hearts and perfused with Tyrode solution at 28 degrees C. Perfusion with ruthenium red (RR) blocks mitochondrial calcium uptake and thus decreases mitochondrial dehydrogenase activities. Perfusion with pyruvate increases pyruvate dehydrogenase activity. The mean response time was 11.8 +/- 0.7 s (means +/- SE) during control, 12.2 +/- 1.2 s during perfusion with 0.9 microgram/ml RR, and 20.7 +/- 3.4 s during perfusion with 2.1 micrograms/ml RR. Blockade with 0.9 microgram/ml RR, which is presumably partial, did not slow the response, suggesting that mitochondrial calcium uptake may not be rate limiting. Strong blockade of mitochondrial calcium uptake increases the mean response time, presumably due to decreased calcium activation of the mitochondrial dehydrogenases. Perfusion with pyruvate significantly decreased the mean response time to 10.0 +/- 1.4 s compared with 11.9 +/- 0.7 s during perfusion with glucose. This decrease with pyruvate is not compatible with a shift to regulation by high-energy phosphates but may reflect increased mitochondrial oxidative capacity caused by increased NADH levels.


Should we stop thinking about inhibition? Searching for individual and age differences in inhibition ability.
Inhibition is often conceptualized as a unitary construct reflecting the ability to ignore and suppress irrelevant information. At the same time, it has been subdivided into inhibition of prepotent responses (i.e., the ability to stop dominant responses) and resistance to distracter interference (i.e., the ability to ignore distracting information). The present study investigated the unity and diversity of inhibition as a psychometric construct, and tested the hypothesis of an inhibition deficit in older age. We measured inhibition in young and old adults with 11 established laboratory tasks: antisaccade, stop-signal, color Stroop, number Stroop, arrow flanker, letter flanker, Simon, global-local, positive and negative compatibility tasks, and n-2 repetition costs in task switching. In both age groups, the inhibition measures from individual tasks had good reliabilities, but correlated only weakly among each other. Structural equation modeling identified a 2-factor model with factors for inhibition of prepotent responses and resistance to distracter interference. Older adults scored worse in the inhibition of prepotent response, but better in the resistance to distracter interference. However, the model had low explanatory power. Together, these findings call into question inhibition as a psychometric construct and the hypothesis of an inhibition deficit in older age. (PsycINFO Database Record


Tuning symmetry breaking charge separation in perylene bichromophores by conformational control.
Understanding structure-property relationships in multichromophoric molecular architectures is a crucial step in establishing new design principles in organic electronics as well as to fully understand how nature exploits solar energy. Here, we study the excited state dynamics of three bichromophores consisting of two perylene chromophores linked to three different crown-ether backbones, using stationary and ultrafast electronic spectroscopy combined with molecular dynamics simulations. The conformational space available to the bichromophores depends on the structure and geometry of the crown-ether and can be significantly changed upon cation binding, strongly affecting the excited-state dynamics. We show that, depending on the conformational restrictions and the local environment, the nature of the excited state varies greatly, going from an excimer to a symmetry-broken charge separated state. These results can be rationalised in terms of a structure-property relationship that includes the effect of the local environment.


Non-leaching, Highly Biocompatible Nanocellulose Surfaces That Efficiently Resist Fouling by Bacteria in an Artificial Dermis Model.
Bacterial biofilm infections incur massive costs on healthcare systems worldwide. Particularly worrisome are the infections associated with pressure ulcers and prosthetic, plastic, and reconstructive surgeries, where staphylococci are the major biofilm-forming pathogens. Non-leaching antimicrobial surfaces offer great promise for the design of bioactive coatings to be used in medical devices. However, the vast majority are cationic, which brings about undesirable toxicity. To circumvent this issue, we have developed antimicrobial nanocellulose films by direct functionalization of the surface with dehydroabietic acid derivatives. Our conceptually unique design generates non-leaching anionic surfaces that reduce the number of viable staphylococci in suspension, including drug-resistant Staphylococcus aureus, by an impressive 4-5 log units, upon contact. Moreover, the films clearly prevent bacterial colonization of the surface in a model mimicking the physiological environment in chronic wounds. Their activity is not hampered by high protein content, and they nurture fibroblast growth at the surface without causing significant hemolysis. In this work, we have generated nanocellulose films with indisputable antimicrobial activity demonstrated using state-of-the-art models that best depict an "in vivo scenario". Our approach is to use fully renewable polymers and find suitable alternatives to silver and cationic antimicrobials.


A critical role for prostaglandin E2 in podosome dissolution and induction of high-speed migration during dendritic cell maturation.
Dendritic cells (DCs) are professional APCs of the immune system that play a key role in regulating T cell-based immunity. The capacity of DCs to activate T cells depends on their maturation state as well as their ability to migrate to the T cell areas of draining lymph nodes. In this study, we investigated the effects of DC maturation stimuli on the actin cytoskeleton and beta(1) integrin-dependent adhesion and migration. Podosomes, specialized adhesion structures found in immature monocyte-derived DCs as well as myeloid DCs, rapidly dissolve in response to maturation stimuli such as TNF-alpha and PGE(2), whereas the TLR agonist LPS induces podosome dissolution only after a long lag time. We demonstrate that LPS-mediated podosome disassembly as well as the onset of high-speed DC migration are dependent on the production of PGs by the DCs. Moreover, both of these processes are inhibited by Ab-induced activation of beta(1) integrins. Together, these results show that maturation-induced podosome dissolution and loss of alpha(5)beta(1) integrin activity allow human DCs to undergo the transition from an adhesive to a highly migratory phenotype.


Serum malondialdehyde, erythrocyte glutathione peroxidase, and erythrocyte superoxide dismutase levels in women with early spontaneous abortions accompanied by vaginal bleeding.
Malondialdehyde (MDA) is a marker of lipid peroxidation. Glutathione peroxidase (GPX) and superoxide dismutase (SOD) are the main enzymes responsible for the detoxification of superoxide anion. The aim was to assess whether serum MDA, erythrocyte GPX, and erythrocyte SOD levels altered during early spontaneous abortions presenting with vaginal bleeding. A group of pregnant women at less than 8 weeks' gestation with spontaneous abortion and vaginal bleeding (n=23) and a control group of healthy pregnancies with similar characteristics (n=25) were included. Serum MDA levels, erythrocyte GPX, and SOD activities were determined and compared among the groups. Characteristics, including maternal age, parity, gestational age, complete blood count values, serum total protein, serum albumin, and serum lipid profile, were similar across the groups. Spontaneous abortion prior to 8 weeks of gestation was associated with increased mean serum MDA levels and decreased mean erythrocyte SOD activity. Erythrocyte GPX values did not differ among the groups. Increased lipid peroxidation and inhibition of SOD activity might be involved in the termination of spontaneous abortions and expulsion of fetoplacental material out of the uterine cavity.


Nonlinear dynamics of the CAM circadian rhythm in response to environmental forcing.
Crassulacean acid metabolism (CAM) photosynthesis functions as an endogenous circadian rhythm coupled to external environmental forcings of energy and water availability. This paper explores the nonlinear dynamics of a new CAM photosynthesis model (Bartlett et al., 2014) and investigates the responses of CAM plant carbon assimilation to different combinations of environmental conditions. The CAM model (Bartlett et al., 2014) consists of a Calvin cycle typical of C3 plants coupled to an oscillator of the type employed in the Van der Pol and FitzHugh-Nagumo systems. This coupled system is a function of environmental variables including leaf temperature, leaf moisture potential, and irradiance. Here, we explore the qualitative response of the system and the expected carbon assimilation under constant and periodically forced environmental conditions. The model results show how the diurnal evolution of these variables entrains the CAM cycle with prevailing environmental conditions. While constant environmental conditions generate either steady-state or periodically oscillating responses in malic acid uptake and release, forcing the CAM system with periodic daily fluctuations in light exposure and leaf temperature results in quasi-periodicity and possible chaos for certain ranges of these variables. This analysis is a first step in quantifying changes in CAM plant productivity with variables such as the mean temperature, daily temperature range, irradiance, and leaf moisture potential. Results may also be used to inform model parametrization based on the observed fluctuating regime.


Life-threatening reaction to vancomycin given for noninfectious fever.
To report a case of vancomycin-induced anaphylaxis (or anaphylactoid reaction) in a patient with a fever of unrecognized noninfectious origin. An 83-year-old white man, who was a patient of the Veterans Affairs Medical Center, developed a serious anaphylactic (or anaphylactoid) reaction while receiving intravenous vancomycin as empiric therapy for a nosocomial fever of unknown origin. The fever was subsequently proved to have been due to acute polyarticular gout rather than an infection. This patient developed respiratory distress and an increased serum troponin concentration, suggestive of a myocardial enzymatic leak as a result of vancomycin therapy. Vancomycin was given before the noninfectious cause of his fever was recognized. Even with cautious slow infusion, intravenous vancomycin can precipitate life-threatening infusion-related reactions in some patients. Because of this, and to reduce selective pressure for vancomycin resistance, sources of fever that do not require treatment with vancomycin should be diligently investigated prior to the institution of empiric vancomycin therapy in febrile patients, particularly when the past medical history is suggestive of an alternative diagnosis.


Genome Integrity in Aging: Human Syndromes, Mouse Models, and Therapeutic Options.
Human syndromes and mouse mutants that exhibit accelerated but bona fide aging in multiple organs and tissues have been invaluable for the identification of nine denominators of aging: telomere attrition, genome instability, epigenetic alterations, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular communication, loss of proteostasis, cellular senescence and adult stem cell exhaustion. However, whether and how these instigators of aging interrelate or whether they have one root cause is currently largely unknown. Rare human progeroid syndromes and corresponding mouse mutants with resolved genetic defects highlight the dominant importance of genome maintenance for aging. A second class of aging-related disorders reveals a cross connection with metabolism. As genome maintenance and metabolism are closely interconnected, they may constitute the main underlying biology of aging. This review focuses on the role of genome stability in aging, its crosstalk with metabolism, and options for nutritional and/or pharmaceutical interventions that delay age-related pathology.


Self-perceived oral health among 19-year-olds in a Swedish County--A comparative study between 2004 and 2011.
For decades, Swedish dental professionals have collected clinical epidemiological data from the dental records. To supplement the epidemiology, Ostergötland County Council decided to examine patient perceptions of oral health: self-rated knowledge, self-perceived oral health, and opinions about oral health. The aim was to compare self-perceived oral health among 19-year-olds to determine differences between genders, various municipalities and between 2004 and 2011. This study analysed the responses from two cross-sectional surveys of the entire population of 19-year-olds in Ostergötland County, Sweden, performed in 2004 and 2011. Of the 2,413 (53%) (50% men, 50% women) 19-year-olds who responded to the questionnaire in 2004 and the 3,803 (67%) (50% men, 50% women) in 2011, most 19-year-olds (88.1% [2004] and 87.5 % [2011]) reported satisfaction with their oral health. Around half of the respondents rated their knowledge on periodontitis as low. Boys rated their knowledge about avoiding periodontitis higher than girls (p < 0.05 in 2004 and p < 0.001 in 2011). In 2004, 84.7% reported shooting pain. In 2011 that figure was 83.7%.The respondents expressed some uncertainty about the benefits of fluoride toothpaste (7.5% in 2004 and 9.3% in 2011), especially the boys (10.3% in 2004 and 10.5% in 2011). Girls reported both a higher social impact and greater concern about aesthetics related to their oral health. They also reported headache (27.5%) nearly twice as often as boys (14.2%) (p > 0.001). Responses between the municipalities did not differ, with the exception of items regarding periodontitis. Thus, this study found indications that perceptions of oral health and knowledge in Ostergötland County complied with Swedish Dental Act. The study also found patient perceptions of oral health among 19-year-olds to be good.


Lateralized readiness potentials reveal properties of a neural mechanism for implementing a decision threshold.
Many perceptual decision making models posit that participants accumulate noisy evidence over time to improve the accuracy of their decisions, and that in free response tasks, participants respond when the accumulated evidence reaches a decision threshold. Research on the neural correlates of these models' components focuses primarily on evidence accumulation. Far less attention has been paid to the neural correlates of decision thresholds, reflecting the final commitment to a decision. Inspired by a model of bistable neural activity that implements a decision threshold, we reinterpret human lateralized readiness potentials (LRPs) as reflecting the crossing of a decision threshold. Interestingly, this threshold crossing preserves signatures of a drift-diffusion process of evidence accumulation that feeds in to the threshold mechanism. We show that, as our model predicts, LRP amplitudes and growth rates recorded while participants performed a motion discrimination task correlate with individual differences in behaviorally-estimated prior beliefs, decision thresholds and evidence accumulation rates. As such LRPs provide a useful measure to test dynamical models of both evidence accumulation and decision commitment processes non-invasively.


Influence of the Heel-to-Toe Drop of Standard Cushioned Running Shoes on Injury Risk in Leisure-Time Runners: A Randomized Controlled Trial With 6-Month Follow-up.
Modern running shoes are available in a wide range of heel-to-toe drops (ie, the height difference between the forward and rear parts of the inside of the shoe). While shoe drop has been shown to influence strike pattern, its effect on injury risk has never been investigated. Therefore, the reasons for such variety in this parameter are unclear. The first aim of this study was to determine whether the drop of standard cushioned running shoes influences running injury risk. The secondary aim was to investigate whether recent running regularity modifies the relationship between shoe drop and injury risk. Randomized controlled trial; Level of evidence, 1. Leisure-time runners (N = 553) were observed for 6 months after having received a pair of shoes with a heel-to-toe drop of 10 mm (D10), 6 mm (D6), or 0 mm (D0). All participants reported their running activities and injuries (time-loss definition, at least 1 day) in an electronic system. Cox regression analyses were used to compare injury risk between the 3 groups based on hazard rate ratios (HRs) and their 95% CIs. A stratified analysis was conducted to evaluate the effect of shoe drop in occasional runners (<6 months of weekly practice over the previous 12 months) versus regular runners (≥6 months). The overall injury risk was not different among the participants who had received the D6 (HR, 1.30; 95% CI, 0.86-1.98) or D0 (HR, 1.17; 95% CI, 0.76-1.80) versions compared with the D10 shoes. After stratification according to running regularity, low-drop shoes (D6 and D0) were found to be associated with a lower injury risk in occasional runners (HR, 0.48; 95% CI, 0.23-0.98), whereas these shoes were associated with a higher injury risk in regular runners (HR, 1.67; 95% CI, 1.07-2.62). Overall, injury risk was not modified by the drop of standard cushioned running shoes. However, low-drop shoes could be more hazardous for regular runners, while these shoes seem to be preferable for occasional runners to limit injury risk.


The decrease of maximal oxygen consumption during hypoxia in man: a mirror image of the oxygen equilibrium curve.
1. Endurance athletes (E) undergo a marked reduction of arterial O2 saturation (Sa,O2) at maximal exercise in normoxia, which disappears when they breathe hyperoxic mixtures. In addition, at a given level of hypoxia, the drop in maximal O2 consumption (VO2,max) is positively related to the individual normoxic VO2,max. 2. These data suggest that the curve relating VO2,max to PI,O2 may be steeper and perhaps less curved in E than in sedentary subjects (S) with low VO2,max values because of the greater hypoxaemia in the latter, whence the hypotheses that (i) the relationship between VO2,max and PI,O2 may be set by the shape of the oxygen equilibrium curve; and (ii) the differences between E and S may be due to the different position on the oxygen equilibrium curve on which these subjects operate. These hypotheses have been tested by performing a systematic comparison of the VO2,max or Sa,O2 vs. PI,O2 relationships in E and S. 3. On ten subjects (five S and five E), VO2,max was measured by standard procedure during cycloergometric exercise. Sa,O2 was measured by finger-tip infrared oximetry. Arterialized blood PO2 (Pa,O2) and PCO2 (Pa,CO2) were determined in 80 microliters blood samples from an ear lobe. The subjects breathed ambient air or a N2-O2 mixture with an inspired O2 fraction (FI,O2) of 0.30, 0.18, 0.16, 0.13 and 0.11, respectively, VO2,max was normalized with respect to that obtained at the highest FI,O2. 4. The relationships between Sa,O2 or normalized VO2,max and FI,O2 (or PI,O2) had similar shapes, the data for E being systematically below and significantly different from those for S. Linear relationships between Sa,O2 and normalized VO2,max, statistically equal between E and S, were found. 5. We conclude that the relationships between either VO2,max or Sa,O2 and FI,O2 (or Pa,O2) may indeed be the mirror images of one another, implying a strict link between the decrease of VO2,max in hypoxia and the shape of the oxygen equilibrium curve, as hypothesized.


Vitamin D insufficient levels during pregnancy and micronuclei frequency in peripheral blood T lymphocytes mothers and newborns (Rhea cohort, Crete).
Vitamin D deficiency is common among pregnant women and may be associated with several adverse health outcomes including cancer. Micronuclei frequency is a biomarker of early genetic effects and has been used to examine the association between genotoxic exposures and cancer. We examined maternal vitamin D levels during pregnancy in associations with micronuclei frequency in maternal blood and in cord blood. 173 mothers and 171 newborns born between 2007 and 2008 in Heraklion (Crete, Greece) were included in the study. Between 14th and 18th weeks of gestation we collected information on maternal diet using food frequency questionnaires (FFQs). We measured maternal serum concentrations of 25-hydroxyvitamin D [25(OH)D] between the first and second trimester of pregnancy. We estimated dietary vitamin D intake using information from FFQ. After delivery we collected cord blood and maternal peripheral blood. We used the cytokinesis-block micronucleus (CBMN) assay to assess the frequencies of micronucleated cells in binucleated T lymphocytes (MNBN). Maternal insufficient serum levels of 25(OH)D (<50 nmol/L) during pregnancy were associated with increased MNBN frequency in cord blood [IRR = 1.32 (95%CI: 1.00, 1.72)]. This increase was higher for newborns with birth weight above the third quartile [≥3.500 kg; IRR = 2.21 (1.26, 3.89)]. Similarly, low levels of dietary vitamin D were associated with increased MNBN frequency in cord blood [middle tertile IRR = 1.08 (0.78, 1.47), lower tertile IRR = 1.51 (1.06, 2.14)]. Insufficient levels of vitamin D were not associated with MNBN in mothers. Our results suggest that vitamin D deficiency during pregnancy increases genotoxic risks in newborns. The prevalence of vitamin D deficiency globally is high and it is important to further investigate whether vitamin D supplementation or similar interventions during pregnancy could prevent DNA damage at early stages of life.


Role and prognostic significance of tumor necrosis factor-related apoptosis-inducing ligand death receptor DR5 in nonsmall-cell lung cancer and precursor lesions.
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor, DR5, mediates proapoptotic signals and is implicated in the pathogenesis of many neoplasms including nonsmall-cell lung cancer (NSCLC). In this study, immunohistochemical expression of DR5 was examined in 146 cases of stage I and II NSCLC as well as neoplastic precursor lesions and regional lymph node metastases using tissue microarrays. High DR5 expression was observed in 67.1% of primary NSCLC, 55.6% of bronchial squamous carcinoma in situ, 40% of squamous metaplasia, as well as 76.5% of lymph node metastases. In all of these lesions, DR5 expression was significantly higher than in normal bronchial epithelium. Increased expression of DR5 correlated with poorly differentiated tumors and was inversely correlated with bronchioloalveolar carcinomas. There was no correlation with other clinicopathologic variables. A significant association was found between high DR5 expression and reduced overall survival in univariate analysis. Among smokers, high DR5 and tumor stage were independent predictors of reduced disease-free survival in multivariate analysis, however, DR5 was not an independent prognostic marker among the entire cohort of NSCLC. These findings suggest that DR5 plays a role in the development of early-stage NSCLC and the high levels of DR5 expression suggest that these tumors may be susceptible to novel anticancer agents targeting the DR5 receptor and may improve patient survival, particularly for patients who are smokers.


Risk indicators for the tick Ixodes ricinus and Borrelia burgdorferi sensu lato in Sweden.
The distributional area of the tick Ixodes ricinus (L.), the primary European vector to humans of Lyme borreliosis spirochaetes (Borrelia burgdorferi sensu lato) and tick-borne encephalitis virus, appears to be increasing in Sweden. It is therefore important to determine which environmental factors are most useful to assess risk of human exposure to this tick and its associated pathogens. The geographical distribution of I. ricinus in Sweden was analysed with respect to vegetation zones and climate. The northern limit of I. ricinus and B. burgdorferi s.l. in Sweden corresponds roughly to the northern limit of the southern boreal vegetation zone, and is characterized climatically by snow cover for a mean duration of 150 days and a vegetation period averaging 170 days. The zoogeographical distribution of I. ricinus in Sweden can be classified as southerly-central, with the centre of the distribution south of the Limes Norrlandicus. Ixodes ricinus nymphs from 13 localities in different parts of Sweden were examined for the presence of B. burgdorferi s.l. and found to be infected with Borrelia afzelii and Borrelia garinii. Tick sampling localities were characterized on the basis of the density of Borrelia-infected I. ricinus nymphs, presence of specific mammals, dominant vegetation and climate. Densities of I. ricinus nymphs and Borrelia-infected nymphs were significantly correlated, and nymphal density can thus serve as a general indicator of risk for exposure to Lyme borreliosis spirochaetes. Analysis of data from this and other studies suggests that high densities of Borrelia-infected nymphs typically occur in coastal, broadleaf vegetation and in mixed deciduous/spruce vegetation in southern Sweden. Ixodes ricinus populations consistently infected with B. burgdorferi s.l. can occur in: (a) biotopes with shrews, rodents, hares and birds; (b) biotopes with shrews, rodents, hares, deer and birds, and (c) island locations where the varying hare (Lepus timidus) is the only mammalian tick host.


Changes in gray matter volume and white matter microstructure in adolescents with obsessive-compulsive disorder.
There is a paucity of neuroimaging data in pediatric-onset obsessive-compulsive disorder (OCD). This multimodal neuroimaging study aimed to identify structural gray (GM) and white matter (WM) microstructure changes in pediatric OCD. We obtained structural and diffusion tensor magnetic resonance images from 26 OCD patients and 26 matched healthy adolescents. We carried out a series of image analyses including, volumetric and shape analysis of subcortical gray structures, as well as voxel-based morphometry on GM volume and fractional anisotropy of the WM. Patients had increased GM volume in the caudate bilaterally and right putamen. Shape analyses revealed specific hypertrophy of the dorsal caudate in pediatric OCD. The striatum was larger in healthy boys compared with healthy girls, whereas such a gender effect was not seen in the OCD group. OCD subjects showed higher fractional anisotropy values in left inferior longitudinal fasciculus, bilateral superior longitudinal fasciculus, right inferior fronto-occipital fasciculus, bilateral corticospinal tract, corpus callosum splenium and genu, bilateral forceps major, bilateral forceps minor, left cingulum, and right uncinate fasciculus. OCD symptom severity was positively correlated with GM volume in right insula, posterior orbitofrontal cortex, brainstem, and cerebellum and inversely correlated with widespread reduction in cortical GM volume. Furthermore, symptom severity positively correlated with increased WM fractional anisotropy in various WM tracts, including the anterior limb of the internal capsule. Adolescents with OCD had a wide range of GM and WM changes compared to healthy control subjects that are broadly consistent with those identified in the adult OCD literature but are more extensive.


A model of mood as integrated advantage.
Mood is an integrative and diffuse affective state that is thought to exert a pervasive effect on cognition and behavior. At the same time, mood itself is thought to fluctuate slowly as a product of feedback from interactions with the environment. Here we present a new computational theory of the valence of mood-the Integrated Advantage model-that seeks to account for this bidirectional interaction. Adopting theoretical formalisms from reinforcement learning, we propose to conceptualize the valence of mood as a leaky integral of an agent's appraisals of the Advantage of its actions. This model generalizes and extends previous models of mood wherein affective valence was conceptualized as a moving average of reward prediction errors. We give a full theoretical derivation of the Integrated Advantage model and provide a functional explanation of how an integrated-Advantage variable could be deployed adaptively by a biological agent to accelerate learning in complex and/or stochastic environments. Specifically, drawing on stochastic optimization theory, we propose that an agent can utilize our hypothesized form of mood to approximate a momentum-based update to its behavioral policy, thereby facilitating rapid learning of optimal actions. We then show how this model of mood provides a principled and parsimonious explanation for a number of contextual effects on mood from the affective science literature, including expectation- and surprise-related effects, counterfactual effects from information about foregone alternatives, action-typicality effects, and action/inaction asymmetry. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Molecular-genetic variance of RH blood group system within human population of Bosnia and Herzegovina.
There are two major theories for inheritance of Rh blood group system: Fisher - Race theory and Wiener theory. Aim of this study was identifying frequency of RHDCE alleles in Bosnian - Herzegovinian population and introduction of this method in screening for Rh phenotype in B&H since this type of analysis was not used for blood typing in B&H before. Rh blood group was typed by Polymerase Chain Reaction, using the protocols and primers previously established by other authors, then carrying out electrophoresis in 2-3% agarose gel. Percentage of Rh positive individuals in our sample is 84.48%, while the percentage of Rh negative individuals is 15.52%. Inter-rater agreement statistic showed perfect agreement (K=1) between the results of Rh blood system detection based on serological and molecular-genetics methods. In conclusion, molecular - genetic methods are suitable for prenatal genotyping and specific cases while standard serological method is suitable for high-throughput of samples.


Potential nutritional conflicts in bariatric and renal transplant patients.
An increasing number of morbidly obese patients with end stage renal disease (ESRD) are sequentially undergoing bariatric surgery followed by renal transplantation. Discrepancies between the nutritional recommendations for obesity and chronic kidney disease (CKD) are often confusing for the obese patient in renal failure. However, when recommendations are structured according to stage and treatment of disease, a consistent plan can be clearly communicated to the patient. Therefore, to optimize patient and graft outcomes we present nutritional recommendations tailored to three patient populations: obese patients with ESRD, patients post Roux-en-Y gastric bypass (RYGBP) with ESRD, and patients post RYGBP and post renal transplantation.


Predictors, Prognosis, and Management of New Clinically Important Atrial Fibrillation After Noncardiac Surgery: A Prospective Cohort Study.
Despite the frequency of new clinically important atrial fibrillation (AF) after noncardiac surgery and its increased association with the risk of stroke at 30 days, there are limited data informing their prediction, association with outcomes, and management. We used the data from the PeriOperative ISchemic Evaluation trial to determine, in patients undergoing noncardiac surgery, the association of new clinically important AF with 30-day outcomes, and to assess management of these patients. We also aimed to derive a clinical prediction rule for new clinically important AF in this population. We defined new clinically important AF as new AF that resulted in symptoms or required treatment. We recorded an electrocardiogram 6 to 12 hours postoperatively and on the 1st, 2nd, and 30th days after surgery. A total of 211 (2.5% [8351 patients]; 95% confidence interval, 2.2%-2.9%) patients developed new clinically important AF within 30 days of randomization (8140 did not develop new AF). AF was independently associated with an increased length of hospital stay by 6.0 days (95% confidence interval, 3.5-8.5 days) and vascular complications (eg, stroke or congestive heart failure). The usage of an oral anticoagulant at the time of hospital discharge among patients with new AF and a CHADS2 score of 0, 1, 2, 3, and ≥4 was 6.9%, 10.2%, 23.0%, 9.4%, and 33.3%, respectively. Two independent predictors of patients developing new clinically important AF were identified (ie, age and surgery). The prediction rule included the following factors and assigned weights: age ≥85 years (4 points), age 75 to 84 years (3 points), age 65 to 74 years (2 points), intrathoracic surgery (3 points), major vascular surgery (2 points), and intra-abdominal surgery (1 point). The incidence of new AF based on scores of 0 to 1, 2, 3 to 4, and 5 to 6 was 0.5%, 1.0%, 3.1%, and 5.3%, respectively. Age and surgery are independent predictors of new clinically important AF in the perioperative setting. A minority of patients developing new clinically important AF with high CHADS2 scores are discharged on an oral anticoagulant. There is a need to develop effective and safe interventions to prevent this outcome and to optimize the management of this event when it occurs.


Regulation of monocyte interleukin-12 production by acute alcohol: a role for inhibition by interleukin-10.
Acute ethanol treatment results in decreased antigen presentation capacity (Th1-type immunity) and elevated interleukin IL-10 (Th2 cytokine) production in human monocytes. Monocytes can contribute to both Th1 (IL-12) and Th2 (IL-10) immune responses via production of IL-12 and IL-10, respectively. Thus, we tested the hypothesis that acute alcohol treatment might affect Th1/Th2 immune balance by altering monocyte production of IL-12 and IL-10. Neither acute ethanol treatment alone (25 to 100 mM) nor its combination with a bacterial challenge Staphylococcal enterotoxin B (SEB) induced IL-12 production in isolated blood monocytes. In contrast, the same physiological alcohol concentrations increased monocyte IL-10 levels, suggesting that ethanol can induce a dysbalance of monocyte-derived mediator production at the expense of Th1 cytokines. However, we found that monocyte activation with interferon-gamma (IFN-gamma) can prevent the preferential IL-10 induction by ethanol. IFN-gamma (100 units/ml) inhibited monocyte IL-10 production whether induced by 1 microg/ml of lipopolysaccharide (p < 0.01), 1 microg/ml of SEB (p < 0.02), or a combination of bacterial stimulation + ethanol (lipopolysaccharide: p < 0.01). Furthermore, decreased IL-10 was concomitant to an increase in IL-12 production in IFN-gamma-treated monocytes. Moreover, acute ethanol treatment augmented IL-12 production in IFN-gamma-treated monocytes in response to SEB stimulation (25 mM ethanol, p < 0.01; 100 mM ethanol, p < 0.01). Experiments with anti-IL-10 neutralizing antibody show that ethanol may prevent monocyte IL-12 induction via IL-10. These results suggest that inhibition of ethanol-induced IL-10 production by IFN-gamma treatment is permissive for IL-12 induction by alcohol stimulation in monocytes. Thus, our results imply that the presence or absence of IFN-gamma is critical in determining the effect of acute ethanol treatment on monocyte IL-12 versus IL-10 induction.


Integrated delivery of school health interventions through the school platform: Investing for the future.
School health and nutrition (SHN) programmes are recognized as a significant contributor to both health and education sector goals. The school system offers an ideal platform from which to deliver basic health interventions that target the most common health conditions affecting school-age children (SAC) in low-income countries, leading to improved participation and learning outcomes. However, governments require evidence to cost, design, and implement these programmes. In Ethiopia, prevalent health conditions affecting SAC's education participation and learning outcomes include infection with soil-transmitted helminths (STHs), hunger, and malnutrition. In recognition of the multiple issues affecting the health and education of SAC, the government has taken a proactive approach, coordinating an integrated SHN programme designed to be implemented in partnership and monitored and financed through a single, integrated mechanism. The programme, known as the Enhanced School Health Initiative (ESHI), integrates three complimentary health interventions: deworming; school feeding; and provision of a water, sanitation, and hygiene (WASH) package in schools, which in delivery aim to maximize the benefits of each of the individual components. Operational research surrounding the ESHI programme includes both qualitative and quantitative analyses. Here, we present an overview of the ESHI programme and its genesis. We also introduce three additional supporting papers that provide in-depth analyses of key findings, including the baseline situational analysis, the costs, and community perceptions of the programme. The findings from ESHI provide initial evidence to develop an understanding of the related costs and synergies of integrating multiple health interventions onto a single platform. The work has translated into strengthened institutional capacity and improved cross-sectoral coordination. The government is now committed to supporting 25 million school children in Ethiopia through SHN. The ESHI model serves as a reference point for other countries looking to scale up targeted SHN interventions.


Does display configuration affect information sampling performance?
This investigation sought to determine the influence of a visual display's spatial configuration on participant's ability to sample linguistic information. Line drawings circumscribed 36 areas shaped like squares, rectangles, 'T', 'L' and '+', among others. Each such 'shape' was presented for 1000 ms, followed by a 12-letter matrix presented for 50 ms. Participants then reported the letters that would have been inside the boundary contour if it were superimposed on the letter matrix. The results indicated that single, spatially contiguous areas could be monitored better than separate areas; the recall of simple configurations seemed better than that of more complex ones, while outlying positions tended to be ignored. The data were thus viewed as compatible with recent theories of perceptual organization in displays, such as the notion of 'common region' and the proximity compatibility principle. Informational complexity (IC) proved somewhat better than figural compactness (FC) in accounting for the data in terms of information theory. The findings may help to specify the optimal spatial configurations for visually displayed linguistic information in a variety of contexts, including head-up displays (HUDs).


The effect of gene overlapping on the rate of RNA virus evolution.
Gene overlapping is widely employed by RNA viruses to generate genetic novelty while retaining a small genome size. However, gene overlapping also increases the deleterious effect of mutations as they affect more than one gene, thereby reducing the evolutionary rate of RNA viruses and hence their adaptive capacity. Although there is general agreement on the benefits of gene overlapping as a mechanism of genomic compression for rapidly evolving organisms, its effect on the pace of RNA virus evolution remains a source of debate. To address this issue, we collected sequence data from 117 instances of gene overlapping across 19 families, 30 genera, and 55 species of RNA viruses. On these data, we analyzed how genetic distances, selective pressures, and the distribution of RNA secondary structures and conserved protein functional domains vary between overlapping (OV) and nonoverlapping (NOV) regions. We show that gene overlapping generally results in a decrease in the rate of RNA virus evolution through a reduction in the frequency of synonymous mutations. However, this effect is less pronounced in genes with a terminal rather than an internal gene overlap, which might result from a greater proportion of protein functional conserved domains in NOV than in OV regions, in turn reducing the number of nonsynonymous mutations in the former. Overall, our analyses clarify the role of gene overlapping as a modulator of the evolutionary rates exhibited by RNA viruses and shed light on the factors that shape the genetic diversity of this important group of pathogens.


Oogenesis in cultures derived from adult human ovaries.
Ten years ago, we reported that in adult human females the ovarian surface epithelium (OSE) is a source of germ cells. Recently, we also demonstrated that new primary follicles are formed by assembly of oocytes with nests of primitive granulosa cells in the ovarian cortex. The components of the new primary follicles, primitive granulosa and germ cells, differentiated sequentially from the OSE, which arises from cytokeratin positive mesenchymal progenitor cells residing in the ovarian tunica albuginea. In the present study, we investigated the possibility that the oocytes and granulosa cells may differentiate in cultures derived from adult human ovaries. Cells were scrapped from the surface of ovaries and cultured for 5 to 6 days, in the presence or absence of estrogenic stimuli [phenol red (PhR)]. The OSE cells cultured in the medium without PhR differentiated into small (15 micron) cells of granulosa phenotype, and epithelial, neural, and mesenchymal type cells. In contrast, OSE cells cultured in the presence of PhR differentiated directly into large (180 micron) cells of the oocyte phenotype. Such cells exhibited germinal vesicle breakdown, expulsion of the polar body, and surface expression of zona pellucida proteins, i.e. characteristics of secondary oocytes. These in vitro studies confirm our in vivo observations that in adult human ovaries, the OSE is a bipotent source of oocytes and granulosa cells. Development of numerous mature oocytes from adult ovarian stem cells in vitro offers new strategies for the egg preservation, IVF utilization, and treatment of female infertility. In addition, other clinical applications aiming to utilize stem cells, and basic stem cell research as well, may employ totipotent embryonic stem cells developing from fertilized oocytes.


Identification of a synaptic vesicle-specific membrane protein with a wide distribution in neuronal and neurosecretory tissue.
Two different monoclonal antibodies, characterized initially as binding synaptic terminal regions of rat brain, bind a 65,000-dalton protein, which is exposed on the outer surface of brain synaptic vesicles. Immunocytochemical experiments at the electron microscope level demonstrate that these antibodies bind the vesicles in many different types of nerve terminals. The antibodies have been used successfully to purify synaptic vesicles from crude brain homogenates by immunoprecipitation onto the surface of polyacrylamide beads. The profiles of the structures precipitated by these beads are almost exclusively vesicular, confirming the vesicle-specificity of the antibodies. In SDS gels, the antibodies bind a single protein of 65,000 daltons. The two antibodies are not identical, but compete for binding sites on this protein. Immune competition experiments also demonstrate that the antigenic components on the 65,000-dalton protein are widely distributed in neuronal and neural secretory tissues. Detectable antigen is not found in uninnervated tissue--blood cells and extrajunctional muscle. Low levels are found in nonneural secretory tissues; it is not certain whether this reflects the presence of low amounts of the antigen on all the exocytotic vesicles in these tissues or whether the antigen is found only in neuronal fibers within these tissues. The molecular weight and at least two antigenic determinants of the 65,000-dalton protein are highly conserved throughout vertebrate phylogeny. The two antibodies recognize a 65,000-dalton protein present in shark, amphibia, birds, and mammals. The highly conserved nature of the determinants on this protein and their specific localization on secretory vesicles of many different types suggest that this protein may be essential for the normal function of neuronal secretory vesicles.


A proteomics platform combining depletion, multi-lectin affinity chromatography (M-LAC), and isoelectric focusing to study the breast cancer proteome.
The discovery of breast cancer associated plasma/serum biomarkers is important for early diagnosis, disease mechanism elucidation, and determination of treatment strategy for the disease. In this study of serum samples, a multidimensional fractionation platform combined with mass spectrometric analysis were used to achieve the identification of medium to lower abundance proteins, as well as to simultaneously detect glycan and abundance changes. Immuno-affinity depletion and multi-lectin chromatography (M-LAC) were integrated into an automated HPLC platform to remove high abundance protein and fractionate glycoproteins. The collected glycoproteomes were then subjected to isoelectric focusing (IEF) separation by a digital ProteomeChip (dPC), followed by in-gel digestion and LC-MS analysis using an Orbitrap mass spectrometer. As a result, the total number of identified proteins increased significantly when the IEF fractionation step was included as part of the platform. Relevant proteins with biological and disease significance were observed and the dynamic range of the serum proteome measurement was extended. In addition, potential glycan changes were indicated by comparing proteins in control and cancer samples in terms of their affinity to the multi-lectin column (M-LAC) and the pI profiles in IEF separation. In conclusion, a proteomics platform including high abundance protein depletion, lectin affinity fractionation, IEF separation, and LC-MS analysis has been applied to discover breast cancer-associated proteins. The following candidates, thrombospondin-1 and 5, alpha-1B-glycoprotein, serum amyloid P-component, and tenascin-X, were selected as promising examples of the use of this platform. They show potential abundance and glycan changes and will be further investigated in future studies.


Farmer to pharmacist: curcumin as an anti-invasive and antimetastatic agent for the treatment of cancer.
A huge number of compounds are widely distributed in nature and many of these possess medicinal/biological/pharmacological activity. Curcumin, a polyphenol derived from the rhizomes (underground stems) of Curcuma longa Linn (a member of the ginger family, commonly known as turmeric) is a culinary spice and therapeutic used in India for thousands of years to induce color and flavor in food as well as to treat a wide array of diseases. The origin of turmeric as spice and folklore medicine is so old that it is lost in legend. Curcumin has many beneficial pharmacological effects which includes, but are not limited with, antimicrobial, anti-inflammatory, antioxidant, antiviral, antiangiogenic, neurodegenerative diseases such as Alzheimer disease, and antidiabetic activities. Most importantly curcumin possesses immense antitumorigenic effect. It prevents tumor invasion and metastasis in a number of animal models, including models of lung, liver, stomach, colon, breast, esophageal cancer etc. Invasion and metastasis are considered as one of the hallmarks in cancer biology. The pertinent recent applications of curcumin as anti-invasive and antimetastatic agent in in vitro and in vivo and ex vivo studies as well as associated molecular mechanisms have been discussed in this review. Curcumin has also demonstrated the ability to improve patient outcomes in clinical trials.


Classification of trochlear dysplasia as predictor of clinical outcome after trochleoplasty.
Sulcus-deepening trochleoplasty restores the trochlear groove in patients with patellofemoral instability and underlying trochlear dysplasia. There are types of dysplasia both with (B and D) and without (A and C) a supratrochlear spur. The aim of this study was to identify influencing factors for the clinical outcome following trochleoplasty. Forty-four knees in 38 patients who underwent trochleoplasty for instability (type A in 9, B in 15, C in 9 and D in 11 knees) were assessed clinically with the Kujala score and radiologically with radiographs and MRI. The median follow-up was 4 (2-7.8) years. At follow-up, the median Kujala score had improved from 68 (29-84) to 90 (42-100) points (P < 0.001). Instability (P < 0.001) and pain (P = 0.027) decreased significantly, but in 3 knees, pain was worse postoperatively. Twenty-seven knees were ranked as excellent, 10 as good, 2 as fair and 5 as poor. Overall, dysplasia types B and D benefited more from surgery than types A and C. The postoperative MRI revealed no chondrolysis or subchondral necrosis, but deterioration of cartilage on the lateral trochlear facet was identified. Trochleoplasty is a useful and reliable surgical technique to improve patellofemoral instability in patients with a dysplastic trochlea. While improved stability is predictable, pain is less predictable and may even increase following surgery. The overall results were directly dependent on the type of the dysplasia, with a significantly better clinical outcome in type B and D. The clinical relevance of this study is that severe dysplasia can successfully be treated with trochleoplasty. III.


Neurological effects of honey: current and future prospects.
Honey is the only insect-derived natural product with therapeutic, traditional, spiritual, nutritional, cosmetic, and industrial value. In addition to having excellent nutritional value, honey is a good source of physiologically active natural compounds, such as polyphenols. Unfortunately, there are very few current research projects investigating the nootropic and neuropharmacological effects of honey, and these are still in their early stages. Raw honey possesses nootropic effects, such as memory-enhancing effects, as well as neuropharmacological activities, such as anxiolytic, antinociceptive, anticonvulsant, and antidepressant activities. Research suggests that the polyphenol constituents of honey can quench biological reactive oxygen species and counter oxidative stress while restoring the cellular antioxidant defense system. Honey polyphenols are also directly involved in apoptotic activities while attenuating microglia-induced neuroinflammation. Honey polyphenols are useful in improving memory deficits and can act at the molecular level. Therefore, the ultimate biochemical impact of honey on specific neurodegenerative diseases, apoptosis, necrosis, neuroinflammation, synaptic plasticity, and behavior-modulating neural circuitry should be evaluated with appropriate mechanistic approaches using biochemical and molecular tools.


TGR5 contributes to glucoregulatory improvements after vertical sleeve gastrectomy in mice.
Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible remain incompletely defined. VSG increases circulating bile acid concentrations and bile acid signalling through TGR5 improves glucose homeostasis. Therefore, we investigated the role of TGR5 signalling in mediating the glucoregulatory benefits of VSG. VSG or sham surgery was performed in high-fat-fed male Tgr5+/+ (wild type) and Tgr5-/- (knockout) littermates. Sham-operated mice were fed ad libitum or food restricted to match their body weight to VSG-operated mice. Body weight, food intake, energy expenditure, insulin signalling and circulating bile acid profiles were measured and oral glucose tolerance testing, islet immunohistochemistry and gut microbial profiling were performed. VSG decreased food intake and body weight, increased energy expenditure and circulating bile acid concentrations, improved fasting glycaemia, glucose tolerance and glucose-stimulated insulin secretion, enhanced nutrient-stimulated glucagon-like peptide 1 secretion and produced favourable shifts in gut microbial populations in both genotypes. However, the body weight-independent improvements in fasting glycaemia, glucose tolerance, hepatic insulin signalling, hepatic inflammation and islet morphology after VSG were attenuated in Tgr5-/- relative to Tgr5+/+ mice. Furthermore, VSG produced metabolically favourable alterations in circulating bile acid profiles that were blunted in Tgr5-/- relative to Tgr5+/+ mice. TGR5-dependent regulation of hepatic Cyp8b1 expression may have contributed to TGR5-mediated shifts in the circulating bile acid pool after VSG. These results suggest that TGR5 contributes to the glucoregulatory benefits of VSG surgery by promoting metabolically favourable shifts in the circulating bile acid pool.


Safety of direct administration of AAV2(CU)hCLN2, a candidate treatment for the central nervous system manifestations of late infantile neuronal ceroid lipofuscinosis, to the brain of rats and nonhuman primates.
Late infantile neuronal ceroid lipofuscinosis (LINCL), a pediatric autosomal recessive neurodegenerative lysosomal storage disorder, results from mutations in the CLN2 gene and consequent deficiency in tripeptidyl-peptidase I (TPP-I) and progressive destruction of neurons. We have previously demonstrated that CNS gene transfer of AAV2(CU)hCLN2 (an AAV2-based vector expressing the human CLN2 cDNA) in rats and nonhuman primates mediates long-term TPP-I expression in the CNS neurons [Sondhi, D., Peterson, D.A., Giannaris, E.L., Sanders, C.T., Mendez, B.S., De, B., Rostkowski, A., Blancard, B., Bjugstad, K., Sladek, J.R., Redmond, D.E., Leopold, P.L., Kaminsky, S.M., Hackett, N.R., and Crystal, R.G. (2005). Gene Ther. 12, 1618-1632]. The present study tests the hypothesis that direct CNS administration of a clinical-grade AAV2(CU)hCLN2 vector to the CNS of rats and nonhuman primates at doses scalable to humans has a long-term safety profile acceptable for initiating clinical trials. Fischer 344 rats were injected bilaterally via the striatum with 2 x 10(10) particle units (PU) of AAV2(CU)hCLN2, using saline as a control. At 13, 26, and 52 weeks, vector and phosphate-buffered salineinjected rats were killed (n = 6 per time point), and blood, brain, and distant organs were assessed. There were no biologically significant differences between control and vector groups for complete blood count, serum chemistry, and neutralizing anti-AAV2 antibody levels. CNS administration of AAV2 CUhCLN2 did not result in any pathological changes in the brain that were attributable to the vector, although microscopic changes were observed along the track consistent with needle trauma. A total dose of 3.6 x 10(10) or 3.6 x 10(11) PU of AAV2(CU)hCLN2 was administered to the CNS of African Green monkeys at 12 locations, targeting the caudate nucleus, hippocampus, and overlying cortices. Monkeys (n = 3 at each dose) were killed 1, 13, 26, or 52 weeks after injection. Controls included sham-injected, saline-injected, and AAV2(CU)Null-injected (3.6 x 10(11) PU) monkeys. There were no biologically significant differences among vector-injected and control groups in any parameter of the general assessment, complete blood count, or serum chemistry assessed at multiple time points after vector administration. Importantly, no abnormal behavior was observed in any group in videotaped neurological assessment, where behaviors were quantified before administration and at multiple time points afterward. Histopathological examination of the CNS demonstrated that 1 week after administration, AAV2(CU)hCLN2 produced transient minor white matter edema with reactive glial cells in the corona radiata of the cerebrum along the injection track and in the surrounding white matter. This abnormality was not observed at 13, 26, or 52 weeks. Together with the long-term gene expression after gene transfer, these findings supported the initiation of clinical trials to assess the safety of AAV2(CU)hCLN2 administration to individuals with LINCL.


Memory specificity training can improve working and prospective memory in amnestic mild cognitive impairment.
Amnestic Mild Cognitive Impairment (MCI) is one of the cognitive profiles of aging. In this study, Memory Specificity Training (MEST) was used as cognitive training in patients with amnestic MCI to understand the effectiveness of the intervention on memory dimensions. Twenty patients that met the criteria for amnestic MCI were selected and randomly assigned to experimental (n=10) or control (n=10) groups. The experimental group received five sessions of training on memory specificity while the participants in the control group took part in two general placebo sessions. Participants were assessed before, immediately after, and three months after, the treatment using the Autobiographical Memory Test, the Prospective and Retrospective Memory Questionnaire, the Wechsler Memory Scale, and the Hospital Anxiety and Depression Scale. Analysis of variance was used to analyze the data. Results from both post-test and follow-up treatment indicated that MEST improves working and prospective memory (p<0.05). These findings support the effectiveness of MEST for MCI patients as a viable cognitive intervention. Also, the findings have implications for the role of brain plasticity in the effectiveness of this intervention.


Photo-degradation in air of the active layer components in a thiophene-quinoxaline copolymer:fullerene solar cell.
We have studied the photo-degradation in air of a blend of [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) and poly[2,3-bis-(3-octyloxyphenyl)quinoxaline-5,8-diyl-alt-thiophene-2,5-diyl] (TQ1), and how the photo-degradation affects the solar cell performance. Using near-edge X-ray absorption fine structure (NEXAFS) spectroscopy, changes to the electronic structure of TQ1 and PCBM caused by illumination in ambient air are investigated and compared between the pristine materials and the blend. The NEXAFS spectra show that the unoccupied molecular orbitals of TQ1 are not significantly changed by the exposure of pristine TQ1 to light in air, whereas those of PCBM are severely affected as a result of photo-induced degradation of PCBM. Furthermore, the photo-degradation of PCBM is accelerated by blending it with TQ1. While the NEXAFS spectrum of TQ1 remains unchanged upon illumination in air, its valence band spectrum shows that the occupied molecular orbitals are weakly affected. Yet, UV-Vis absorption spectra demonstrate photo-bleaching of TQ1, which is attenuated in the presence of PCBM in blend films. Illumination of the active layer of TQ1:PCBM solar cells prior to cathode deposition causes severe losses in electrical performance.


Tissue-specific targeting of cytokine unresponsiveness in transgenic mice.
The ubiquitous cellular distribution of certain cytokine receptors has hampered attempts to define the physiologically important cell-specific functions of cytokines in vivo. Herein, we report the generation of transgenic mice that express a dominant-negative IFN gamma receptor alpha chain mutant under the control of either the human lysozyme promoter or the murine lck proximal promoter, which display tissue-specific unresponsiveness in the macrophage or T cell compartments, respectively, to the pleiotropic cytokine, IFN gamma. We utilize these mice to identify previously undefined cellular targets of IFN gamma action in the development of a murine antimicrobial response and the mixed lymphocyte reaction. Moreover, we identify the macrophage as a critical responsive cell in manifesting the effects of IFN gamma in regulating CD4+ T helper subset development. These studies thus represent a novel approach to studying the cell-specific actions of an endogenously produced pleiotropic cytokine in vivo.


Queensland nursing staffs' perceptions of the preparation for practice of registered and enrolled nurses.
In Australia, unlike other countries, programmes which lead to registration as a registered or enrolled nurse (called "entry to practice" programmes) are carried out solely in the tertiary sector. In Australian nursing and the wider community, there continues to be a debate over the place of preparation and the "work readiness" of graduates. Despite several opinion papers on the preparation of registered nurses, there is a dearth of published research on the perceptions of the clinical nursing workforce on the suitability of the current preparation for practice models. Data were collected from approximately 3000 nurses in Queensland, Australia in 2007 and 2010. The aim of these studies was to ascertain issues around nursing work. This paper reports on qualitative data that were collected as part of that larger survey. Specifically this paper provides the thematic analysis of one open-ended question: "what are the five key issues and strategies that you see could improve nursing and nursing work?" as it was apparent when we undertook thematic analysis of this question that there was a major theme around the preparation of nurses for the nursing workforce. We therefore carried out a more detailed thematic analysis around this major theme. The major sub-themes that we identified from comments on the preparation of the nursing workforce were: perceptions of lack of clinical exposure and the need to increase the amount of clinical hours; the design of the curriculum, the place of preparation (solely within industry or a great focus on industry), financial consideration (students to be paid for their work); and in 2007 only, the need for students to have better time management. The findings suggest that a majority of respondents believed there should be changes to the entry to practice preparation for nurses. The major focus of these comments was the perception of insufficient clinical experience and inappropriate curriculum content. Thus, graduates are not "work ready". The attitude of clinical nurses, who work closely with student nurses, influences the workplace experience of student nurses. It is apparent from the statements of respondents in this study, that there is a need for stronger industry/academic partnerships, particularly around the design and implementation of the entry-to-practice curriculum.


Diabetes in pregnancy among indigenous women in Australia, Canada, New Zealand, and the United States: a method for systematic review of studies with different designs.
Diabetes in pregnancy, which includes gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM), is associated with poor outcomes for both mother and infant during pregnancy, at birth and in the longer term. Recent international guidelines recommend changes to the current GDM screening criteria. While some controversy remains, there appears to be consensus that women at high risk of T2DM, including indigenous women, should be offered screening for GDM early in pregnancy, rather than waiting until 24-28 weeks as is current practice. A range of criteria should be considered before changing screening practice in a population sub-group, including: prevalence, current practice, acceptability and whether adequate treatment pathways and follow-up systems are available. There are also specific issues related to screening in pregnancy and indigenous populations. The evidence that these criteria are met for indigenous populations is yet to be reported. A range of study designs can be considered to generate relevant evidence for these issues, including epidemiological, observational, qualitative, and intervention studies, which are not usually included within a single systematic review. The aim of this paper is to describe the methods we used to systematically review studies of different designs and present the evidence in a pragmatic format for policy discussion. The inclusion criteria will be broad to ensure inclusion of the critical perspectives of indigenous women. Abstracts of the search results will be reviewed by two persons; the full texts of all potentially eligible papers will be reviewed by one person, and 10% will be checked by a second person for validation. Data extraction will be standardised, using existing tools to identify risks for bias in intervention, measurement, qualitative studies and reviews; and adapting criteria for appraising risk for bias in descriptive studies. External validity (generalisability) will also be appraised. The main findings will be synthesised according to the criteria for population-based screening and summarised in an adapted "GRADE" tool. This will be the first systematic review of all the published literature on diabetes in pregnancy among indigenous women. The method provides a pragmatic approach for synthesizing relevant evidence from a range of study designs to inform the current policy discussion.


Engineered fibrin matrices for functional display of cell membrane-bound growth factor-like activities: study of angiogenic signaling by ephrin-B2.
With the rapid increase in approaches to pro- or anti-angiogenic therapy, new and effective methodologies for administration of cell-bound growth factors will be required. We sought to develop the natural hydrogel matrix fibrin as platform for extensive interactions and continuous signaling by the vascular morphogen ephrin-B2 that normally resides in the plasma membrane and requires multivalent presentation for ligation and activation of Eph receptors on apposing endothelial cell surfaces. Using fibrin and protein engineering technology to induce multivalent ligand presentation, a recombinant mutant ephrin-B2 receptor binding domain was covalently coupled to fibrin networks at variably high densities. The ability of fibrin-bound ephrin-B2 to act as ligand for endothelial cells was preserved, as demonstrated by a concomitant, dose-dependent increase of endothelial cell binding to engineered ephrin-B2-fibrin substrates in vitro. The therapeutic relevance of ephrin-B2-fibrin implant matrices was demonstrated by a local angiogenic response in the chick embryo chorioallontoic membrane evoked by the local and prolonged presentation of matrix-bound ephrin-B2 to tissue adjacing the implant. This new knowledge on biomimetic fibrin vehicles for precise local delivery of membrane-bound growth factor signals may help to elucidate specific biological growth factor function, and serve as starting point for development of new treatment strategies.


Environmental regulation of the fim switch controlling type 1 fimbrial phase variation in Escherichia coli K-12: effects of temperature and media.
Expression of type 1 fimbriae in Escherichia coli K-12 is phase variable and associated with the inversion of a short DNA element (switch). The fim switch requires either fimB (on-to-off or off-to-on switching) or fimE (on-to-off switching only) and is affected by the global regulators leucine-responsive regulatory protein (Lrp), integration host factor (IHF), and H-NS. Here it is shown that switching frequencies are regulated by both temperature and media and that these effects appear to be independent. fimE-promoted on-to-off switching occurs far more rapidly than previously estimated (0.3 per cell per generation in defined rich medium at 37 degrees C) and faster at lower than at higher temperatures. In direct contrast, fimB-promoted switching increases with temperature, with optima between 37 and 41 degrees C. Switching promoted by both fimB and fimE is stimulated by aliphatic amino acids (alanine, isoleucine, leucine, and valine), and this stimulation requires lrp. Furthermore, lrp appears to differentially regulate fimB- and fimE-promoted switching in different media.


Theory of change for the delivery of talking therapies by lay workers to survivors of humanitarian crises in low-income and middle-income countries: protocol of a systematic review.
There is a severe shortage of specialist mental healthcare providers in low-income and middle-income countries (LMICs) affected by humanitarian crises. In these settings, talking therapies may be delivered by non-specialists, including lay workers with no tertiary education or formal certification in mental health. This systematic review will synthesise the literature on the implementation and effectiveness of talking therapies delivered by lay workers in LMICs affected by humanitarian crises, in order to develop a Theory of Change (ToC). Qualitative, quantitative and mixed-methods studies assessing the implementation or effectiveness of lay-delivered talking therapies for common mental disorders provided to adult survivors of humanitarian crises in LMICs will be eligible for inclusion. Studies set in high-income countries will be excluded. No restrictions will be applied to language or year of publication. Unpublished studies will be excluded. Seven electronic databases will be searched: MEDLINE, Embase, PsycINFO, PsycEXTRA, Global Health, Cochrane Library and ClinicalTrials.gov. Contents pages of three peer-reviewed journals will be hand-searched. Sources of grey literature will include resource directories of two online mental health networks (MHPSS.net and MHInnovation.net) and expert consultation. Forward and backward citation searches of included studies will be performed. Two reviewers will independently screen studies for inclusion, extract data and assess study quality. A narrative synthesis will be conducted, following established guidelines. A ToC map will be amended iteratively to take into account the review results and guide the synthesis. Findings will be presented in a manuscript for publication in a peer-reviewed journal and disseminated through a coordinated communications strategy targeting knowledge generators, enablers and users. CRD42017058287.


Analysis of multiple mycotoxins in beer employing (ultra)-high-resolution mass spectrometry.
The objective of the presented study was to develop and optimize a simple, high-throughput method for the control of 32 mycotoxins (Fusarium and Alternaria toxins, aflatoxins, ergot alkaloids, ochratoxins, and sterigmatocystin) in beer. Due to the broad range of their physicochemical properties, the sample preparation step was simplified as much as possible to avoid analyte losses. The addition of acetonitrile to beer samples enabled precipitation of abundant matrix components. The clean-up efficiency was controlled by ambient mass spectrometry employing a direct analysis in real time (DART) ion source. For determination of analytes, ultra-high-performance liquid chromatography hyphenated with high-resolution mass spectrometry utilizing an orbitrap (U-HPLC-orbitrapMS) or time-of-flight (TOFMS) technology was used. Because of significantly better detection capabilities of the orbitrap technology, the U-HPLC-orbitrapMS method was chosen as a determinative step and fully validated. To compensate matrix effects, matrix-matched calibration was employed. The lowest calibration levels for most of the target mycotoxins ranged from 1 to 8 µg L(-1) beer and the recoveries of analytes were in range from 86 to 124%.


Core competencies for shared decision making training programs: insights from an international, interdisciplinary working group.
Shared decision making is now making inroads in health care professionals' continuing education curriculum, but there is no consensus on what core competencies are required by clinicians for effectively involving patients in health-related decisions. Ready-made programs for training clinicians in shared decision making are in high demand, but existing programs vary widely in their theoretical foundations, length, and content. An international, interdisciplinary group of 25 individuals met in 2012 to discuss theoretical approaches to making health-related decisions, compare notes on existing programs, take stock of stakeholders concerns, and deliberate on core competencies. This article summarizes the results of those discussions. Some participants believed that existing models already provide a sufficient conceptual basis for developing and implementing shared decision making competency-based training programs on a wide scale. Others argued that this would be premature as there is still no consensus on the definition of shared decision making or sufficient evidence to recommend specific competencies for implementing shared decision making. However, all participants agreed that there were 2 broad types of competencies that clinicians need for implementing shared decision making: relational competencies and risk communication competencies. Further multidisciplinary research could broaden and deepen our understanding of core competencies for shared decision making training.