Spectrum of germline AIRE mutations causing APS-1 and familial hypoparathyroidism.
The autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disorder characterised by immune dysregulation and autoimmune endocrine gland destruction. APS-1 is caused by biallelic mutations affecting the autoimmune regulator (AIRE) gene on chromosome 21q22.3, which facilitates immunological self-tolerance. The objective was to investigate >300 probands with suspected APS-1 or isolated hypoparathyroidism for AIRE abnormalities. Probands were assessed by DNA sequence analysis. Novel variants were characterised using 3D modelling of the AIRE protein. Restriction enzyme and microsatellite analysis were used to investigate for uniparental isodisomy. Biallelic AIRE mutations were identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. These included a novel homozygous p.(His14Pro) mutation, predicted to disrupt the N-terminal caspase activation recruitment domain of the AIRE protein. Furthermore, an apparently homozygous AIRE mutation, p.Leu323fs, was identified in an APS-1 proband, who is the child of non-consanguineous asymptomatic parents. Microsatellite analysis revealed that the proband inherited two copies of the paternal mutant AIRE allele due to uniparental isodisomy. Hypoparathyroidism was the most common endocrine manifestation in AIRE mutation-positive probands and >45% of those harbouring AIRE mutations had at least two diseases out of the triad of candidiasis, hypoparathyroidism, and hypoadrenalism. In contrast, type 1 diabetes and hypothyroidism occurred more frequently in AIRE mutation-negative probands with suspected APS-1. Around 30% of AIRE mutation-negative probands with isolated hypoparathyroidism harboured mutations in other hypoparathyroid genes. This study of a large cohort referred for AIRE mutational analysis expands the spectrum of genetic abnormalities causing APS-1.


Inequalities in health by social class dimensions in European countries of different political traditions.
To compare inequalities in self-perceived health in the population older than 50 years, in 2004, using Wright's social class dimensions, in nine European countries grouped in three political traditions (Social democracy, Christian democracy and Late democracies). Cross-sectional design, including data of the Survey of Health, Ageing and Retirement in Europe (Sweden, Denmark, Austria, France, Germany, The Netherlands, Spain, Italy and Greece). The population aged from 50 to 74 years was included. Absolute and relative social class dimension inequalities in poor self-reported health and long-term illness were determined for each sex and political tradition. Relative inequalities were assessed by fitting Poisson regression models with robust variance estimators. Absolute and relative health inequalities by social class dimensions are found in the three political traditions, but these differences are more marked in Late democracies and mainly among women. For example the prevalence ratio of poor self-perceived health comparing poorly educated women with highly educated women, was 1.75 (95% CI: 1.39-2.21) in Late democracies and 1.36 (95% CI: 1.21-1.52) in Social democracies. The prevalence differences were 24.2 and 13.7%, respectively. This study is one of the first to show the impact of different political traditions on social class inequalities in health. These results emphasize the need to evaluate the impact of the implementation of public policies.


Imaging of Pregnancy-related Vascular Complications.
Pregnancy results in substantial hemodynamic and prothrombotic changes that form the foundation for downstream vascular complications, both during pregnancy and in the postpartum period. In addition, several important risk factors, including older patient age, diabetes, and smoking, can increase the risk for vascular-related pregnancy complications. Because radiologists often play an important role in evaluation of the pregnant patient, understanding the pathophysiology of vascular-related complications in pregnancy and their imaging appearances is essential for diagnostic accuracy. The authors review relevant normal physiologic changes of pregnancy, pathophysiologic changes, and imaging features of vascular conditions that can manifest in conjunction with pregnancy. Particular attention is given to pertinent imaging information that radiologists should provide to referring clinicians to optimally affect the management of pregnant patients as well as women in the peripartum and postpartum stages. Among the complications discussed are preeclampsia; hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome; spontaneous coronary artery dissection; placental abruption; amniotic fluid embolism and acute pulmonary embolism; dural venous sinus thrombosis; ovarian vein thrombophlebitis; vasa previa; uterine arteriovenous malformations; heritable aortopathies; and hereditary hemorrhagic telangiectasia. To help radiologists avoid the use of unnecessary ionizing radiation in pregnancy, imaging examination selection and optimization are also reviewed. Radiologists should be familiar with the physiologic changes of pregnancy, radiation risks during gestation, and pregnancy-related vascular complications to improve imaging examination selection, diagnosis, and clinical management. ©RSNA, 2017.


Psychometric properties of a computerized mobile phone method for assessing mood in daily life.
Ecological momentary assessment is a method that is now largely used to study behavior and mood in the settings in which they naturally occur. It maximizes ecological validity and avoids the limitations of retrospective self-reports. Studies on the psychometric properties of scales administered via mobile phone ecological momentary assessment are lacking. Therefore, we collected data on a 4-item mood scale measuring well being on six occasions per day for 7 days (N = 307) and examined compliance rate across time, within day, and within week. Using specific latent state-trait structural equation models, we analyzed the degree to which interindividual mood differences on an occasion of measurement were because of (a) measurement error, (b) stable differences in mood level, and (c) occasion-specific differences. Results show good compliance (mean compliance: 74.9% of calls answered). Moreover, the scale showed good reliability (M = .82). Mood was mostly stable, especially the first 3 days of the week. It depended weakly albeit significantly on the previous assessment (autoregressive coefficient). In conclusion, computerized mobile phone assessment is an appropriate, easy-to-use, and promising method to measure mood.


Clinical and demographic trends in a sexually transmitted infection clinic in Mumbai (1994-2006): an epidemiologic analysis.
People presenting to sexually transmitted infections (STIs) clinics represent an important risk group for HIV infection; prevention strategies will depend on the clinical attendance. The demographic and clinical changes in clinic attendees in Mumbai, as well as the factors associated with HIV infection in this clinic over a 13-year period, were assessed. STI clinic data in 3417 individuals (1994 to 2006) were analyzed: clinical presentation, types of STIs, and serology over the 13-year period. We used a logistic regression model to assess socio-demographic and clinical associations with HIV infection. The clinic evaluated 689 patients in 1994 and the number had dropped to 97 in 2006. In 1994, the majority of STIs seen in the clinic were bacterial (53%, 95% confidence interval [CI] 50% to 57%); however, this proportion had dropped in 2006 (28%, 95% CI: 19% to 38%). There was a proportional increase in viral STIs during the same time period. Although women attending the clinic were younger than men, they were more likely to be married. The overall seropositivity for HIV was 28%. Viral STIs were more likely to be associated with HIV than bacterial infections (odds ratio: 1.5, 95% CI: 1.2 to 1.9). Viral infections were the most common STIs in recent years in a tertiary care center in Mumbai. HIV prevalence was high in this population. Thus, these clinical data suggest that STI patients were and continue to be an important group for HIV prevention in the country.


Stroke risk and outcomes in epilepsy patients: Two retrospective cohort studies based on National Health Insurance in Taiwan.
The risk of stroke in epileptic patients and the impact of epilepsy history on stroke patients' outcome have not been studied completely. Our purpose is to evaluate whether patients with epilepsy have increased risk of stroke or post-stroke mortality. In Study I, we conducted a retrospective cohort study of 6746 patients with newly diagnosed epilepsy and 26,984 persons without epilepsy between 2000 and 2008, in the database of National Health Insurance in Taiwan. The incidences and risks of stroke during the follow-up period were compared between cohorts until the end of 2013. In Study II, we conducted a nested cohort study of 484,990 hospitalized patients with newly diagnosed stroke between 2000 and 2009. We compared the short-term mortality and complications during stroke admission between stroke patients with previous epilepsy and those without epilepsy. The epileptic cohort had an increased stroke risk (hazard ratio [HR] 2.24, 95% CI 2.02 to 2.49). The relationship between epilepsy and stroke risk remains significant in every age group and both sexes. Among hospitalized stroke patients, history of epilepsy was associated with complications, including pneumonia (odds ratio [OR] 1.08, 95% CI 1.00 to 1.18), urinary tract infection (OR 1.16, 95% CI 1.08 to 1.26), and longer stay (p < 0.0001) during the index stroke admission. Epileptic patients face increased stroke risk and adverse outcomes of stroke admission. It is necessary to develop a prevention strategy for stroke in epileptic patients.


Knowledge will Propel Machine Understanding of Content: Extrapolating from Current Examples.
Machine Learning has been a big success story during the AI resurgence. One particular stand out success relates to learning from a massive amount of data. In spite of early assertions of the unreasonable effectiveness of data, there is increasing recognition for utilizing knowledge whenever it is available or can be created purposefully. In this paper, we discuss the indispensable role of knowledge for deeper understanding of content where (i) large amounts of training data are unavailable, (ii) the objects to be recognized are complex, (e.g., implicit entities and highly subjective content), and (iii) applications need to use complementary or related data in multiple modalities/media. What brings us to the cusp of rapid progress is our ability to (a) create relevant and reliable knowledge and (b) carefully exploit knowledge to enhance ML/NLP techniques. Using diverse examples, we seek to foretell unprecedented progress in our ability for deeper understanding and exploitation of multimodal data and continued incorporation of knowledge in learning techniques.


Maternal TET3 is dispensable for embryonic development but is required for neonatal growth.
The development of multicellular organisms is accompanied by reprogramming of the epigenome in specific cells, with the epigenome of most cell types becoming fixed after differentiation. Genome-wide reprogramming of DNA methylation occurs in primordial germ cells and in fertilized eggs during mammalian embryogenesis. The 5-methylcytosine (5mC) content of DNA thus undergoes a marked decrease in the paternal pronucleus of mammalian zygotes. This loss of DNA methylation has been thought to be mediated by an active demethylation mechanism independent of replication and to be required for development. TET3-mediated sequential oxidation of 5mC has recently been shown to contribute to the genome-wide loss of 5mC in the paternal pronucleus of mouse zygotes. We now show that TET3 localizes not only to the paternal pronucleus but also to the maternal pronucleus and oxidizes both paternal and maternal DNA in mouse zygotes, although these phenomena are less pronounced in the female pronucleus. Genetic ablation of TET3 in oocytes had no significant effect on oocyte development, maturation, or fertilization or on pregnancy, but it resulted in neonatal sublethality. Our results thus indicate that zygotic 5mC oxidation mediated by maternal TET3 is required for neonatal growth but is not essential for development.


Top 10 health care ethics challenges facing the public: views of Toronto bioethicists.
There are numerous ethical challenges that can impact patients and families in the health care setting. This paper reports on the results of a study conducted with a panel of clinical bioethicists in Toronto, Ontario, Canada, the purpose of which was to identify the top ethical challenges facing patients and their families in health care. A modified Delphi study was conducted with twelve clinical bioethicist members of the Clinical Ethics Group of the University of Toronto Joint Centre for Bioethics. The panel was asked the question, what do you think are the top ten ethical challenges that Canadians may face in health care? The panel was asked to rank the top ten ethical challenges throughout the Delphi process and consensus was reached after three rounds. The top challenge ranked by the group was disagreement between patients/families and health care professionals about treatment decisions. The second highest ranked challenge was waiting lists. The third ranked challenge was access to needed resources for the aged, chronically ill, and mentally ill. Although many of the challenges listed by the panel have received significant public attention, there has been very little attention paid to the top ranked challenge. We propose several steps that can be taken to help address this key challenge.


Combination treatment of rheumatoid arthritis using azathioprine and methotrexate: a 48 week controlled clinical trial.
To assess the relative efficacy of methotrexate (MTX), azathioprine (AZA), and their combination in the treatment of rheumatoid arthritis (RA), a double blind, prospective, multicenter, controlled trial was carried out. Two hundred nine patients with active RA were treated with escalating doses of MTX (5-15 mg/week), AZA (50-150 mg/day), or combination (5/50-7.5/100) with opportunity to increase dosage at 6 week intervals. Patients were evaluated for clinical and laboratory improvement and assessed for radiologic progression at 48 weeks. One hundred ten patients remained on the initial, randomly assigned therapy. Response was defined as 30% or greater improvement in at least 3 of 4 variables, and occurred in the following: 38% on the combination arm, 26% on AZA, and 45% on MTX (p = 0.06). A trend for decreased radiologic progression was seen in the MTX group. Adverse experiences and treatment termination occurred more frequently in the combination and AZA arms relative to the MTX group. The most frequent causes for treatment discontinuations were lack of effectiveness, gastrointestinal adverse effects and liver enzyme elevation. This study establishes that the combination of MTX and AZA in the dosages employed is not associated with more toxicity than treatment with single agents, but enhanced efficacy is not seen. A trend toward decreased radiographic progression was noted in the MTX treated patients.


Erectile dysfunction and coronary artery disease prediction: evidence-based guidance and consensus.
* A significant proportion of men with erectile dysfunction (ED) exhibit early signs of coronary artery disease (CAD), and this group may develop more severe CAD than men without ED (Level 1, Grade A). * The time interval among the onset of ED symptoms and the occurrence of CAD symptoms and cardiovascular events is estimated at 2-3 years and 3-5 years respectively; this interval allows for risk factor reduction (Level 2, Grade B). * ED is associated with increased all-cause mortality primarily due to increased cardiovascular mortality (Level 1, Grade A). * All men with ED should undergo a thorough medical assessment, including testosterone, fasting lipids, fasting glucose and blood pressure measurement. Following assessment, patients should be stratified according to the risk of future cardiovascular events. Those at high risk of cardiovascular disease should be evaluated by stress testing with selective use of computed tomography (CT) or coronary angiography (Level 1, Grade A). * Improvement in cardiovascular risk factors such as weight loss and increased physical activity has been reported to improve erectile function (Level 1, Grade A). * In men with ED, hypertension, diabetes and hyperlipidaemia should be treated aggressively, bearing in mind the potential side effects (Level 1, Grade A). * Management of ED is secondary to stabilising cardiovascular function, and controlling cardiovascular symptoms and exercise tolerance should be established prior to initiation of ED therapy (Level 1, Grade A). * Clinical evidence supports the use of phosphodiesterase 5 (PDE5) inhibitors as first-line therapy in men with CAD and comorbid ED and those with diabetes and ED (Level 1, Grade A). * Total testosterone and selectively free testosterone levels should be measured in all men with ED in accordance with contemporary guidelines and particularly in those who fail to respond to PDE5 inhibitors or have a chronic illness associated with low testosterone (Level 1, Grade A). * Testosterone replacement therapy may lead to symptomatic improvement (improved wellbeing) and enhance the effectiveness of PDE5 inhibitors (Level 1, Grade A). * Review of cardiovascular status and response to ED therapy should be performed at regular intervals (Level 1, Grade A).


An inducible ESCRT-III inhibition tool to control HIV-1 budding.
HIV-1 budding as well as many other cellular processes require the Endosomal Sorting Complex Required for Transport (ESCRT) machinery. Understanding the architecture of the native ESCRT-III complex at HIV-1 budding sites is limited due to spatial resolution and transient ESCRT-III recruitment. Here, we developed a drug-inducible transient HIV-1 budding inhibitory tool to enhance the ESCRT-III lifetime at budding sites. We generated auto-cleavable CHMP2A, CHMP3, and CHMP4B fusion proteins with the hepatitis C virus NS3 protease. We characterized the CHMP-NS3 fusion proteins in the absence and presence of protease inhibitor Glecaprevir with regard to expression, stability, localization and HIV-1 Gag VLP budding. Immunoblotting experiments revealed rapid and stable accumulation of CHMP-NS3 fusion proteins with variable modification of Gag VLP budding upon drug administration. Notably, CHMP2A-NS3 and CHMP4B-NS3 fusion proteins substantially decrease VLP release while CHMP3-NS3 exerted a minor effect and synergized with CHMP2A-NS3. Localization studies demonstrated the re-localization of CHMP-NS3 fusion proteins to the plasma membrane, endosomes, and Gag VLP budding sites. Through the combined use of transmission electron microscopy and video-microscopy, we unveiled drug-dependent accumulation of CHMP2A-NS3 and CHMP4B-NS3, causing a delay in HIV-1 Gag-VLP release. Our findings provide novel insight into the functional consequences of inhibiting ESCRT-III during HIV-1 budding and establish new tools to decipher the role of ESCRT-III at HIV-1 budding sites and other ESCRT-catalyzed cellular processes.


Individual and team consensus ratings of child functioning.
The authors examined agreement between interdisciplinary teams of professionals in rating the functional abilities of children with disabilities. 129 children were rated on the ABILITIES index by 72 professionals working in nine developmental evaluation centers. Independent individual ratings were made first, followed by a consensus rating. Team members had a high degree of agreement on independent ratings of abilities and limitations, with nearly 90 per cent of the ratings within one point of each other. More disagreement was associated with rating areas of behavior and communication, team experience and increased severity of disability. The team's consensus ratings were more likely to defer to the ratings of the expert in particular areas. Implications for team assessment and team functioning are discussed.


The Cord Blood Apgar: a novel scoring system to optimize selection of banked cord blood grafts for transplantation (CME).
Engraftment failure and delays, likely due to diminished cord blood unit (CBU) potency, remain major barriers to the overall success of unrelated umbilical cord blood transplantation (UCBT). To address this problem, we developed and retrospectively validated a novel scoring system, the Cord Blood Apgar (CBA), which is predictive of engraftment after UCBT. In a single-center retrospective study, utilizing a database of 435 consecutive single cord myeloablative UCBTs performed between January 1, 2000, to December 31, 2008, precryopreservation and postthaw graft variables (total nucleated cell, CD34+, colony-forming units, mononuclear cell content, and volume) were initially correlated with neutrophil engraftment. Subsequently, based on the magnitude of hazard ratios (HRs) in univariate analysis, a weighted scoring system to predict CBU potency was developed using a randomly selected training data set and internally validated on the remaining data set. The CBA assigns transplanted CBUs three scores: a precryopreservation score (PCS), a postthaw score (PTS), and a composite score (CS), which incorporates the PCS and PTS values. CBA-PCS scores, which could be used for initial unit selection, were predictive of neutrophil (CBA-PCS ≥ 7.75 vs. <7.75, HR 3.5; p < 0.0001) engraftment. Likewise, CBA-PTS and CS scores were strongly predictive of Day 42 neutrophil engraftment (CBA-PTS ≥ 9.5 vs. <9.5, HR 3.16, p < 0.0001; CBA-CS ≥ 17.75 vs. <17.75, HR 4.01, p < 0.0001). The CBA is strongly predictive of engraftment after UCBT and shows promise for optimizing screening of CBU donors for transplantation. In the future, a segment could be assayed for the PTS score providing data to apply the CS for final CBU selection.


Dental caries among disadvantaged 3- to 4-year-old children in northern Manhattan.
The study was conducted to determine the prevalence of early childhood caries (ECC), untreated caries, and the ratio of posterior to anterior caries in a disadvantaged predominantly Hispanic or African-American urban population. Data are compared to NHANES III to assess the caries burden in our cohort. Comparisons are made to the aggregate and to minorities within the national database. A retrospective chart review was conducted for children enrolled in a Head Start or day care program in the communities of Washington-Heights and Central and East Harlem and seen on the community organization's mobile dental van between 1995 and 1997. The study included only children 3 to 4 years of age at the initial examination (n=1,605). A single examiner provided all the examinations. The mean number of decayed and filled surfaces (dfs), decayed surfaces (ds) and filled surfaces (fs), the percentage of decayed of total decayed and filled surfaces (%d/dfs), decayed and filled teeth (dft), decayed teeth (dt) and filled teeth (ft), and the percentage of decayed of total decayed and filled teeth (%d/dft) were calculated. Posterior vs anterior d, f, dft, dfs and d-anterior/total d, and d-posterior/total d were tabulated. Northern Manhattan data was tabulated and compared to NHANES III (1988-1994) in the aggregate and for subpopulations categorized by gender and ethnicity. All results are also reported for children with at least one decayed or filled tooth. T-tests were used to assess for significant differences. There was even representation of males (50%) and females (50%). Mean dft was 1.08 overall, and 3.14 for children with dft>0. The level of untreated decay, %d/ dft, was 91%, significantly higher than the US national population which is 76% overall, and 76% for African Americans and Mexican Americans within the US national population. The children in this population have higher caries prevalence and a higher level of untreated caries than the national means as reported in NHANES III. The high level of untreated decay found in this particularly disadvantaged community suggests that enhanced dental services targeting the very young are needed in these communities.


Glycoprotein D of herpes simplex virus encodes a domain which precludes penetration of cells expressing the glycoprotein by superinfecting herpes simplex virus.
Earlier studies have shown that herpes simplex viruses adsorb to but do not penetrate permissive baby hamster kidney clonal cell lines designated the BJ series and constitutively expressing the herpes simplex virus 1 (HSV-1) glycoprotein D (gD). To investigate the mechanism of the restriction, the following steps were done. First, wild-type HSV-1 strain F [HSV-1(F)] virus was passaged blindly serially on clonal line BJ-1 and mutant viruses [HSV-1(F)U] capable of penetration were selected. The DNA fragment capable of transferring the capacity to infect BJ cells by marker transfer contains the gD gene. The mutant gD, designated gDU, differed from wild-type gD only in the substitution of Leu-25 by proline. gDU reacted with monoclonal antibodies which neutralize virus and whose epitopes encompass known functional domains involved in virus entry into cells. It did not react with the monoclonal antibody AP7 previously shown to react with an epitope which includes Leu-25. Second, cell lines expressing gDU constitutively were constructed and cloned. Unlike the clonal cell lines constitutively expressing gD (e.g., the BJ cell line), those expressing gDU were infectable by both HSV-1(F) and HSV-1(F)U. Lastly, exposure of BJ cells to monoclonal antibody AP7 rendered the cells capable of being infected with HSV-1(F). The results indicate that (i) gD expresses a specific function, determined by sequences at or around Leu-25, which blocks entry of virus into cells synthesizing gD, (ii) the gD which blocks penetration by superinfecting virus is located in the plasma membrane, (iii) the target of the restriction to penetration is the identical domain of the gD molecule contained in the envelope of the superinfecting virus, and (iv) the molecular basis of the restriction does not involve competition for a host protein involved in entry, as was previously thought.


Malpractice risk and cost are significantly reduced after tort reform.
Rising medical malpractice premiums have reached a crisis point in many areas of the United States. In 2003 the Texas legislature passed a comprehensive package of tort reform laws that included a cap at $250,000 on noneconomic damages in most medical malpractice cases. We hypothesized that tort reform laws significantly reduce the risk of malpractice lawsuit in an academic medical center. We compared malpractice prevalence, incidence, and liability costs before and after comprehensive state tort reform measures were implemented. Two prospectively maintained institutional databases were used to calculate and characterize malpractice risk: a surgical operation database and a risk management and malpractice database. Risk groups were divided into pretort reform (1992 to 2004) and post-tort reform groups (2004 to the present). Operative procedures were included for elective, urgent, and emergency general surgery procedures. During the study period, 98,513 general surgical procedures were performed. A total of 28 lawsuits (25 pre-reform, 3 postreform) were filed, naming general surgery faculty or residents. The prevalence of lawsuits filed/100,000 procedures performed is as follows: before reform, 40 lawsuits/100,000 procedures, and after reform, 8 lawsuits/100,000 procedures (p < 0.01, relative risk 0.21 [95% CI 0.063 to 0.62]). Virtually all of the liability and defense cost was in the pretort reform period: $595,000/year versus $515/year in the postreform group (p < 0.01). Implementation of comprehensive tort reform in Texas was associated with a significant decrease in the prevalence and cost of surgical malpractice lawsuits at one academic medical center.


Impact of alternative reimbursement strategies in the new cooperative medical scheme on caesarean delivery rates: a mixed-method study in rural China.
The rate of caesarean delivery (CD) in rural China has been rapidly increasing in recent decades. Due to the exorbitant costs associated with CD, paying for this expensive procedure is often a great challenge for the majority of rural families. Since 2003, the Chinese government has re-established the New Cooperative Medical Scheme (NCMS), aimed to improve the access of essential healthcare to rural residents and reduce financial burden owing to high out of pocket payments. This paper seeks to test the hypothesis that NCMS may provide service users and providers with financial incentives to select CD. It also assesses the effect of different health insurance reimbursement strategies of NCMS on CD rates in rural China. Mixed quantitative and qualitative methods were adopted for data collection. Two cross-sectional household surveys were conducted with women having babies delivered in 2006 and 2009; 2326 and 1515 women, respectively, from the study sites were interviewed using structured questionnaires, to collect demographic and socio-economic data, maternal and child care characteristics and health-related expenditures. Focus group discussions (FGDs) and in-depth key informant interviews (KIIs) were undertaken with policy makers, health managers, providers and mothers to understand their perceptions of the influence of NCMS on the choices of delivery mode. The CD rates in the two study counties were 46.0 percent and 64.7 percent in 2006, increasing to 63.6 percent and 82.1 percent, respectively, in 2009. The study found that decisions on the selection of CD largely came from the pregnant women. Logistic regression analysis, after adjusting for socio-economic, maternal and fetal characteristics, did not indicate a significant effect of either proportional reimbursement or fixed amount reimbursement on the choice of CD for both study years. Interviews with stakeholders reflected that different reimbursable rates for CD and vaginal deliveries did not have a significant effect on controlling the rising CD rate in the study countries. NCMS reimbursement strategies adopted in the study counties of China did not have a significant effect on the selection of CD for baby deliveries. The rapid rise of the CD rates of rural China has remained a serious issue. Other effective measures, such as health education to increase awareness of mothers' knowledge, and improving training of health staff in evidence-based delivery care, maybe could do more to promote rational baby delivery in rural China.


Blood pressure, plasma renin activity and aldosterone concentrations in vegans and omnivore controls.
Blood pressure, plasma renin activity and the concentrations of aldosterone and cholesterol in plasma and sodium and potassium in urine (48-h collections) and nutrient intakes were determined in 22 vegans (11 male and 11 female) and omnivore controls matched for age, sex and body build. The vegan diets contained less protein, sodium, calcium and sulphur but more carbohydrate, potassium and fibre than the diets of their controls. The mean urinary potassium sodium ratio was 1.13 in the vegans compared with 0.64 in the omnivores. Plasma renin and cholesterol concentrations were lower in the male but not female vegans compared with their respective controls. Blood pressures of the vegan subjects were inside the normal range but they tended to have higher mean diastolic blood pressures than their controls.


Efficacy and safety of certolizumab pegol plus methotrexate in Japanese rheumatoid arthritis patients with an inadequate response to methotrexate: the J-RAPID randomized, placebo-controlled trial.
This 24-week, multicenter, double-blind, randomized, placebo-controlled study (NCT00791999) compared efficacy and safety of certolizumab pegol (CZP) in combination with methotrexate (MTX) vs placebo plus MTX in Japanese rheumatoid arthritis (RA) patients with inadequate response to MTX. In total, 316 patients were randomized 1:1:1:1 to subcutaneous CZP 100, 200, or 400 mg (induction dose: 200 mg or 400 mg CZP at Weeks 0, 2, and 4) plus MTX or placebo plus MTX every 2 weeks. Primary endpoint was ACR20 response at Week 12. ACR20 response rates were 62.5%, 76.8%, 77.6%, and 28.6% at Week 12, and 61.1%, 73.2%, 71.8%, and 24.7% at Week 24 for CZP 100, 200, and 400 mg, and placebo groups, respectively, with statistical significance between each CZP group and placebo. Change in Total Sharp Score over 24 weeks was significantly smaller in CZP 200 and 400 mg groups vs placebo. Improvements in health-related quality of life (HRQoL) were observed in all three CZP groups vs placebo. Incidence of adverse events was similar between CZP groups. CZP plus MTX resulted in rapid, sustained reductions in RA signs and symptoms in Japanese patients with inadequate response to MTX, with significant inhibition of radiographic progression and improved HRQoL.


A complex signaling module governs the activity of MalT, the prototype of an emerging transactivator family.
MalT, the specific activator of the maltose regulon, is the prototype of a family of high-molecular-mass ATP-binding bacterial transcription activators. On binding of its two positive effectors, the inducer maltotriose and ATP, MalT oligomerizes to an active state competent for promoter binding and transcription activation. In addition to its previously known DNA-binding domain, limited proteolysis showed that MalT contains three other domains, the boundaries of which were accurately delimited by N-terminal microsequencing. The N-terminal domain alone binds ATP. Maltotriose binding involves an extended region corresponding to domains 2 and 3, although weak binding to domain 3 alone was also observed. Moreover, maltotriose binding induces a conformational shift involving a movement of both domains 1 and 3 with respect to domain 2, leading to the active form of the protein. Sequence examination of the MalT homologues suggests that these three domains might constitute a signaling module.


A new filtering technique for removing anti-Stokes emission background in gated CW-STED microscopy.
Stimulated emission depletion (STED) microscopy is a prominent approach of super-resolution optical microscopy, which allows cellular imaging with so far unprecedented unlimited spatial resolution. The introduction of time-gated detection in STED microscopy significantly reduces the (instantaneous) intensity required to obtain sub-diffraction spatial resolution. If the time-gating is combined with a STED beam operating in continuous wave (CW), a cheap and low labour demand implementation is obtained, the so called gated CW-STED microscope. However, time-gating also reduces the fluorescence signal which forms the image. Thereby, background sources such as fluorescence emission excited by the STED laser (anti-Stokes fluorescence) can reduce the effective resolution of the system. We propose a straightforward method for subtraction of anti-Stokes background. The method hinges on the uncorrelated nature of the anti-Stokes emission background with respect to the wanted fluorescence signal. The specific importance of the method towards the combination of two-photon-excitation with gated CW-STED microscopy is demonstrated.


A functional human Poly(A) site requires only a potent DSE and an A-rich upstream sequence.
We have analysed the sequences required for cleavage and polyadenylation in the intronless melanocortin 4 receptor (MC4R) pre-mRNA. Unlike other intronless genes, 3'end processing of the MC4R primary transcript is independent of any auxiliary sequence elements and only requires the core poly(A) sequences. Mutation of the AUUAAA hexamer had little effect on MC4R 3'end processing but small changes in the short DSE severely reduced cleavage efficiency. The MC4R poly(A) site requires only the DSE and an A-rich upstream sequence to direct efficient cleavage and polyadenylation. Our observation may be highly relevant for the understanding of how human noncanonical poly(A) sites are recognised. This is supported by a genome-wide analysis of over 10 000 poly(A) sites where we show that many human noncanonical poly(A) signals contain A-rich upstream sequences and tend to have a higher frequency of U and GU nucleotides in their DSE compared with canonical poly(A) signals. The importance of A-rich elements for noncanonical poly(A) site recognition was confirmed by mutational analysis of the human JUNB gene, which contains an A-rich noncanonical poly(A) signal.


Characterization of Seedling Infection Types and Adult Plant Infection Responses of Monogenic Sr Gene Lines to Race TTKS of Puccinia graminis f. sp. tritici.
Stem rust, caused by Puccinia graminis f. sp. tritici, historically was one of the most destructive diseases of wheat and barley. The disease has been under effective control worldwide through the widespread use of host resistance. A number of stem rust resistance genes in wheat have been characterized for their reactions to specific races of P. graminis f. sp. tritici. Adult plant responses to race TTKS (also known as Ug99) of monogenic lines for Sr genes, a direct measurement of the effectiveness for a given gene, have not been investigated to any extent. This report summarizes adult plant infection responses and seedling infection types for monogenic lines of designated Sr genes challenged with race TTKS. High infection types at the seedling stage and susceptible infection responses in adult plants were observed on monogenic lines carrying Sr5, 6, 7a, 7b, 8a, 8b, 9a, 9b, 9d, 9g, 10, 11, 12, 15, 16, 17, 18, 19, 20, 23, 30, 31, 34, 38, and Wld-1. Monogenic lines of resistance genes Sr13, 22, 24, 25, 26, 27, 28, 32, 33, 35, 36, 37, 39, 40, 44, Tmp, and Tt-3 were effective against TTKS both at the seedling and adult plant stages. The low infection types to race TTKS observed for these resistance genes corresponded to the expected low infections of these genes to other incompatible races of P. graminis f. sp. tritici. The level of resistance conferred by these genes at the adult plant stage varied between highly resistant to moderately susceptible. The results from this study were inconclusive for determining the effectiveness of resistance genes Sr9e, 14, 21, and 29 against race TTKS. The understanding of the effectiveness of individual Sr genes against race TTKS will facilitate the utilization of these genes in breeding for stem rust resistance in wheat.


Hyperpolarization of deuterated metabolites via remote cross-polarization and dissolution dynamic nuclear polarization.
In deuterated molecules such as [1-(13)C]pyruvate-d3, the nuclear spin polarization of (13)C nuclei can be enhanced by combining Hartmann-Hahn cross-polarization (CP) at low temperatures (1.2 K) with dissolution dynamic nuclear polarization (D-DNP). The polarization is transferred from remote solvent protons to the (13)C spins of interest. This allows one not only to slightly reduce build-up times but also to increase polarization levels and extend the lifetimes T1((13)C) of the enhanced (13)C polarization during and after transfer from the polarizer to the NMR or MRI system. This extends time scales over which metabolic processes and chemical reactions can be monitored.


Fate and activity of microorganisms introduced into soil.
Introduced microorganisms are potentially powerful agents for manipulation of processes and/or components in soil. Fields of application include enhancement of crop growth, protection of crops against plant-pathogenic organisms, stimulation of biodegradation of xenobiotic compounds (bioaugmentation), and improvement of soil structure. Inoculation of soils has already been applied for decades, but it has often yielded inconsistent or disappointing results. This is caused mainly by a commonly observed rapid decline in inoculant population activity following introduction into soil, i.e., a decline of the numbers of inoculant cells and/or a decline of the (average) activity per cell. In this review, we discuss the available information on the effects of key factors that determine the fate and activity of microorganisms introduced into soil, with emphasis on bacteria. The factors addressed include the physiological status of the inoculant cells, the biotic and abiotic interactions in soil, soil properties, and substrate availability. Finally, we address the possibilities available to effectively manipulate the fate and activity of introduced microorganisms in relation to the main areas of their application.


Attempt to improve the performance of pyrrole-containing dyes in dye sensitized solar cells by adjusting isolation groups.
Four new pyrrole-based organic sensitizers with different isolation groups were conveniently synthesized and applied to dye sensitized solar cells (DSCs). The introduction of isolation group in the side chain could both suppress the formation of dye aggregates and electron recombination. Especially, when two pieces of D-π-A chromophore moieties shared one isolation group to construct the "H" type dye, the performance was further improved. Consequently, in the corresponding solar cell of LI-57, a short-circuit photocurrent density (Jsc) was tested to be 13.85 mA cm(-2), while 0.72 V for the open-circuit photovoltage (Voc), 0.64 for the fill factor (FF), and 6.43% for the overall conversion efficiency (η), exceeding its analogue LI-55 (5.94%) with the same isolation group. The results demonstrated that both the size (bulk and shape) and the linkage mode between the D-π-A chromophores and the isolation groups, could affect the performance of sensitizers in DSCs in a large degree, providing a new approach to optimize the chemical structure of dyes to achieve high conversion efficiencies.


Evaluating Cost-effectiveness of Interventions That Affect Fertility and Childbearing: How Health Effects Are Measured Matters.
Current guidelines for economic evaluations of health interventions define relevant outcomes as those accruing to individuals receiving interventions. Little consensus exists on counting health impacts on current and future fertility and childbearing. Our objective was to characterize current practices for counting such health outcomes. We developed a framework characterizing health interventions with direct and/or indirect effects on fertility and childbearing and how such outcomes are reported. We identified interventions spanning the framework and performed a targeted literature review for economic evaluations of these interventions. For each article, we characterized how the potential health outcomes from each intervention were considered, focusing on quality-adjusted life-years (QALYs) associated with fertility and childbearing. We reviewed 108 studies, identifying 7 themes: 1) Studies were heterogeneous in reporting outcomes. 2) Studies often selected outcomes for inclusion that tend to bias toward finding the intervention to be cost-effective. 3) Studies often avoided the challenges of assigning QALYs for pregnancy and fertility by instead considering cost per intermediate outcome. 4) Even for the same intervention, studies took heterogeneous approaches to outcome evaluation. 5) Studies used multiple, competing rationales for whether and how to include fertility-related QALYs and whose QALYs to include. 6) Studies examining interventions with indirect effects on fertility typically ignored such QALYs. 7) Even recent studies had these shortcomings. Limitations include that the review was targeted rather than systematic. Economic evaluations inconsistently consider QALYs from current and future fertility and childbearing in ways that frequently appear biased toward the interventions considered. As the Panel on Cost-Effectiveness in Health and Medicine updates its guidelines, making the practice of cost-effectiveness analysis more consistent is a priority. Our study contributes to harmonizing methods in this respect.


Conflicting immune responses can prolong the length of infection in Plasmodium falciparum malaria.
We have recently proposed a new model for antigenic variation in Plasmodium falciparum that relies on a network of partially cross-protective immune responses to orchestrate this complex immune evasion process. In addition to exhibiting prolonged oscillations of single variants that resemble the sequential dominance of immunologically distinct antigenic types, the model implies that a higher efficacy of cross-reactive immunity actually increases the length of infection while reducing severity of disease. Here, we analyse the behaviour of a reduced system under conditions of perfect synchrony between variants to demonstrate that these features of this system can be attributed to the antagonism between cross-reactive and variant-specific responses.


Breast cancer screening programmes--results of studies in foreign countries--situation in Belgium.
Results of randomized trials and case-control studies on breast cancer screening are reviewed. A combined analysis of data from the randomized studies indicates that a mortality reduction (29%) can be achieved by mammographic screening in women. Regular breast cancer screening by mammography for women aged 50-69 years reduces breast cancer mortality by 40% (confidence interval [CI] 95% about 27-55) in women who are screened at least once. In younger women, the results are inconclusive. The programme Europe against Cancer has recommended the setting-up of a network of pilot studies on breast cancer screening by mammography in the European Community in order to obtain the necessary experience, with a view to implementation of a national screening programme before the year 2000. In the Brussels project, the main objective is to develop a programme of quality assurance. In Belgium, there are other projects with different designs, for which the results are not yet available.


Genesis of phase 3 early afterdepolarizations and triggered activity in acquired long-QT syndrome.
Both phase 2 and phase 3 early afterdepolarizations (EADs) occur in long-QT syndromes, but their respective roles in generating arrhythmias in intact cardiac tissue are incompletely understood. Intracellular Ca (Ca(i)) and membrane voltage (V(m)) were optically mapped in a quasi 2-dimensional model of cryoablated Langendorff-perfused rabbit ventricles (n=16). E-4031 (an I(Kr) blocker) combined with reduced extracellular K ([K(+)](o)) and Mg ([Mg(2+)](o)) prolonged action potential duration heterogeneously and induced phase 2 and phase 3 EADs. Whereas phase 2 EADs were Ca(i)-dependent, phase 3 EADs were not. The origins of 47 triggered activity episodes were attributed to phase 2 EADs in 12 episodes (26%) and phase 3 EADs in 35 episodes (74%). When phase 2 EADs accompanied phase 3 EADs, they accentuated action potential duration heterogeneity, creating a large V(m) gradient across the boundary between long and short action potential duration regions from which triggered activity emerged. The amplitude of phase 3 EADs correlated with the V(m) gradient (r=0.898, P<0.001). Computer simulation studies showed that coupling of cells with heterogeneous repolarization could extrinsically generate phase 3 EADs via electrotonic current flow. Alternatively, reduced I(K1) caused by low [K(+)](o) could generate intrinsic phase 3 EADs capable of inducing triggered activity at the boundary zone. Phase 3 EADs can be extrinsic as the result of electrotonic current across steep repolarization gradients or intrinsic as the result of low I(K1) and do not require spontaneous sarcoplasmic reticulum Ca release. Reduction of I(K1) by low [K(+)](o) strongly promotes ventricular arrhythmias mediated by phase 3 EADs in acquired long-QT syndrome caused by I(Kr) blockade.


Calcitriol in the treatment of prostate cancer.
Calcitriol, the principal active metabolite of vitamin D and a naturally occurring hormone, showed significant antineoplastic activity in pre-clinical models of prostate cancer and many other tumor types. These antineoplastic effects were observed at calcitriol concentrations substantially above the physiological range. While a number of mechanisms of action have been postulated, the induction of apoptosis and inhibition of proliferation have been most extensively reported. These pre-clinical findings motivated several investigators to pursue a series of clinical trials to examine the potential of targeting the vitamin D receptor for cancer treatment using calcitriol. Initial studies tested daily dosing of calcitriol and showed that substantial dose escalation was not feasible due to hypercalciuria and/or hypercalcemia. In contrast, weekly dosing of calcitriol allowed substantial dose escalation without dose-limiting toxicities. Notably, however, the commercially available formulation of calcitriol exhibited nonlinear pharmacokinetics at the highest doses tested. While substantially higher concentrations were achieved, the maximum tolerated dose was not established due to this pharmacological limitation. Intermittently-dosed calcitriol was then combined with several antineoplastic agents, including steroids, bisphosphonates and chemotherapeutic agents. The activity seen in a phase II study of weekly calcitriol plus docetaxel was particularly encouraging and led to the development of DN-101, a proprietary formulation designed for cancer treatment. DN-101 in combination with docetaxel is being evaluated in a placebo-controlled randomized clinical trial that has completed accrual.


AMPK is a direct adenylate charge-regulated protein kinase.
The adenosine monophosphate (AMP)-activated protein kinase (AMPK) regulates whole-body and cellular energy balance in response to energy demand and supply. AMPK is an αβγ heterotrimer activated by decreasing concentrations of adenosine triphosphate (ATP) and increasing AMP concentrations. AMPK activation depends on phosphorylation of the α catalytic subunit on threonine-172 (Thr(172)) by kinases LKB1 or CaMKKβ, and this is promoted by AMP binding to the γ subunit. AMP sustains activity by inhibiting dephosphorylation of α-Thr(172), whereas ATP promotes dephosphorylation. Adenosine diphosphate (ADP), like AMP, bound to γ sites 1 and 3 and stimulated α-Thr(172) phosphorylation. However, in contrast to AMP, ADP did not directly activate phosphorylated AMPK. In this way, both ADP/ATP and AMP/ATP ratios contribute to AMPK regulation.


Attention capture by eye of origin singletons even without awareness--a hallmark of a bottom-up saliency map in the primary visual cortex.
Human observers are typically unaware of the eye of origin of visual inputs. This study shows that an eye of origin or ocular singleton, e.g., an item in the left eye among background items in the right eye, can nevertheless attract attention automatically. Observers searched for a uniquely oriented bar, i.e., an orientation singleton, in a background of horizontal bars. Their reports of the tilt direction of the search target in a brief (200 ms) display were more accurate in a dichoptic congruent (DC) condition, when the target was also an ocular singleton, than in a monocular (M) condition, when all bars were presented to the same single eye, or a dichoptic incongruent (DI) condition, when an ocular singleton was a background bar. The better performance in DC did not depend on the ability of the observers to report the presence of an ocular singleton by making forced choices in the same stimuli (though without the orientation singleton). This suggests that the ocular singleton exogenously cued attention to its location, facilitating the identification of the tilt singleton in the DC condition. When the search display persisted without being masked, observers' reaction times (RTs) for reporting the location of the search target were shorter in the DC, and longer in the DI, than the M condition, regardless of whether the observers were aware that different conditions existed. In an analogous design, similar RT patterns were observed for the task of finding an orientation contrast texture border. These results suggest that in typical trials, attention was more quickly attracted to or initially distracted from the target in the DC or DI condition, respectively. Hence, an ocular singleton, though elusive to awareness, can effectively compete for attention with an orientation singleton (tilted 20 or 50 degrees from background bars in the current study). Similarly, it can also make a difficult visual search easier by diminishing the set size effect. Since monocular neurons with the eye of origin information are abundant in the primary visual cortex (V1) and scarce in other cortical areas, and since visual awareness is believed to be absent or weaker in V1 than in other cortical areas, our results provide a hallmark of the role of V1 in creating a bottom-up saliency map to guide attentional selection.


Immortalization of human marrow stromal cells by retroviral transduction with a temperature sensitive oncogene: identification of bipotential precursor cells capable of directed differentiation to either an osteoblast or adipocyte phenotype.
The etiology of osteoporosis is multifactorial, but there is evidence from both animal and human studies that the volume of marrow adipose tissue increases when bone volume is reduced in osteoporosis. The cell-related mechanism that may account for this inverse relationship between the volume of marrow adipose tissue and bone remains to be clarified, although it is known that both adipocytes and osteoblasts are derived from stromal cells precursors in bone marrow. We report that retroviral transduction with a temperature-sensitive oncogene (SV40 large T antigen) can generate bipotential cell lines from human marrow stroma that are capable of directed differentiation, in vitro, down either an osteogenic or adipocytic lineage pathway. One such clone, designated hOP 7, expresses type alpha 1(I) procollagen and has low alkaline phosphatase (AP) activity under basal culture conditions that is reminiscent of an osteoprogenitor cell. Exposure of hOP 7 cells to dexamethasone upregulates AP activity and enables the cells to mineralize their extracellular matrix. Also, treatment with calcitriol induces osteocalcin expression and both PTH and PGE2 induce/augment cAMP formation. Incubation with normal rabbit serum, however, causes the cells to become adipogenic as demonstrated by histological staining with Oil-red-O, expression of mRNA for the early and late adipocyte markers lipoprotein lipase and glycerol 3-phosphate dehydrogenase, respectively, and loss of type alpha 1(I) procollagen mRNA. The generation of homogeneous populations of these cells, as confirmed by Southern blot analysis, demonstrates the capacity of a human clonal cell line to differentiate in either an osteogenic or adipogenic direction.


Tricornered Kinase Regulates Synapse Development by Regulating the Levels of Wiskott-Aldrich Syndrome Protein.
Precise regulation of synapses during development is essential to ensure accurate neural connectivity and function of nervous system. Many signaling pathways, including the mTOR (mechanical Target of Rapamycin) pathway operate in neurons to maintain genetically determined number of synapses during development. mTOR, a kinase, is shared between two functionally distinct multi-protein complexes- mTORC1 and mTORC2, that act downstream of Tuberous Sclerosis Complex (TSC). We and others have suggested an important role for TSC in synapse development at the Drosophila neuromuscular junction (NMJ) synapses. In addition, our data suggested that the regulation of the NMJ synapse numbers in Drosophila largely depends on signaling via mTORC2. In the present study, we further this observation by identifying Tricornered (Trc) kinase, a serine/threonine kinase as a likely mediator of TSC signaling. trc genetically interacts with Tsc2 to regulate the number of synapses. In addition, Tsc2 and trc mutants exhibit a dramatic reduction in synaptic levels of WASP, an important regulator of actin polymerization. We show that Trc regulates the WASP levels largely, by regulating the transcription of WASP. Finally, we show that overexpression of WASP (Wiskott-Aldrich Syndrome Protein) in trc mutants can suppress the increase in the number of synapses observed in trc mutants, suggesting that WASP regulates synapses downstream of Trc. Thus, our data provide a novel insight into how Trc may regulate the genetic program that controls the number of synapses during development.


Prediction of Arterial Blood Gas Factors from Venous Blood Gas Factors in Intensive Care Unit Admitted Patients.
Blood gas analysis is very important in the patients with respiratory problems. Arterial puncture may cause complications such as pain, local hematoma, infection and nerve injury. The procedure itself can be technically difficult. In contrast, venous sampling is an easier procedure with fewer complications. Therefore, this study aims to determine the possibility of replacement of venous blood gas (VBG) values by ABG values in ICU wards admitted patients. In this study, 155 paired blood gas samples collected from patients admitted to ICU wards in Motahari hospital, Marvdasht, Fars, Iran. Statistical means of blood gas parameters, including PO2, PCO2, HCO3 and PH have been compared in both, arterial and venous, blood samples in parallel using paired t-test. Mean difference of arterial and venous gas parameters, PO2, PCO2 and HCO3 , was significantly differ. All paired gas parameters in arterial and venous blood samples were significantly correlated, while this correlation was stronger between PCO2 and HCO3. To predict the arterial blood gas parameters from VBG parameters, single regression models are of more statistical value compared to multiple regression models. Defined single regression prediction models could be used to predict arterial PCO2 and HCO3 , which may reduce arterial sampling in ICU wards.


Retinal function in high refractive error assessed electroretinographically.
The retinal function of patients with high refractive error was studied electroretinographically. Thirty-one hypermetropic patients, 7 myopic patients, and 7 patients with either unilateral or bilateral aphakia participated in the study. The ERG responses were measured in the light- and dark-adapted states. It was found that myopic eyes were characterised by subnormal amplitude but normal pattern, expressed by normal relationship between the b-wave amplitude and the a-wave amplitude. In aphakia the ERG responses were of normal amplitude and pattern. However, the hypermetropic patients could be divided into 3 groups. One group included subjects with a subnormal b-wave to a-wave relationship. The second group was characterised by a normal b- to a-wave relationship, while patients belonging to the third group exhibited supernormal b-wave to a-wave relationship. This classification of hypermetropic subjects did not correlate with the axial length of the eye or the refraction of the ocular media.


Neurological Manifestation of Incretin-Based Therapies in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis.
As a new class of antidiabetic drug, incretin-based therapies, which include dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have raised concerns about symptoms of withdrawal in patients with type 2 diabetes mellitus (T2DM), such as dizziness and headache. To systematically evaluate whether incretin-based therapies may lead to dizziness and headache in patients with T2DM compared to other traditional antidiabetic drugs or placebo. We searched Medline, Embase, the Cochrane library, and clinicaltrials.gov from inception through June 23, 2017, to identify randomized controlled trials of the safety of DPP-4Is or GLP-1 RAs versus placebo or other antidiabetic drugs in T2DM patients. We used the network meta-analysis under the frequentist framework to compare the association between multiple antidiabetic drugs and dizziness and headache. A total of 233 clinical trials with nine treatments and 147,710 patients were included: two incretin-based therapies, one placebo, and six traditional antidiabetic drugs (metformin, insulin, sulfonylurea, thiazolidinediones, alpha-glucosidase inhibitor, and sodium-glucose co-transporter 2). Compared to insulin, thiazolidinediones, or placebo, GLP-1 RAs statistically significantly increased the risk of dizziness (odds ratios [ORs]: 1.92, 1.57, and 1.40, respectively) and headache (ORs: 1.34, 1.41, and 1.18, respectively). DPP-4Is increased the risk of headache (OR: 1.22, 95% confidence interval [CI]: 1.02 to 1.46; moderate quality) and dizziness (OR: 1.46, 95% CI: 1.05 to 2.03; moderate quality) compared to insulin. Of the incretin-based therapies, DPP-4Is had a lower risk of dizziness than GLP-1 RAs (OR: 0.76, 95% CI: 0.67 to 0.87; high quality). Ranking probability analysis indicated that GLP-1 RAs may have the greatest risk of both dizziness and headache among the nine treatments (22.5% and 23.4%, respectively), whereas DPP-4Is were in the middle (46.2% and 45.0%, respectively). Incretin-based therapies increase the risk of dizziness and headache compared to insulin, thiazolidinediones, and placebo.


Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.
The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.


Human viruses and cancer.
The first human tumor virus was discovered in the middle of the last century by Anthony Epstein, Bert Achong and Yvonne Barr in African pediatric patients with Burkitt's lymphoma. To date, seven viruses -EBV, KSHV, high-risk HPV, MCPV, HBV, HCV and HTLV1- have been consistently linked to different types of human cancer, and infections are estimated to account for up to 20% of all cancer cases worldwide. Viral oncogenic mechanisms generally include: generation of genomic instability, increase in the rate of cell proliferation, resistance to apoptosis, alterations in DNA repair mechanisms and cell polarity changes, which often coexist with evasion mechanisms of the antiviral immune response. Viral agents also indirectly contribute to the development of cancer mainly through immunosuppression or chronic inflammation, but also through chronic antigenic stimulation. There is also evidence that viruses can modulate the malignant properties of an established tumor. In the present work, causation criteria for viruses and cancer will be described, as well as the viral agents that comply with these criteria in human tumors, their epidemiological and biological characteristics, the molecular mechanisms by which they induce cellular transformation and their associated cancers.


Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials.
To determine how length of anticoagulation and clinical presentation of venous thromboembolism influence the risk of recurrence after anticoagulant treatment is stopped and to identify the shortest length of anticoagulation that reduces the risk of recurrence to its lowest level. Pooled analysis of individual participants' data from seven randomised trials. Outpatient anticoagulant clinics in academic centres. 2925 men or women with a first venous thromboembolism who did not have cancer and received different durations of anticoagulant treatment. First recurrent venous thromboembolism after stopping anticoagulant treatment during up to 24 months of follow-up. Recurrence was lower after isolated distal deep vein thrombosis than after proximal deep vein thrombosis (hazard ratio 0.49, 95% confidence interval 0.34 to 0.71), similar after pulmonary embolism and proximal deep vein thrombosis (1.19, 0.87 to 1.63), and lower after thrombosis provoked by a temporary risk factor than after unprovoked thrombosis (0.55, 0.41 to 0.74). Recurrence was higher if anticoagulation was stopped at 1.0 or 1.5 months compared with at 3 months or later (hazard ratio 1.52, 1.14 to 2.02) and similar if treatment was stopped at 3 months compared with at 6 months or later (1.19, 0.86 to 1.65). High rates of recurrence associated with shorter durations of anticoagulation were confined to the first 6 months after stopping treatment. Three months of treatment achieves a similar risk of recurrent venous thromboembolism after stopping anticoagulation to a longer course of treatment. Unprovoked proximal deep vein thrombosis and pulmonary embolism have a high risk of recurrence whenever treatment is stopped.


Relationship of tacrolimus exposure and mycophenolate mofetil dose with renal function after renal transplantation.
The most common immunosuppressive treatment in de novo renal transplantation is a triple regimen that includes tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, and that may also include antibody induction. Whether nephrotoxicity is an issue with tacrolimus at the currently used dosages remains an open question. We pooled data from three large, randomized, de novo renal transplantation studies (Symphony, Fixed Dose Concentration Controlled [FDCC], and OptiCept) that used variations of the triple regimen with respect to tacrolimus target levels, MMF dosing, and antibody induction. We used multivariate linear regression to explore the relationship of renal function at 1 year after transplantation (estimated glomerular filtration rate) with tacrolimus levels and MMF dose measured over the previous 6 months. The model included also a series of possible confounders. RESULTS.: The analysis population consisted of 998 patients. On average, tacrolimus levels were in a range considered low (mean ± standard deviation 7.2 ± 2.54 ng/mL), and MMF dose was 1.5 ± 0.61 g/day. Lower tacrolimus levels and higher MMF doses were associated with significantly better renal function. There were other variables associated with renal function, most notably acute rejection, donor age, and delayed graft function. Subanalyses in each of the three studies gave a consistent picture. There was no overt difference in the effect sizes when patients with stage II (estimated glomerular filtration rate 60-89 mL/min) or stage III (30-59 mL/min) chronic kidney disease were assessed separately. Tacrolimus seems to have a moderate but consistent nephrotoxic effect even in modern efficient immunosuppressive regimens where it is used at lower doses than in previous years.


Paired-end analysis of transcription start sites in Arabidopsis reveals plant-specific promoter signatures.
Understanding plant gene promoter architecture has long been a challenge due to the lack of relevant large-scale data sets and analysis methods. Here, we present a publicly available, large-scale transcription start site (TSS) data set in plants using a high-resolution method for analysis of 5' ends of mRNA transcripts. Our data set is produced using the paired-end analysis of transcription start sites (PEAT) protocol, providing millions of TSS locations from wild-type Columbia-0 Arabidopsis thaliana whole root samples. Using this data set, we grouped TSS reads into "TSS tag clusters" and categorized clusters into three spatial initiation patterns: narrow peak, broad with peak, and weak peak. We then designed a machine learning model that predicts the presence of TSS tag clusters with outstanding sensitivity and specificity for all three initiation patterns. We used this model to analyze the transcription factor binding site content of promoters exhibiting these initiation patterns. In contrast to the canonical notions of TATA-containing and more broad "TATA-less" promoters, the model shows that, in plants, the vast majority of transcription start sites are TATA free and are defined by a large compendium of known DNA sequence binding elements. We present results on the usage of these elements and provide our Plant PEAT Peaks (3PEAT) model that predicts the presence of TSSs directly from sequence.


Health-related quality of life in young survivors of childhood cancer.
Childhood cancer and its treatment may affect health-related quality of life (HRQoL) in childhood cancer survivors, but population-based studies in young survivors are scarce. We aimed to: (1) compare HRQoL between young survivors and population norms and (2) find factors that influence parent-reported HRQoL in survivors. As part of the Swiss Childhood Cancer Survivor Study, a questionnaire was mailed to parents of survivors aged 8-16 years, registered in the Swiss Childhood Cancer Registry, ≥5 years after diagnosis. We used the KIDSCREEN-27 instrument to compare self- and parent-reported HRQoL between survivors (N = 425) and standardized norms in the five dimensions of physical well-being, psychological well-being, autonomy, peers and school environment (mean = 50, SD = 10). We then used multivariable linear regressions to test the influence of socio-demographic and cancer-related factors on HRQoL. Self-reported physical well-being was comparable to norms. Other HRQoL dimensions were higher than norms, with the highest mean = 52.2 (p < 0.001) for school environment. Parent-reported HRQoL in survivors was comparable to population norms; only physical well-being was lower (mean = 47.1, p < 0.001), and school environment was higher (mean = 51.1, p = 0.035). Parent-reported HRQoL was lower for survivors of CNS tumors (physical well-being: β = -5.27, p = 0.007; psychological well-being: β = -4.39, p = 0.044; peers β = -5.17, p = 0.028), survivors of neuroblastoma (psychological well-being β = -5.20, p = 0.047), and survivors who had had a relapse (physical well-being β = -5.41, p = 0.005). Assessing HRQoL during follow-up care, with a focus on physical well-being, specific diagnoses (e.g., CNS tumor) and late complications (e.g., relapse) might help to early identify problems and offer support to survivors with reduced HRQoL.


Characterization of the monomethylarsonate reductase and dehydroascorbate reductase activities of Omega class glutathione transferase variants: implications for arsenic metabolism and the age-at-onset of Alzheimer's and Parkinson's diseases.
There are two functional Omega class glutathione transferase (GST) genes in humans. GSTO1 is polymorphic with several coding region alleles, including an A140D substitution, a potential deletion of E155 and an E208K substitution. GSTO2 is also polymorphic with an N142D substitution in the coding region. We investigated the effect of these variations on the enzyme's thioltransferase, dehydroascorbate reductase, monomethylarsonate reductase and dimethylarsonate reductase activities. Variant proteins were expressed in Escherichia coli and purified by Ni-agarose affinity chromatography. GSTO2-2 was insoluble and had to be dissolved and refolded from 8 M urea. The A140D and E208K substitutions in GSTO1-1 did not alter specific activity. The deletion of E155 caused a two- to three-fold increase in the specific activity with each substrate. This deletion also caused a significant decrease in the enzyme's heat stability. The E155 deletion has been linked to abnormal arsenic excretion patterns; however, the available data do not clearly identify the cause of this abnormality. We found that GSTO2-2 has activity with the same substrates as GSTO1-1, and the dehydroascorbate reductase activity of GSTO2-2 is approximately 70-100-fold higher than that of GSTO1-1. The polymorphic N142D substitution had no effect on the specific activity of the enzyme with any substrate. The most notable feature of GSTO2-2 was its very high dehydroascorbate reductase activity, which suggests that GSTO2-2 may significantly protect against oxidative stress by recycling ascorbate. A defect in ascorbate metabolism may provide a common mechanism by which the Omega class GSTs influence the age-at-onset of Alzheimer's and Parkinson's diseases.


Effect of Kinesio taping on electromyographic activity of leg muscles during gait in children with developmental coordination disorder: A randomized controlled trial.
This study aimed to evaluate the effectiveness of Kinesio tape (KT) on lower limb muscle activation pattern in children with developmental coordination disorder (DCD) during walking. A parallel-group randomized controlled trial. University laboratory setting. Twenty-five children with DCD were randomly allocated to the KT group (mean age = 7.97 years) and 24 to the control group (mean age = 8.04 years). KT group received KT application to the quadriceps and gastrocnemius muscles whereas the control group received no intervention. Peak muscle activation (in percentage of maximal voluntary isometric contraction [%MVIC]) in the lower limbs during gait was measured by means of surface electromyography, electrogoniometry, and foot contact switches. Gastrocnemius medialis activation during mid stance (23.46%MVIC, 95% CI = -32.53, -14.39) and late stance phases (3.25%MVIC, 95% CI = -5.67, -0.81) of gait increased after the application of KT in the KT group compared to baseline values. The KT group demonstrated 26.87%MVIC (95% CI = 26.87, 7.11) higher gastrocnemius medialis muscle peak activation during mid stance phase at post-test when compared with the control group. Moreover, gastrocnemius medialis and biceps femoris muscle peak activation during loading response decreased by 8.36%MVIC (95% CI = 2.71, 14.02) and 3.54%MVIC (95% CI = 1.08, 6.01), respectively, in the control group overtime. The application of KT on children with DCD had an increased gastrocnemius medialis muscle activation during stance phase. KT could be incorporated into gait re-education programmes to facilitate muscle contraction in these children.


Serological responses in porcine cysticercosis: a link with the parasitological outcome of infection.
An oral infection model with Taenia solium whole proglottids was used to study host-parasite relationships and the mechanisms underlying resistance to infection in pigs. In addition, an attempt was made to link the parasitological findings to serological data. Groups of six piglets aged 1, 3 and 5 months were infected and slaughtered 3 months p.i. Circulating antibody and antigen levels were monitored weekly. At autopsy total cyst counts were performed. Although the detailed carcass dissection at necropsy revealed a high variation in the number of cysts, the trend was that the number of viable cysts decreased with the age at which the animals were infected. The kinetics of the antigen levels throughout the course of the infection differed markedly between the three age groups of the experimental infection model. In the younger animals, a fast increase in titres of circulating antigen was observed in most animals, reaching a plateau as early as 2 weeks p.i. Besides its faster increase, antigen levels in pigs infected at younger ages also reached higher levels than in older animals and were associated with weaker antibody responses. Results also demonstrated that a relationship exists between the number of cysts and the titre of circulating antigen. This is promising in view of the development of an assay to quantify the progress of an active T. solium infection and would be a useful tool in epidemiological studies to assess the infection burden and the risk of transmission of the disease. The use of specific antibody-detection assays combined with circulating antigen detection could improve our understanding of this relationship.


Cancer statistics, 2009.
Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are standardized by age to the 2000 United States standard million population. A total of 1,479,350 new cancer cases and 562,340 deaths from cancer are projected to occur in the United States in 2009. Overall cancer incidence rates decreased in the most recent time period in both men (1.8% per year from 2001 to 2005) and women (0.6% per year from 1998 to 2005), largely because of decreases in the three major cancer sites in men (lung, prostate, and colon and rectum [colorectum]) and in two major cancer sites in women (breast and colorectum). Overall cancer death rates decreased in men by 19.2% between 1990 and 2005, with decreases in lung (37%), prostate (24%), and colorectal (17%) cancer rates accounting for nearly 80% of the total decrease. Among women, overall cancer death rates between 1991 and 2005 decreased by 11.4%, with decreases in breast (37%) and colorectal (24%) cancer rates accounting for 60% of the total decrease. The reduction in the overall cancer death rates has resulted in the avoidance of about 650,000 deaths from cancer over the 15-year period. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, education, geographic area, and calendar year. Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years of age. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population and by supporting new discoveries in cancer prevention, early detection, and treatment.


Gadolinium-enhanced phase-contrast magnetic resonance portography.
The purpose of this study was to investigate the effect and usefulness of gadolinium-chelated contrast medium in phase-contrast magnetic resonance (MR) portography. Twenty-six patients (21 men, 5 women; aged 34 to 79 years, mean 62 years) underwent respiratory-triggered 3-dimensional phase-contrast portography before and after administration of gadolinium in a 1.5T MR unit. Coronal maximum intensity projection (MIP) images of the portal vein were reconstructed and compared to conventional arterial portograms regarding visualization. Signal-to-noise ratio (SNR) and portal vein-to-liver contrast-to-noise ratios (CNR) of main, right, right anterior, right posterior, left portal veins, and umbilical portion were measured on both non-enhanced and gadolinium-enhanced images and compared. Portal veins and branches were more clearly visualized on the gadolinium-enhanced than on the non-enhanced images. Compared to arterial portography, gadolinium-enhanced portography showed similar performances in visualization, except in the right posterior branch and left portal vein. No severe image degradation from respiration was experienced. SNR was significantly higher on the gadolinium-enhanced than on non-enhanced images except in the right anterior branch. CNR was significantly higher on the gadolinium-enhanced than on the non-enhanced images at all measured locations. Administration of gadolinium improves the SNR and CNR of phase-contrast portography and visualization of the portal vein. The phase-contrast technique with gadolinium enhancement can be used to evaluate the portal vein as a supplemental technique.


Detection of seed dormancy QTL in multiple mapping populations derived from crosses involving novel barley germplasm.
Seed dormancy is one of the most important traits in germination process to control malting and pre-harvest sprouting in barley (Hordeum vulgare L.). EST based linkage maps were constructed on seven recombinant inbred (RI) and one doubled haploid (DH) populations derived from crosses including eleven cultivated and one wild barley strains showing the wide range of seed dormancy levels. Seed dormancy of each RI and DH line was estimated from the germination percentage at 5 and 10 weeks post-harvest after-ripening periods in 2003 and 2005. Quantitative trait loci (QTLs) controlling seed dormancy were detected by the composite interval mapping procedure on the RI and DH populations. A total of 38 QTLs clustered around 11 regions were identified on the barley chromosomes except 2H among the eight populations. Several QTL regions detected in the present study were reported on similar positions in the previous QTL studies. The QTL on at the centromeric region of long arm of chromosome 5H was identified in all the RI and DH populations with the different degrees of dormancy depth and period. The responsible gene of the QTL might possess a large allelic variation among the cross combinations, or can be multiple genes located on the same region. The various loci and their different effects in dormancy found in the barley germplasm in the present study enable us to control the practical level of seed dormancy in barley breeding programs.


Conjunctival and corneal ulceration associated with nicorandil.
To report an association between conjunctival and corneal ulceration and nicorandil therapy for angina. Review of the literature and spontaneous reports collected at the National Registry of Drug-Induced Ocular Side Effects (Portland, Oregon), the FDA Spontaneous Reporting System (Bethesda, Maryland) and the World Health Organization's Uppsala Monitoring Center (Uppsala, Sweden). Thirteen case reports of adverse ocular reactions were collected. Abnormal vision (5 reports), corneal ulcer (4 reports) and conjunctival ulcer (4 reports) were associated with nicorandil. Eight subjects were male and 5 female with an average age of 75.4 ± 8.3 years. The average duration of therapy to development of the ADR was 30.4 days ±3 days. Eleven case reports had positive dechallenge and the patients fully recovered. The average dose was 21.6 mg daily. Using WHO classification for adverse drug reactions, the association between nicorandil and conjunctival and corneal ulceration is "possible". The case reports indicate that, if recognized, withdrawing nicorandil will lead to resolution of the conjunctival or corneal ulceration. Advanced age and accumulation of nicotinic acid in tissues may be contributory to the risk of developing ocular ulcerations from nicorandil.


The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target.
There is a great clinical need to identify the underlying mechanisms, as well as related biomarkers, and treatment targets, for traumatic brain injury (TBI). Neuroinflammation is a central pathophysiological feature of TBI. NLRP3 inflammasome activity is a necessary component of the innate immune response to tissue damage, and dysregulated inflammasome activity has been implicated in a number of neurological conditions. This paper introduces the NLRP3 inflammasome and its implication in the pathogenesis of neuroinflammatory-related conditions, with a particular focus on TBI. Although its role in TBI has only recently been identified, findings suggest that priming and activation of the NLRP3 inflammasome are upregulated following TBI. Moreover, recent studies utilizing specific NLRP3 inhibitors have provided further evidence that this inflammasome is a major driver of neuroinflammation and neurobehavioral disturbances following TBI. In addition, there is emerging evidence that circulating inflammasome-associated proteins may have utility as diagnostic biomarkers of neuroinflammatory conditions, including TBI. Finally, novel and promising areas of research will be highlighted, including the potential involvement of the NLRP3 inflammasome in mild TBI, how factors such as biological sex may affect NLRP3 activity in TBI, and the use of emerging biomarker platforms. Taken together, this review highlights the exciting potential of the NLRP3 inflammasome as a target for treatments and biomarkers that may ultimately be used to improve TBI management.


Investigating the impact of physical activity interventions on delirium outcomes in intensive care unit patients: A systematic review and meta-analysis.
To investigate the impact of physical activity interventions, including early mobilisation, on delirium outcomes in critically ill patients. Electronic database literature searches were conducted, and studies were selected based on pre-specified eligibility criteria. Cochrane Risk of Bias-2 and Risk Of Bias In Non-randomised Studies-of Interventions quality assessment tools were utilised. Grading of Recommendations, Assessment, Development and Evaluations was used to assess levels of evidence for delirium outcomes. The study was prospectively registered on PROSPERO (CRD42020210872). Twelve studies were included; ten randomised controlled trials one observational case-matched study and one before-after quality improvement study. Only five of the included randomised controlled trial studies were judged to be at low risk of bias, with all others, including both non-randomised controlled trials deemed to be at high or moderate risk. The pooled relative risk for incidence was 0.85 (0.62-1.17) which was not statistically significant in favour of physical activity interventions. Narrative synthesis for effect on duration of delirium found favour towards physical activity interventions reducing delirium duration with median differences ranging from 0 to 2 days in three comparative studies. Studies comparing varying intervention intensities showed positive outcomes in favour of greater intensity. Overall levels of evidence were low quality. Currently there is insufficient evidence to recommend physical activity as a stand-alone intervention to reduce delirium in Intensive Care Units. Physical activity intervention intensity may impact on delirium outcomes, but a lack of high-quality studies limits the current evidence base.


Complete digestion of edible bird's nest releases free N-acetylneuraminic acid and small peptides: an efficient method to improve functional properties.
Edible bird's nest (EBN), an Asian health food, contains insoluble proteins and conjugated N-acetylneuraminic acid (NANA) that are difficult to be absorbed by humans. In order to increase the nutritional value of EBN, we developed methods to digest EBN targeting the release of proteins and NANA. By using simulated gastric fluid under acidic conditions, the complex proteins were fully digested into smaller peptides, and in parallel, NANA was fully released from the conjugated form. The completely digested EBN showed better nutraceutical properties. In a skin whitening test, the EBN digest showed stronger inhibition of melanogenesis of cultured B16 cells and enzymatic activity of tyrosinase, as compared to that of undigested EBN. In addition, the EBN digest exhibited stronger osteogenic activity in cultured osteoblasts. Thus, the complete digestion of EBN could be applied to the development of a new generation of EBN health food products, including EBN drinks and skincare products.


The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure.
Cycle and treadmill exercise tests are unsuitable for elderly, frail and severely limited patients with heart failure and may not reflect capacity to undertake day-to-day activities. Walking tests have proved useful as measures of outcome for patients with chronic lung disease. To investigate the potential value of the 6-minute walk as an objective measure of exercise capacity in patients with chronic heart failure, the test was administered six times over 12 weeks to 18 patients with chronic heart failure and 25 with chronic lung disease. The subjects also underwent cycle ergometer testing, and their functional status was evaluated by means of conventional measures. The walking test proved highly acceptable to the patients, and stable, reproducible results were achieved after the first two walks. The results correlated with the conventional measures of functional status and exercise capacity. The authors conclude that the 6-minute walk is a useful measure of functional exercise capacity and a suitable measure of outcome for clinical trials in patients with chronic heart failure.


Both HIV-Infected and Uninfected Cells Express TRAILshort, Which Confers TRAIL Resistance upon Bystander Cells within the Microenvironment.
TNF-related apoptosis-inducing ligand (TRAIL) was initially described to induce apoptosis of tumor cells and/or virally infected cells, although sparing normal cells, and has been implicated in the pathogenesis of HIV disease. We previously identified TRAILshort, a TRAIL splice variant, in HIV-infected patients and characterized it as being a dominant negative ligand to subvert TRAIL-mediated killing. Herein, using single-cell genomics we demonstrate that TRAILshort is produced by HIV-infected cells, as well as by uninfected bystander cells, and that the dominant stimulus which induces TRAILshort production are type I IFNs and TLR7, TLR8, and TLR9 agonists. TRAILshort has a short t1/2 by virtue of containing a PEST domain, which targets the protein toward the ubiquitin proteasome pathway for degradation. Further we show that TRAILshort binds preferentially to TRAIL receptors 1 and 2 with significantly reduced interaction with the decoy TRAIL receptors 3 and 4. Recombinant TRAILshort is sufficient to protect cells against TRAIL-induced killing, whereas immunodepletion of TRAILshort with a specific Ab restores TRAIL sensitivity. Importantly we show that TRAILshort is shed in microvesicles into the cellular microenvironment and therefore confers TRAIL resistance not only on the cell which produces it, but also upon neighboring bystander cells. These results establish a novel paradigm for understanding and overcoming TRAIL resistance, in particular how HIV-infected cells escape immune elimination by the TRAIL:TRAILshort receptor axis.


Serogroup-specific meningococcal carriage by age group: a systematic review and meta-analysis.
Neisseria meningitidis carriage prevalence has known variation across the lifespan, but it is unclear whether carriage varies among meningococcal capsular groups. Therefore, we aimed to characterise group-specific meningococcal carriage by age group and world region from 2007 to 2016. Systematic review and meta-analysis. MEDLINE, Embase, Global Health Database, WHO Global Health Library, Web of Science, Current Contents Connects, China National Knowledge Infrastructure and Wanfang were systematically searched. Database searches were conducted through July 2018 and Google Scholar forward searches of included studies were conducted through August 2018. References of included studies and relevant conference abstracts were also searched to identify additional articles for inclusion. Studies were eligible for inclusion if they reported capsular group-specific meningococcal carriage in a healthy population of a specified age group and geographical region. For this review, only studies conducted between 2007 and 2016 were included. Data were independently extracted by two authors into Microsoft Access. Studies were assessed for risk of bias using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data. Studies eligible for inclusion in quantitative analyses by pre-specified age groups were pooled using random effects meta-analyses. Results are reported by capsular group, age group and WHO region. Where meta-analyses were not appropriate, study results were discussed narratively. 7511 articles were identified and 65 were eligible for inclusion. Adolescents and young adults were the focus of many studies (n=24), especially in the Americas and Europe. Studies from China and Africa, typically, included data from a wider age range. The overall carriage prevalence varied markedly by age group and region. Based on the available data, 21 studies were included in meta-analyses reporting serogroup carriage for: all ages in Africa, 18-24-year olds in the Americas, and 11-17 and 18-24-year olds in Europe. Capsular groups W, X, Y and 'other' (non-ABCWXY, including non-groupable) were the most prevalent in Africa, and 5-17-year olds had higher carriage prevalence than other age groups. 'Other' serogroups (11.5%, 95% CI 1.6% to 16.1%) were the most common among 18-24-year olds from the Americas. In Europe, 18-24-year old were carriers more frequently than 11-17-year olds, and groups B (5.0%, 95% CI 3.0% to 7.5%), Y (3.9%, 95% CI 1.3% to 7.8%) and 'other' (6.4%, 95% CI 3.1% to 10.8%) were the most commonly carried in the older age group. Of the age groups included in the analysis, carriage patterns by age were similar across capsular groups within a region but differed between regions. Data gaps remain for age- and capsular group-specific carriage in many regions, especially in the Eastern Mediterranean and South-East Asia. As such, clear and robust conclusions about the variation of capsular group-specific carriage by age group and WHO region were unable to be determined. CRD42017074671.


Shrinky-Dink microfluidics: rapid generation of deep and rounded patterns.
We present a rapid and non-photolithographic approach to microfluidic pattern generation by leveraging the inherent shrinkage properties of biaxially oriented polystyrene thermoplastic sheets. This novel approach yields channels deep enough for mammalian cell assays, with demonstrated heights up to 80 microm. Moreover, we can consistently and easily achieve rounded channels, multi-height channels, and channels as thin as 65 microm in width. Finally, we demonstrate the utility of this simple microfabrication approach by fabricating a functional gradient generator. The whole process--from device design conception to working device--can be completed within minutes.


Using Poisson mixed-effects model to quantify transcript-level gene expression in RNA-Seq.
RNA sequencing (RNA-Seq) is a powerful new technology for mapping and quantifying transcriptomes using ultra high-throughput next-generation sequencing technologies. Using deep sequencing, gene expression levels of all transcripts including novel ones can be quantified digitally. Although extremely promising, the massive amounts of data generated by RNA-Seq, substantial biases and uncertainty in short read alignment pose challenges for data analysis. In particular, large base-specific variation and between-base dependence make simple approaches, such as those that use averaging to normalize RNA-Seq data and quantify gene expressions, ineffective. In this study, we propose a Poisson mixed-effects (POME) model to characterize base-level read coverage within each transcript. The underlying expression level is included as a key parameter in this model. Since the proposed model is capable of incorporating base-specific variation as well as between-base dependence that affect read coverage profile throughout the transcript, it can lead to improved quantification of the true underlying expression level. POME can be freely downloaded at http://www.stat.purdue.edu/~yuzhu/pome.html. email@example.com; firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Cell-free DNA concentration and integrity as a screening tool for cancer.
This study aims to evaluate cell-free DNA (CFDNA) concentration and integrity in patients with malignant and nonmalignant diseases and in controls to investigate their value as a screening test for cancer, and to correlate them with clinicopathological parameters of cancer patients. The study included three groups; group I: 120 cancer patients, group II: 120 patients with benign diseases and group III: 120 normal healthy volunteers as control. One plasma sample was collected from each subject. CFDNA was purified from the plasma then its concentration was measured and integrity was assessed by PCR amplification of 100, 200, 400, and 800 bp bands. There was a highly significant difference in CFDNA levels between cancer group and each of benign and control groups. AUC of ROC curve for cancer group versus normal and benign groups were 0.962 and 0.895, which indicated the efficiency of CFDNA as a marker of cancer. As for integrity, normal and benign subjects showed only two bands at 100 and 200 bp, while all cancer patients demonstrated the 400 bp band and 78% of them had the 800 bp whose presence correlated with vascular invasion. The combined use of CFDNA concentration and integrity is a candidate for a universal screening test of cancer. Upon setting suitable boundaries for the test it might be applied to identify cancer patients, particularly among subjects with predisposing factors. Being less expensive, CFDNA concentration could be applied for mass screening and for patients with values overlapping those of normal and benign subjects, the use of the more expensive, yet more specific, integrity test is suggested.