The visit-data warehouse: enabling novel secondary use of health information exchange data.
Health Information Exchange (HIE) efforts face challenges with data quality and performance, and this becomes especially problematic when data is leveraged for uses beyond primary clinical use. We describe a secondary data infrastructure focusing on patient-encounter, nonclinical data that was built on top of a functioning HIE platform to support novel secondary data uses and prevent potentially negative impacts these uses might have otherwise had on HIE system performance. HIE efforts have generally formed for the primary clinical use of individual clinical providers searching for data on individual patients under their care, but many secondary uses have been proposed and are being piloted to support care management, quality improvement, and public health. This infrastructure review describes a module built into the Healthix HIE. Healthix, based in the New York metropolitan region, comprises 107 participating organizations with 29,946 acute-care beds in 383 facilities, and includes more than 9.2 million unique patients. The primary infrastructure is based on the InterSystems proprietary Caché data model distributed across servers in multiple locations, and uses a master patient index to link individual patients' records across multiple sites. We built a parallel platform, the "visit data warehouse," of patient encounter data (demographics, date, time, and type of visit) using a relational database model to allow accessibility using standard database tools and flexibility for developing secondary data use cases. These four secondary use cases include the following: (1) tracking encounter-based metrics in a newly established geriatric emergency department (ED), (2) creating a dashboard to provide a visual display as well as a tabular output of near-real-time de-identified encounter data from the data warehouse, (3) tracking frequent ED users as part of a regional-approach to case management intervention, and (4) improving an existing quality improvement program that analyzes patients with return visits to EDs within 72 hours of discharge. Setting up a separate, near-real-time, encounters-based relational database to complement an HIE built on a hierarchical database is feasible, and may be necessary to support many secondary uses of HIE data. As of November 2014, the visit-data warehouse (VDW) built by Healthix is undergoing technical validation testing and updates on an hourly basis. We had to address data integrity issues with both nonstandard and missing HL7 messages because of varied HL7 implementation across the HIE. Also, given our HIEs federated structure, some sites expressed concerns regarding data centralization for the VDW. An established and stable HIE governance structure was critical in overcoming this initial reluctance. As secondary use of HIE data becomes more prevalent, it may be increasingly necessary to build separate infrastructure to support secondary use without compromising performance. More research is needed to determine optimal ways of building such infrastructure and validating its use for secondary purposes.


Development of Privacy Features on Anecdata.org, a Free Citizen Science Platform for Collecting Datasets for Climate Change and Related Projects.
The Anecdata website and its corresponding mobile app provide unique features to meet the needs of a wide variety of diverse citizen science projects from across the world. The platform has been developed with the help of continuous feedback from community partners, project leaders, and website users and currently hosts more than 200 projects. Over 8,000 registered users have contributed more than 30,000 images and over 50,000 observations since the platform became open to the public in 2014. From its inception, one of the core tenets of Anecdata's mission has been to make data from citizen science projects freely accessible to project participants and the general public, and in the platform's first few years, it followed a completely open data access model. As the platform has grown, hosting ever more projects, we have found that this model does not meet all project needs, especially where endangered species, property access rights, participant safety in the field, and personal privacy are concerned. We first introduced features for data and user privacy as part of "All About Arsenic," a National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS) Science Education Partnership Award (SEPA)-funded project at MDI Biological Laboratory, which engages middle and high school teachers and students from schools across Maine and New Hampshire in sampling their home well water for analysis of arsenic and other heavy metals. In order to host this project on Anecdata, we developed features for spatial privacy or "geoprivacy" to conceal the coordinates of samplers' homes, partial data redaction tools we call "private fields" to withhold certain sample registration questions from public datasets, and "participant anonymity" to conceal which user account uploaded an observation. We describe the impetus for the creation of these features, challenges we encountered, and our technical approach. While these features were originally developed for the purposes of a public health and science literacy project, they are now available to all project leaders setting up projects on Anecdata.org and have been adopted by a number of projects, including Mass Audubon's Eastern Meadowlark Survey, South Carolina Aquarium's SeaRise, and Coastal Signs of the Seasons (SOS) Monitoring projects.


Ego, drives, and the dynamics of internal objects.
This paper addresses the relationship between the ego, id, and internal objects. While ego psychology views the ego as autonomous of the drives, a less well-known alternative position views the ego as constituted by the drives. Based on Freud's ego-instinct account, this position has developed into a school of thought which postulates that the drives act as knowers. Given that there are multiple drives, this position proposes that personality is constituted by multiple knowers. Following on from Freud, the ego is viewed as a composite sub-set of the instinctual drives (ego-drives), whereas those drives cut off from expression form the id. The nature of the "self" is developed in terms of identification and the possibility of multiple personalities is also established. This account is then extended to object-relations and the explanatory value of the ego-drive account is discussed in terms of the addressing the nature of ego-structures and the dynamic nature of internal objects. Finally, the impact of psychological conflict and the significance of repression for understanding the nature of splits within the psyche are also discussed.


Alcohol Consumption among the Elderly Citizens in Hungary and Serbia-Comparative Assessment.
Studies in the alcohol consumption area are mostly related to the (ab)use of alcohol in young people. However, today, a growing number of researchers are emphasizing the clinical and public health significance of alcohol consumption in the elderly. In the WHO reports, harmful alcohol consumption is responsible for 5.3% of the global burden of the disease. The aim of this study was to investigate the prevalence of alcohol consumption among men and women aged 55 and over in Serbia and Hungary, leveraging data from the 2013 Serbian National Health Survey and from the 2014 Hungarian National Health Survey. Respondents aged 55 and over were analysed based on logistic multivariate models. The prevalence of alcohol consumption was 41.5% and 62.5% in Serbia and Hungary, respectively. It was higher among men in both countries, but among women, it was significantly higher in Hungary than in Serbia. The statistically significant predictors affecting alcohol consumption in Serbia included age, education, well-being index, long-term disease and overall health status, with marital status being an additional factor among men. In Hungary, education and long-term disease affected alcohol consumption in both sexes, while age and employment were additional factors among women. In both countries for both sexes, younger age, more significantly than primary education and good health, was associated with a higher likelihood of alcohol consumption.


Innervation patterns of mystacial vibrissae support active touch behaviors in California sea lions (Zalophus californianus).
Vibrissae or follicle-sinus complexes (F-SCs) are highly developed mammalian sensory structures. These blood-filled sinuses are richly innervated and possess novel mechanoreceptors. Although much is known regarding the function of F-SCs in terrestrial mammals, much less is known regarding marine carnivores such as pinnipeds. Pinnipeds possess the largest, most highly innervated vibrissae of any mammal. One such pinniped is the California sea lion, which are generalist marine predators that rely heavily upon tactile discrimination capabilities. Psychophysical studies demonstrate that haptic tactile discrimination using F-SCs is exceptionally sensitive. However, our knowledge of the structure and function of F-SCs in otariids is limited. Our objectives were to investigate the innervation and microstructure of F-SCs across the mystacial vibrissal field and infer function from haptic performance studies in California sea lions. Innervation and microstructure of vibrissae differed considerably compared to similar data available for phocids. Total innervation of mystacial vibrissae was estimated to be 86,042 axons. Investigations of innervation density and investment of microvibrissae versus macrovibrissae demonstrated a significantly increased axon density per F-SC in medial microvibrissal regions compared to lateral macrovibrissae, which supports psychophysical data and somatotopic organization of the central nervous system involved with tactile discrimination capability. Innervation increased from medial microvibrissae (705 ± 125 axons/F-SC) to lateral macrovibrissae (1,447 ± 154) as well as from dorsal (541 ± 60) to ventral (1,493 ± 327) vibrissal regions. These data provide a more complete picture of the sensory ecology of this important aquatic mammalian lineage; the specialization of peripheral sensory structures, central nervous structures with demonstrated enhanced haptic capabilities behaviorally has likely led to the ecological success of California sea lions.


Bayesian inference in a piecewise Weibull proportional hazards model with unknown change points.
The main difference between parametric and non-parametric survival analyses relies on model flexibility. Parametric models have been suggested as preferable because of their lower programming needs although they generally suffer from a reduced flexibility to fit field data. In this sense, parametric survival functions can be redefined as piecewise survival functions whose slopes change at given points. It substantially increases the flexibility of the parametric survival model. Unfortunately, we lack accurate methods to establish a required number of change points and their position within the time space. In this study, a Weibull survival model with a piecewise baseline hazard function was developed, with change points included as unknown parameters in the model. Concretely, a Weibull log-normal animal frailty model was assumed, and it was solved with a Bayesian approach. The required fully conditional posterior distributions were derived. During the sampling process, all the parameters in the model were updated using a Metropolis-Hastings step, with the exception of the genetic variance that was updated with a standard Gibbs sampler. This methodology was tested with simulated data sets, each one analysed through several models with different number of change points. The models were compared with the Deviance Information Criterion, with appealing results. Simulation results showed that the estimated marginal posterior distributions covered well and placed high density to the true parameter values used in the simulation data. Moreover, results showed that the piecewise baseline hazard function could appropriately fit survival data, as well as other smooth distributions, with a reduced number of change points.


The use of pathological grief outcomes in bereavement studies on African Americans.
Pathological bereavement outcomes (i.e., complicated grief, traumatic grief, prolonged grief disorder) are a robust and growing research area in the psychological and medical sciences. Although grief is considered to be a universal phenomenon, it is well documented that grieving processes and outcomes are culturally and contextually bound. The objectives of this study were: (a) to examine representations of African Americans in the grief and mourning literature and to assess the extent to which this research utilizes pathological grief outcomes; and (b) to examine the characteristics of pathological grief constructs in the literature to assess their relevance for African American populations. We conducted comprehensive searches of three scientific databases including PsycNET, Medline, and CINAHL, which contain the majority of grief and mourning literature published between January 1998 and February 2014. We found 59 studies addressing grief and mourning in African Americans. Thirteen of these studies used pathological grief outcomes. Pathological grief outcomes that were constructed and validated on White populations were frequently used as outcome variables with African American participants. We discuss the implications for the grief and mourning field and argue that the failure to use culturally sensitive outcome measures in research studies is a form of epistemological violence that may have negative research and clinical implications for African Americans and other ethnic minorities.


Catheter-associated urinary tract infections.
Millions of urethral catheters are used each year. This device subverts several host defenses to allow bacterial entry at the rate of 3% to 10% incidence per day, and its presence encourages the organism's persistent residence in the urinary tract. Most catheter-associated bacteriurias are asymptomatic. The complications in short-term catheterized patients include fever, acute pyelonephritis, bacteremia, and death; patients with long-term catheters in place are at risk for these complications and catheter obstruction, urinary tract stones, local periurinary infections, chronic renal inflammation, chronic pyelonephritis, and, over years, bladder cancer. The closed catheter system has been a magnificant step forward in the prevention of catheter-associated bacteriuria. Indeed, only two catheter principles are universally recommended: keep the closed catheter system closed and remove the catheter as soon as possible. Most modifications of the closed catheter system have not improved markedly on its ability to postpone bacteriuria. On first inspection, systemic antibiotics seem to be an exception to this rule, but their use results in infection of the bladder with resistant organisms, including candida. This and the effect of side effects on the patient and emergence of resistant bacteria in the medical unit have led most authorities to conclude that antibiotics are not useful for prevention of bacteriuria, nor for treatment of bacteriuria in the asymptomatic catheterized patient. For symptomatic patients, usually with fever or signs of sepsis, treatment of bacteriuria with appropriate systemic antibiotics and removal or replacement of the urethral catheter are indicated. Gloves, hand washing, and segregation of catheterized patients can minimize nosocomial clusters. Because clinicians can only postpone bacteriuria, and once it occurs, clinicians seem unable to prevent its complications, methodologies other than urethral catheters should be used for urine drainage assistance whenever possible. These options include condom, intermittent, suprapubic, and intraurethral catheterization for appropriate patients. The few data available suggest that each one of these catheterization options yields a lower incidence of bacteriuria-and its consequent complications-than urethral catheterization.


Assessing the Performance of Ks Plots for Detecting Ancient Whole Genome Duplications.
Genomic data have provided evidence of previously unknown ancient whole genome duplications (WGDs) and highlighted the role of WGDs in the evolution of many eukaryotic lineages. Ancient WGDs often are detected by examining distributions of synonymous substitutions per site (Ks) within a genome, or "Ks plots." For example, WGDs can be detected from Ks plots by using univariate mixture models to identify peaks in Ks distributions. We performed gene family simulation experiments to evaluate the effects of different Ks estimation methods and mixture models on our ability to detect ancient WGDs from Ks plots. The simulation experiments, which accounted for variation in substitution rates and gene duplication and loss rates across gene families, tested the effects of WGD age and gene retention rates following WGD on inferring WGDs from Ks plots. Our simulations reveal limitations of Ks plot analyses. Strict interpretations of mixture model analyses often overestimate the number of WGD events, and Ks plot analyses typically fail to detect WGDs when ≤10% of the duplicated genes are retained following the WGD. However, WGDs can accurately be characterized over an intermediate range of Ks. The simulation results are supported by empirical analyses of transcriptomic data, which also suggest that biases in gene retention likely affect our ability to detect ancient WGDs. Although our results indicate mixture model results should be interpreted with great caution, using node-averaged Ks estimates and applying more appropriate mixture models can improve the accuracy of detecting WGDs.


Efficacy of gemcitabine plus platinum agents for biliary tract cancers: a meta-analysis.
The objective of this study was to carry out a meta-analysis of the efficacy of gemcitabine+platinum agent regimens in the treatment of advanced biliary tract cancer (BTC). PubMed and Google Scholar were searched using the following combination of search terms: gemcitabine, oxaliplatin, cholangiocarcinoma, biliary, gallbladder, bile duct. Studies were eligible for inclusion in the meta-analysis if they were randomized trials on the use of gemcitabine plus a platinum agent for the treatment of advanced (unresectable or metastatic cancer) BTC. Outcomes of interest were response rate, overall survival, and progression-free survival. Pooled odds ratios/differences in median survival and 95% confidence intervals (CIs) were determined for each outcome. A total of 47 records were identified in the initial search. Ultimately, three open-label randomized trials (two phase 2 and one phase 3) met the eligibility criteria and were included in the meta-analysis. Two studies compared gemcitabine plus cisplatin with gemcitabine alone, whereas the other study compared gemcitabine plus oxaliplatin with fluorouracil-folinic acid. The total number of patients in the studies ranged from 54 to 410. The overall analyses revealed that all survival outcomes assessed were significantly more favorable for patients treated with gemcitabine plus platinum agents than for patients not treated with this combination. Response rates: odds ratio=2.639, 95% CI=1.210-5.757, Z=2.439, P=0.015; pooled difference in median overall survival=3.822 months, 95% CI=1.798-5.845 months, Z=3.702, P<0.001; pooled difference in median progression-free survival=3.268 months, 95% CI=1.996-4.541 months, Z=5.035, P<0.001. Patients with advanced BTC who are treated with gemcitabine plus platinum agents may experience better survival outcomes compared with patients who are not treated with this combination of chemotherapy.


[The effect of certain factors on the prognosis of the course of acute pancreatitis].
An analysis of treatment of 2740 patients with acute destructive pancreatitis from 1973 up to the present has been performed together with that of relevant published literature. Different factors of diagnosis and those of treatment of acute pancreatitis were found to influence the prognosis of the illness in some way or other. It has been noted that delayed surgery permit obtaining better results. Data are presented on long-term results of medical and surgical treatment of those patients who had become ill with necrotic forms of acute pancreatitis.


CRISPR/Cas9: a cutting-edge solution for combatting the fall armyworm, Spodoptera frugiperda.
The utilization of CRISPR/Cas9 in Spodoptera frugiperda, commonly known as fall armyworm, presents a groundbreaking avenue for pest management. With its ability to precisely modify the insect's genome, CRISPR/Cas9 offers innovative strategies to combat this destructive pest. The application of CRISPR/Cas9 in S. frugiperda holds immense potential. It enables the identification and functional analysis of key genes associated with its behavior, development, and insecticide resistance. This knowledge can unveil novel target sites for more effective and specific insecticides. Additionally, CRISPR/Cas9 can facilitate the development of population control methods by disrupting vital genes essential for survival. However, challenges such as off-target effects and the efficient delivery of CRISPR/Cas9 components remain. Addressing these obstacles is vital to ensure accurate and reliable results. Furthermore, ethical considerations, biosafety protocols, and regulatory frameworks must be integral to the adoption of this technology. Looking forward, CRISPR/Cas9-based gene drive systems hold the potential to promulgate desirable genetic traits within S. frugiperda populations, offering a sustainable and eco-friendly approach. This could curtail their reproductive capabilities or make them more susceptible to certain interventions. In conclusion, CRISPR/Cas9 presents a transformative platform for precise and targeted pest management in S. frugiperda. By deciphering the insect's genetic makeup and developing innovative strategies, we can mitigate the devastating impact of fall armyworm on agriculture while ensuring environmental sustainability.


[Prevention of severe reactions after iodinated contrast media injection: review of the literature].
One of the goal of a premedication before contrast agent injection is to decrease their adverse effects. However, no randomized study was published to date on the value of a systematic premedication for the prevention of immediate severe reactions. A knowledge of pathophysiological mechanisms and patients at risk seems to be essential. The allergic mechanism is probably one of the etiologic diagnosis, but this hypothesis needs to be confirmed by a multicenter prospective study. A patient who has had previous allergic reaction with contrast agent should undergo intradermal tests so as to identify and eliminate the culprit contrast medium in order to avoid any subsequent allergic accidents. Indeed, measurement of specific IgEs has not been validated for contrast media. The test dose should be discarded because it is a false security. The eventuality of adverse effects of the drugs used for premedication should not be underestimated.


Intracellular chloride activity in mammalian ventricular muscle.
The intracellular chloride activity (formula, see text) of quiescent rabbit right papillary muscle was measured with ion-selective microelectrodes (ISE) made with Corning 477315 liquid ion-exchange resin. The (formula, see text) was 9.8 +/- 2.4 (SD) mM, a value significantly greater than the 6.1 +/- 0.6 mM expected from passive distribution. The chloride equilibrium potential (ECl) was -64.4 +/- 6.6 mV, while membrane potential was -75.9 +/- 2.2 mV and significantly negative to ECl. These values are corrected for a nonchloride signal detected by the ISE. An apparent (formula, see text) of 4.8 +/- 0.6 mM was measured after exposure to Cl-free media for 1 h. Since isotopic chloride was totally washed out by this time, the apparent (formula, see text) in Cl-free media was interpreted as interference and subtracted from the (formula, see text) measured in other media. The conclusion that chloride is not passively distributed is supported by the observation that the (formula, see text) increase in high potassium media was smaller than predicted. In contrast to findings in papillary muscle, (formula, see text) of frog sartorius muscle was consistent with passive distribution, if it is assumed that interference was less than 0.5 mM.


Guideline harmonization and implementation plan for the BETTER trial: Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Family Practice.
The aim of the Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Family Practice (BETTER) randomized controlled trial is to improve the primary prevention of and screening for multiple conditions (diabetes, cardiovascular disease, cancer) and some of the associated lifestyle factors (tobacco use, alcohol overuse, poor nutrition, physical inactivity). In this article, we describe how we harmonized the evidence-based clinical practice guideline recommendations and patient tools to determine the content for the BETTER trial. We identified clinical practice guidelines and tools through a structured literature search; we included both indexed and grey literature. From these guidelines, recommendations were extracted and integrated into knowledge products and outcome measures for use in the BETTER trial. End-users (family physicians, nurse practitioners, nurses and dieticians) were engaged in reviewing the recommendations and tools, as well as tailoring the content to the needs of the BETTER trial and family practice. In total, 3-5 high-quality guidelines were identified for each condition; from these, we identified high-grade recommendations for the prevention of and screening for chronic disease. The guideline recommendations were limited by conflicting recommendations, vague wording and different taxonomies for strength of recommendation. There was a lack of quality evidence for manoeuvres to improve the uptake of guidelines among patients with depression. We developed the BETTER clinical algorithms for the implementation plan. Although it was difficult to identify high-quality tools, 180 tools of interest were identified. The intervention for the BETTER trial was built by integrating existing guidelines and tools, and working with end-users throughout the process to increase the intervention's utility for practice. ISRCTN07170460.


Lymphoid subpopulation changes after thermal injury and thermal injury with infection in an experimental model.
Subpopulation analysis of peripheral blood lymphocytes is a frequently used measure of immunocompetence. Yet, little is known about the lymphocyte subpopulations in the circulation and lymphoid organs after severe trauma. Blood, spleen, and lymph node (LN) subpopulations were compared in a rat model of burn injury (B) and burn injury with infection (BI). B and BI rats received 30% total body surface scald burns. Infection was induced by seeding wounds with Pseudomonas aeruginosa. Subpopulations were identified by flow cytometry 48 hours after burn. Helper lymphocytes were selectively depleted from the circulation of BI but not B animals, which caused the ratio of helper to suppressor cells (HSR) in BI animals to decrease significantly compared with the unburned controls. Both LN helper and suppressor cells were decreased in BI animals and the HSR was unchanged, but a selective reduction in suppressor cells in B LN increased the HSR relative to unburned controls. Spleen subpopulations were unchanged for both B and BI groups. Subpopulation changes after trauma and infection were different for each tissue examined.


Racial and ethnic differences in cognitive health appraisals: a comparison of non-Hispanic White, non-Hispanic Black, and Hispanic older adults.
To investigate the relationship between cognitive performance and cognitive health appraisals across non-Hispanic White, non-Hispanic Black, and Hispanic older adults in the United States and to explore within-group variations by examining interactions between cognitive performance and background and health variables. The sample (N = 3,099) included 2,260 non-Hispanic White, 498 non-Hispanic Black, and 341 Hispanic adults aged 65 or older, from the 2016-2017 Harmonized Cognitive Assessment Protocol. Regression models of cognitive health appraisals, indicated by self-rated cognitive health, were examined in the entire sample and in racial and ethnic subgroups to test direct and interactive effects of cognitive performance, indicated by the Mini-Mental State Examination (MMSE). The regression model for the entire sample showed direct effects of cognitive performance and race/ethnicity on cognitive health appraisals, as well as a significant interaction between cognitive performance and being non-Hispanic Black. Cognitive performance and cognitive health appraisals were positively associated in non-Hispanic Whites but not significantly associated in non-Hispanic Blacks. Our subsequent analysis within each racial/ethnic group showed that the effect of cognitive performance in non-Hispanic Blacks and Hispanics became either reversed or nonsignificant when background and health variables were considered. Modification by age or chronic medical conditions in each racial and ethnic group was also observed. Overall, these findings suggest that perceptions and appraisals of cognitive health vary by race and ethnicity and hold implications for how these differences should be considered in research and practice with diverse groups of older adults.


Coping with employee departures.
Resignations should be treated as minicrises. The highly structured procedure for handling employee exists described in this article can be effective in reducing employee turnover problems. Employees are recipients of your supervisory service, and therefore are your clients and should be treated as such. Suggestions are offered for maintaining staff efficiency during transitions and for conducting effective exist interviews.


Contributions of Fusarium virguliforme and Heterodera glycines to the disease complex of sudden death syndrome of soybean.
Sudden death syndrome (SDS) of soybean caused by Fusarium virguliforme spreads and reduces soybean yields through the North Central region of the U.S. The fungal pathogen and Heterodera glycines are difficult to manage. The objective was to determine the contributions of H. glycines and F. virguliforme to SDS severity and effects on soybean yield. To quantify DNA of F. virguliforme in soybean roots and soil, a specific real time qPCR assay was developed. The assay was used on materials from soybean field microplots that contained in a four-factor factorial-design: (i) untreated or methyl bromide-fumigated; (ii) non-infested or infested with F. virguliforme; (iii) non-infested or infested with H. glycines; (iv) natural precipitation or additional weekly watering. In years 2 and 3 of the trial, soil and watering treatments were maintained. Roots of soybean 'Williams 82' were collected for necrosis ratings at the full seed growth stage R6. Foliar symptoms of SDS (area under the disease progress curve, AUDPC), root necrosis, and seed yield parameters were related to population densities of H. glycines and the relative DNA concentrations of F. virguliforme in the roots and soil. The specific and sensitive real time qPCR was used. Data from microplots were introduced into models of AUDPC, root necrosis, and seed yield parameters with the frequency of H. glycines and F. virguliforme, and among each other. The models confirmed the close interrelationship of H. glycines with the development of SDS, and allowed for predictions of disease risk based on populations of these two pathogens in soil. The results modeled the synergistic interaction between H. glycines and F. virguliforme quantitatively in previously infested field plots and explained previous findings of their interaction. Under these conditions, F. virguliforme was mildly aggressive and depended on infection of H. glycines to cause highly severe SDS.


Immediate, lag and time window effects of meteorological factors on ST-elevation myocardial infarction incidence.
The influence of several meteorological parameters on acute myocardial infarction (AMI) incidences with immediately and/or delayed effects has been widely reported. It remains unknown whether the individual AMI subtypes reveal similar patterns. To date, generally seasonal variation in ST elevation MI (STEMI) has been investigated. However, these approaches couldn't detect the effects of changes in multiple meteorological variables on STEMI incidence within a specific season. Therefore, the aim of our study is to explore immediate, delayed and cumulative effects of average daily temperature, atmospheric pressure and humidity on nation-wide STEMI hospital admissions. We linked daily hospitals' STEMI admission data with meteorological stations' data according to the patient's permanent residence. Subsequently, a multivariate analysis based on a main effect generalised linear model, assuming a log-link function with a Poisson distribution, was conducted. With the help of lags, we were able to analyse delayed effects, while the cumulative effects of specific meteorological variables were analysed utilising time windows. As a result, we confirmed immediate and delayed negative effect of low temperature and low relative humidity for all observed lags as well as cumulative average effects of low temperature and low relative humidity for all observed time windows. However, no delayed, single-day effect for atmospheric pressure was detected. Nevertheless, the cumulative average effect was confirmed in all time windows suggesting that prolonged low pressure influences the incidence of STEMI. A novelty of our approach is the comparative examination of immediate, delayed and cumulative effect of specific meteorological variables on the incidence of STEMI. This approach enables us to gain a new insight into the phenomenon studied.


Family-Focused Treatment for Childhood Depression: Model and Case Illustrations.
Although the evidence base for treatment of depressive disorders in adolescents has strengthened in recent years, less is known about the treatment of depression in middle to late childhood. A family-based treatment may be optimal in addressing the interpersonal problems and symptoms frequently evident among depressed children during this developmental phase, particularly given data indicating that attributes of the family environment predict recovery versus continuing depression among depressed children. Family-Focused Treatment for Childhood Depression (FFT-CD) is designed as a 15-session family treatment with both the youth and parents targeting two putative mechanisms involved in recovery: (a) enhancing family support, specifically decreasing criticism and increasing supportive interactions; and (b) strengthening specific cognitive-behavioral skills within a family context that have been central to CBT for depression, specifically behavioral activation, communication, and problem solving. This article describes in detail the FFT-CD protocol and illustrates its implementation with three depressed children and their families. Common themes/challenges in treatment included family stressors, comorbidity, parental mental health challenges, and inclusion/integration of siblings into sessions. These three children experienced positive changes from pre- to posttreatment on assessor-rated depressive symptoms, parent- and child-rated depressive symptoms, and parent-rated internalizing and externalizing symptoms. These changes were maintained at follow-up evaluations 4 and 9 months following treatment completion.


Identifying important barriers to recruitment of patients in randomised clinical studies using a questionnaire for study personnel.
Many randomised controlled trials (RCT) fail to meet their recruitment goals. Study personnel play a key role in recruitment. The aim of this study was to identify successful strategies that study personnel consider to be important in patient recruitment to RCT. We constructed a questionnaire based on the literature, discussions with colleagues and our own experience as trialists. The survey was named "What is Important for Making a Study Successful questionnaire" (WIMSS-q). Our target group was the study personnel in the ongoing EFFECTS study. The questionnaire was sent out electronically to all physicians and nurses (n = 148). Success factors and barriers were divided according to patient, centre and study level, respectively. Responses were received from 94% of the study personnel (139/148). The five most important factors at centre level for enhancing recruitment were that the research question was important (97%), a simple procedure for providing information and gaining consent (92%), a highly engaged local principal investigator and research nurse (both 87%), and that study-related follow-ups are practically feasible and possible to coordinate with the clinical follow-up (87%). The most significant barrier at the local centre was lack of time and resources devoted to research (72%). Important patient-related barriers were fear of side effects (35%) and language problems (30%). For recruitment in an RCT to be successful, the research question must be relevant, and the protocol must be simple and easy to implement in the daily routine. The protocol for this study was registered at the Northern Ireland Hub for trials methodology research (SWAT ID 64 ). The EFFECTS study has EudraCT number 2011-006130-16 and was registered 17 February 2016 at ClinicalTrials.gov number NCT02683213 .


Apobec-1 complementation factor modulates liver regeneration by post-transcriptional regulation of interleukin-6 mRNA stability.
Apobec-1 complementation factor (ACF) is the RNA binding subunit of a core complex that mediates C to U RNA editing of apolipoprotein B (apoB) mRNA. Targeted deletion of the murine Acf gene is early embryonic lethal and Acf(-/-) blastocysts fail to implant and proliferate, suggesting that ACF plays a key role in cell growth and differentiation. Here we demonstrate that heterozygous Acf(+/-) mice exhibit decreased proliferation and impaired liver mass restitution following partial hepatectomy (PH). To pursue the mechanism of impaired liver regeneration we examined activation of interleukin-6 (IL-6) a key cytokine required for induction of hepatocyte proliferation following PH. Peak induction of hepatic IL-6 mRNA abundance post PH was attenuated >80% in heterozygous Acf(+/-) mice, along with decreased serum IL-6 levels. IL-6 secretion from isolated Kupffer cells (KC) was 2-fold greater in wild-type compared with heterozygous Acf(+/-) mice. Recombinant ACF bound an AU-rich region in the IL-6 3'-untranslated region with high affinity and IL-6 mRNA half-life was significantly shorter in KC isolated from Acf(+/-) mice compared with wild-type controls. These findings suggest that ACF regulates liver regeneration following PH at least in part by controlling the stability of IL-6 mRNA. The results further suggest a new RNA target and an unanticipated physiological function for ACF beyond apoB RNA editing.


Rewinding sarcopenia: a narrative review on the renin-angiotensin system.
The purpose of this review was two-fold. First, we aimed to provide an in-depth glance on the relationship between renin-angiotensin system (RAS) dysregulation and sarcopenia. Second, we aimed to touch upon potential treatments of sarcopenia (including RAS blockers, vitamin D, and exercise) in light of the pertinent literature. Currently available research regarding the effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers on knee extensor strength, grip strength, chair stand test, gate speed together with the effects of exercise on muscle mass, strength, physical performance, blood pressure and cognitive tests (particularly in older adults) was reviewed. Although some studies have shown favorable effects of ACEIs on muscle strength and/or physical function tests, some studies have reported no/negative association in between. The favorable impact of exercise on reducing blood pressure is shown, and exercise treatment is widely recommended in the relevant literature. Different types of exercises (aerobic, resistance, dancing, music movement, water-based, golf, knitting activities or multicomponent exercises) have shown improvement in cognitive functions as well. Classical RAS activity results in deleterious effects not only on the cardiovascular but also on the neuromusculoskeletal system. Therefore, treatments targeting inhibition of the classical RAS activity seem to be important in the management of several age-related pathologies, including sarcopenia. As such, ACEIs, vitamin D, exercise, and healthy diet can have prominent effects not only on the modulation of RAS but also on physical and cognitive functions and sarcopenia as well.


Effects of tryptophan depletion on drug-free patients with seasonal affective disorder during a stable response to bright light therapy.
A dysfunction of the serotonin system may play a major role in the pathogenesis of seasonal affective disorder. Bright light therapy has been shown to be effective in the treatment of winter depression in patients with seasonal affective disorder. Light therapy-induced remission from depression may be associated with changes in brain serotonin function. After at least 2 weeks of clinical remission, 12 drug-free patients who had had depression with seasonal affective disorder underwent tryptophan depletion in a double-blind, placebo-controlled, balanced cross-over design study. Short-term tryptophan depletion induced a significant decrease in plasma free and total tryptophan levels (P < .001 for both, repeated measures analysis of variance), with peak effects occurring 5 hours after ingestion of a tryptophan-free amino acid drink. It emerged that tryptophan depletion leads to a transient depressive relapse, which was most pronounced on the day after the tryptophan-depletion testing. No clinically relevant mood changes were observed in the control testing. The maintenance of light therapy-induced remission from depression in patients with seasonal mood cycles seems to depend on the functional integrity of the brain serotonin system. Our results suggest that the serotonin system might be involved in the mechanism of action of light therapy.


Contribution of colony-stimulating factor 1 to neuropathic pain.
Molecular and cellular interactions among spinal dorsal horn neurons and microglia, the resident macrophages of the central nervous system, contribute to the induction and maintenance of neuropathic pain after peripheral nerve injury. Emerging evidence also demonstrates that reciprocal interactions between macrophages and nociceptive sensory neurons in the dorsal root ganglion contribute to the initiation and persistence of nerve injury-induced mechanical hypersensitivity (allodynia). We previously reported that sensory neuron-derived colony-stimulating factor 1 (CSF1), by engaging the CSF1 receptor (CSF1R) that is expressed by both microglia and macrophages, triggers the nerve injury-induced expansion of both resident microglia in the spinal cord and macrophages in the dorsal root ganglion and induces their respective contributions to the neuropathic pain phenotype. Here, we review recent research and discuss unanswered questions regarding CSF1/CSF1R-mediated microglial and macrophage signaling in the generation of neuropathic pain.


Virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients.
To determine the rate of virological treatment failure with protease inhibitor therapy in unselected patients and to assess underlying risk factors. Retrospective study in two German tertiary care treatment centres. A total of 198 HIV-infected patients treated with protease inhibitors in 1996. Levels of HIV RNA 1-6 months after start of treatment; definition of treatment failure of < 1 log10 reduction in plasma HIV RNA within 6 months after starting protease inhibitor therapy; multivariate analysis of risk factors for treatment failures. A total of 226 treatment episodes with protease inhibitors were evaluable (saquinavir, 83; ritonavir, 47; indinavir, 96). The rate of virological treatment failure was 44% (saquinavir, 64%; ritonavir, 38%; indinavir, 30%). In a multivariate analysis, the following independent risk factors for virological failure were found: CD4 cell count, pretreatment with antiretroviral drugs (number), and protease inhibitor (compound). The relative risk reduction for each CD4 cell count increase was 0.997 (P = 0.012), 2.64 for pretreatment with one or two drugs versus no drug (P = 0.05), 2.97 for pretreatment with more than two drugs versus no drug (P = 0.05), and 4.62 for treatment with saquinavir versus indinavir (P = 0.001). An unexpectedly high rate of virological treatment failure of protease inhibitor therapy was found in an unselected cohort of HIV-infected patients. Response to antiretroviral combination therapy in normal clinical practice may considerably differ from results of randomized clinical trials. Further studies are warranted to find optimal treatment strategies for both initial and salvage therapy.


Organosilane self-assembled monolayer growth from supercritical carbon dioxide in microstructured optical fiber capillary arrays.
Microstructured optical fibers form a new class of extreme aspect ratio templates that are well-suited for precise, designed spatial organization of materials and molecules at dimensions down to the nanoscale. The extreme aspect ratios of the nanoscale to microscale pores in the templates necessitates new approaches to fabrication of nanowires, nanotubes, and self-assembled monolayers within them. High-pressure fluids, which have lower viscosities than liquids and no surface tension, are well-suited for penetrating such extreme aspect ratio capillaries. Here we report an approach to fabricating self-assembled monolayers within microstructured optical fibers using near supercritical or supercritical carbon dioxide. An AFM-based "shaving" technique has been developed to characterize the monolayers formed in capillaries that are too small to allow for characterization by conventional approaches.


Comparison of Clinical and Social Characteristics of Canadian Youth Living With Type 1 and Type 2 Diabetes.
Our aim in this study was to describe the clinical and social characteristics of 2 Canadian cohorts of adolescents with diabetes. Participants from the Improving renal Complications in Adolescents with type 2 diabetes through REsearch (iCARE) study (n=322) and the Early Determinants of Cardio-Renal Disease in Youth With Type 1 Diabetes (n=199) study were compared. Adolescents were 10 to 18 years of age (mean ± standard deviation: 14.8±2.4 years). The T2DM cohort had a shorter duration of diabetes. Both groups had glycated hemoglobin levels above target. The type 2 diabetes (T2D) cohort was comprised of predominantly Indigenous youth. The type 1 diabetes (T1D) cohort was 58.3% European/Caucasian, with a high proportion (41.7%) of visible minority groups (Afro-Caribbean, Asian/Pacific Islander, Hispanic). The prevalence of obesity, hypertension, left ventricular hypertrophy, albuminuria and hyperfiltration was higher in the T2D cohort. The T1D cohort was more socially and economically advantaged in all 4 dimensions of health inequality. There are significant differences in clinical and social characteristics of adolescents with T2D and T1D in Canada. Both have inadequate glycemic control with evidence of onset and progression of diabetes-related complications.


Single-molecule real-time detection of telomerase extension activity.
The ends of eukaryotic chromosomes are capped by telomeres which consist of tandem G-rich DNA repeats stabilized by the shelterin protein complex. Telomeres shorten progressively in most normal cells due to the end replication problem. In more than 85% of cancers however, the telomere length is maintained by telomerase; a reverse transcriptase that adds telomeric TTAGGG repeats using its integral RNA template. The strong association between telomerase activity and malignancy in many cancers suggests that telomerase activity could serve as a diagnostic marker. We demonstrate single-molecule, real-time telomerase extension activity observed digitally as the telomeric repeats are added to a substrate. The human telomerase complex pulled down from mammalian cells displays extension activity dependent on dNTP concentration. In complex with the processivity factor, POT1-TPP1, telomerase adds repeats at an accelerated rate and yields longer products. Our assay provides a unique detection platform that enables the study of telomerase kinetics with single molecule resolution.


Predictive Factors for a Successful Treatment Outcome in Patients with Different Voiding Dysfunction Subtypes Who Received Urethral Sphincter Botulinum Injection.
Voiding dysfunction is a common but bothersome problem in both men and women. Urethral sphincter botulinum toxin A (BoNT-A) injections could serve as an option in refractory cases. This study analyzed the efficacy and outcome predictors of the injections in patients with functional, non-neurogenic voiding dysfunction. Patients who received urethral sphincter BoNT-A injection for refractory voiding dysfunction due to detrusor underactivity (DU) or urethral sphincter dysfunction were retrospectively reviewed. A successful outcome was defined as a marked improvement as reported in the global response assessment. The study evaluated the therapeutic efficacy of urethral sphincter BoNT-A injections and measured the changes in urodynamic parameters after the procedure in the patients. A total of 181 patients including 138 women and 43 men were included. The overall success rate was 64%. A lower success rate was noted in patients with DU compared to those with urethral sphincter dysfunction in both genders. In the multivariable analysis, recurrent urinary tract infection (UTI) and bladder voiding efficiency (BVE) were positive predictors for a successful outcome, while DU was a negative predictor. Urethral sphincter BoNT-A injection is an effective treatment for refractory non-neurogenic voiding dysfunction. Baseline BVE and history of recurrent UTI positively predict a successful outcome. DU is a negative outcome predictor.


Electron Transfer Mediated by Iron Carbonyl Clusters Enhance Light-Driven Hydrogen Evolution in Water by Quantum Dots.
Photocatalytic water splitting has become a promising strategy for converting solar energy into clean and carbon-neutral solar fuels in a low-cost and environmentally benign way. Hydrogen gas is such a potential solar fuel/energy carrier. In a classical artificial photosynthetic system, a photosensitizer is generally associated with a co-catalyst to convert photogenerated charge into (a) chemical bond(s). In the present study, assemblies consisting of CdSe quantum dots that are coupled with one of two molecular complexes/catalysts, that is, [Fe2 S2 (CO)6 ] or [Fe3 Te2 (CO)9 ], using an interface-directed approach, have been tested as catalytic systems for hydrogen production in aqueous solution/organic solution. In the presence of ascorbic acid as a sacrificial electron donor and proton source, these assemblies exhibit enhanced activities for the rate of hydrogen production under visible light irradiation for 8 h in aqueous solution at pH 4.0 with up to 110 μmol of H2 per mg of assembly, almost 8.5 times that of pure CdSe quantum dots under the same conditions. Transient absorption and time-resolved photoluminescence spectroscopies have been used to investigate the charge carrier transfer dynamics in the quantum dot/iron carbonyl cluster assemblies. The spectroscopic results indicate that effective electron transfer from the molecular iron complex to the valence band of the excited CdSe quantum dots significantly inhibits the recombination of photogenerated charge carriers, boosting the photocatalytic activity for hydrogen generation; that is, the iron clusters function as effective intermediaries for electron transfer from the sacrificial electron donor to the valence band of the quantum dots.


Evaluating implementation of LEAPS, a youth-led early childhood care and education intervention in rural Pakistan: protocol for a stepped wedge cluster-randomized trial.
The Sustainable Development Goals (SDGs) highlight the importance of investments in early childhood care and education (ECCE) and youth development. Given Pakistan's large young population, and gender and urban-rural inequalities in access to education, training, and employment, such investments offer opportunities. LEAPS is a youth-led ECCE program that trains female youth, 18-24 years, as Community Youth Leaders (CYLs) to deliver high-quality ECCE for children, 3.5-5.5 years, in rural Sindh, Pakistan. We use a stepped wedge cluster-randomized trial to evaluate implementation of LEAPS. Ninety-nine clusters will be randomized to receive the intervention in one of three 7-month steps (33 clusters/step). The primary outcome is children's school readiness (indexed by the total score on the International Development and Early Learning Assessment (IDELA)). Secondary child outcomes are children's IDELA domain scores and executive functions. Data are collected in cross-sectional surveys of 1089 children (11 children/cluster from 99 clusters) aged 4.5-5.5 years at four timepoints (baseline and at the end of each step). Additionally, we will enroll three non-randomized youth participant open cohorts, one per step (33 CYLs: 66 comparison youth per cohort; 99:198 in total). Youth cohorts will be assessed at enrollment and every 7 months thereafter to measure secondary outcomes of youth personal and professional development, depressive symptoms, and executive functions. A non-randomized school cohort of 330 LEAPS students (10 students/cluster from 33 clusters) will also be enrolled and assessed during Step 1 after intervention rollout and at endline. The quality of the learning environment will be assessed in each LEAPS ECCE center and in a comparison center at two timepoints midway following rollout and at endline. A concurrent mixed-methods implementation evaluation will assess program fidelity and quality, and the extent to which a technical support strategy is successful in strengthening systems for program expansion. A cost evaluation will assess cost per beneficiary. Data collection for implementation and cost evaluations will occur in Step 3. Youth-led models for ECCE offer a promising approach to support young children and youth. This study will contribute to the evidence as a means to promote sustainable human development across multiple SDG targets. ClinicalTrials.gov NCT03764436 . Registered on December 5, 2018.


Distress and quality of life after autologous stem cell transplantation: a randomized clinical trial to evaluate the outcome of a web-based stepped care intervention.
Psychological distress (i.e. depression and anxiety) is a strong predictor of functional status and other aspects of quality of life in autologous stem cell transplantation following high-dose chemotherapy. Treatment of psychological distress is hypothesized to result in improvement of functional status and other aspects of quality of life. The aim is to evaluate the outcome of stepped care for psychological distress on functional status and other aspects of quality of life in patients with hematological malignancy treated with autologous stem cell transplantation. The study is designed as a randomized clinical trial with 2 treatment arms: a stepped care intervention program versus care as usual. Patients are randomized immediately pre transplant. Stepped care and care as usual are initiated after a 6 weeks buffer period. Outcome is evaluated at 13, 30, and 42 weeks post transplant.In the experimental group, the first step includes an Internet-based self-help program. If psychological distress persists after the self-help intervention, the second step of the program is executed, i.e. a diagnostic evaluation and a standardized interview, yielding a problem analysis. Based on this information, a contract is made with the patient and treatment is provided consisting of individual face-to-face counseling, medication, or referral to other services. Care as usual comprises an interview with the patient, on ad hoc basis; emotional support and advice, on ad hoc basis; if urgent problems emerge, the patient is referred to other services.Primary outcome variables are psychological distress and functional status. Data are analyzed according to the intention to treat-principle. This study has several innovative characteristics. First, the outcome of the intervention for psychological distress in patients with hematological malignancy treated with autologous stem cell transplantation is evaluated in a randomized controlled study. Second, the impact of the intervention on functional status is evaluated: it is hypothesized that reduction of psychological distress results in improved functional status. Furthermore, the intervention concerns an Internet-based treatment in the first step. Finally, the intervention is characterized by an emphasis on self-management, efficiency, and a multi-disciplinary approach with nurses taking up a central role. NTR1770.


A new subfamily of fungal subtilases: structural and functional analysis of a Pleurotus ostreatus member.
Pleurotus ostreatus produces several extracellular proteases which are believed to be involved in the regulation of the ligninolytic activities of this fungus. Recently, purification and characterization of the most abundant P. ostreatus extracellular protease (PoSl) have been reported. The sequence of the posl gene and of the corresponding cDNA has been determined, allowing the identification of its pre- and pro-sequences. A mature protein sequence has been verified by mass spectrometry mapping, the N-glycosylation sites have been identified and the glycosidic moieties characterized. Mature PoSl shows a cleaved peptide bond in the C-terminal region, which remains associated with the catalytic domain in a non-covalent complex. Reported results indicate that this enzyme is involved in the activation of other P. ostreatus secreted proteases, thus suggesting its leading role in cascade activation mechanisms. Analyses of the PoSl sequence by homology search resulted in the identification of a DNA sequence encoding a new protease, homologous to PoSl, in the Phanerochaete chrysosporium genome. A new subgroup of subtilisin-like proteases, belonging to the pyrolysin family, has been defined, which includes proteases from ascomycete and basidiomycete fungi.


Relative effectiveness of C primary afferent fibers of different origins in evoking a prolonged facilitation of the flexor reflex in the rat.
Changes in the excitability of the hamstring flexor withdrawal reflex produced by conditioning stimuli applied to C-afferent fibers of different origins have been examined in the decerebrate spinal rat. In the absence of conditioning stimuli, the flexor reflex elicited by a standard suprathreshold mechanical stimulus to the toes is stable when tested repeatedly for hours. Three categories of conditioning stimuli have been used in an attempt to modify the excitability of the flexor reflex; electrical stimulation of a cutaneous (sural) nerve or a muscle (gastrocnemius-soleus) nerve at C-fiber strength; the application of mustard oil, a chemical irritant that activates chemosensitive C-afferents, to the skin or injected intramuscularly and intraarticularly; and the indirect activation of high-threshold muscle afferents by fused tetanic contractions of the tibial muscles. Conditioning stimuli of an intensity sufficient to activate C-afferent fibers result in a heterosynaptic facilitation of the flexor motoneuronal response to the standard test input, which lasts from 3 min to more than 3 hr, depending on the stimulus and the C-afferents activated. Pretreatment of the sciatic nerve with the C-fiber neurotoxin capsaicin abolishes all the postconditioning facilitations, which is an indication that it is likely that it is C-afferents that are primarily responsible for the facilitatory effects of the conditioning stimuli, although some A delta afferents may contribute. Capsaicin pretreatment does not modify the reflex response to the test stimulus. The most prolonged increase in the excitability of the flexor reflex resulted from intraarticular injections of 5 microliter mustard oil. Using the subsequent injection of lignocaine intraarticulary, it was found that the prolonged facilitation of the reflex is triggered by the afferent input generated by the conditioning stimulus and does not require an ongoing input for its maintenance. These results indicate that there is a spectrum of central changes in the stimulus response relations of the spinal cord resulting from the activation of C-fibers of different origins. The prolonged duration of some of these changes means that the peripheral activation of C-afferents will modify the functional response of the spinal cord to other inputs applied long after the conditioning input, and this may be responsible for some of the sensory and motor alterations found after peripheral tissue injury.


Comparison of bleeding risks among non-vitamin K antagonist oral anticoagulants using the Korea adverse event reporting system database.
In order to ensure safer use of non-vitamin K antagonist oral anticoagulants (NOACs), continuously detecting unexpected adverse drug reactions (ADRs) after market approval is necessary. We performed disproportionality analysis to evaluate association between ADRs and NOACs including apixaban, dabigatran, and rivaroxaban using data from the Korea Institute of Drug Safety and Risk Management-Korea Adverse Event Reporting System database (KIDS-KD) between 2012 and 2016. There was no significant signal other than bleeding when considering quantity, signal strength, seriousness, and causality. In order to evaluate the NOAC reports about bleeding, we selected 62 WHO-ART diagnostic codes associated with bleeding. Among the 26 codes that referred to major bleeding, 18 codes referred to gastrointestinal bleeding and 8 were referred to intracranial bleeding. We evaluated the significance of the signals using reporting odds ratios (RORs) adjusted for age and sex. Treatments with apixaban, dabigatran, and rivaroxaban were associated with 1989, 1668, and 2960 adverse events, respectively. Any type of bleeding with apixaban, dabigatran, rivaroxaban, and warfarin was reported in 174 (8.8%), 209 (12.5%), 523 (17.8%), and 620 (9.5%) events, respectively. For any bleeding, adjusted RORs of apixaban, dabigatran, and rivaroxaban were 0.99 [95% confidence interval (CI): 0.83-1.17], 1.47 (95% CI: 1.25-1.75), and 2.48 (95% CI: 2.16-2.84), respectively. With respect to major bleeding, the adjusted RORs of apixaban, dabigatran, and rivaroxaban were 1.08 (95% CI: 0.82-1.41), 1.46 (95% CI: 1.10-1.90), and 1.82 (95% CI: 1.43-2.32), respectively. Rivaroxaban might have stronger association with bleeding than apixaban and dabigatran.


Halving Your Cake and Eating it, Too: A Case-based Discussion and Review of Metabolic Rehabilitation for Obese Adults with Diabetes.
The global epidemic of obesity will see normal weight adults constituting a mere one-third of the global population by 2025. Although appetite and weight are regulated by a complex integration of neurological, endocrine and gastrointestinal feedback mechanisms, there is a constant interaction between psychological state, physical impairment, presence of comorbid chronic disease and medications. We discuss two cases and reveal a practical approach to investigating and managing patients with obesity and diabetes in the 'real world'. Within this scope, the aetiology, associated disease burden, and pharmacological therapies for the treatment of the obese patient with type 2 diabetes are reviewed. An insight into non-surgical metabolic rehabilitation is also provided. Lifestyle, including diet, exercise, medications, as well as genetic predisposition, and rarely, endocrinopathies should be considered in the assessment of the obese patient. Investigations are not complex and include cardiometabolic and nutritional screens and an assessment for institution of graded, safe levels of exercise. In more complicated patients, referral to a multidisciplinary outpatient program may be necessary and it is not uncommon for patients to lose between 10-20% of their initial weight. Despite this, metabolic surgery may be necessary as further weight loss with long-term weight maintenance may be medically indicated. The type of surgery is tailored to the patient's medical risk and co-morbidities as well as likelihood of compliance with the required follow-up. It is the opinion of the authors that metabolic rehabilitation should be intensive, multidisciplinary, and have a supervised exercise program, as the gold standard of care. These suggestions are based on the clinical pearls gained over two decades of clinical experience working in one of Australia's most innovative multidisciplinary metabolic rehabilitation programs caring for patients with severe obesity.


Forskolin stimulation of water and cation permeability in aquaporin 1 water channels.
Aquaporin 1, a six-transmembrane domain protein, is a water channel present in many fluid-secreting and -absorbing cells. In Xenopus oocytes injected with aquaporin 1 complementary RNA, the application of forskolin or cyclic 8-bromo- adenosine 3',5'-monophosphate increased membrane permeability to water and triggered a cationic conductance. The cationic conductance was also induced by direct injection of protein kinase A (PKA) catalytic subunit, reduced by the kinase inhibitor H7, and blocked by HgCl2, an inhibitor of aquaporin 1. The cationic permeability of the aquaporin 1 channel is activated by a cyclic adenosine monophosphate-dependent mechanism that may involve direct or indirect phosphorylation by PKA.


Microtubules and associated microfilaments in the tentacles of the suctorian Heliophrya erhardi Matthes.
At the ultrastructural level length changes accompanying linear movements of resting (non-feeding) tentacles of the suctorian Heliophrya involve not only altered microtubule numbers, but also marked changes in the specific microtubule pattern of cross-sectioned tentacles. These changes in number and pattern indicate a sliding between axonemal microtubules. The visualization of microfilaments in the cytoplasm at the tentacle base and in the knob region could shed new light on the problem of whether microtubular sliding is an active or passive process. At the tentacle base, microfilaments are either arranged in a ring-shaped configuration around the axoneme, or they run parallel to the axonemal microtubules, whereas at the tentacle tip during the resting state, microfilaments are closely associated with the plasma membrane of the knob. They form a filamentous reticular layer, which is continuous at the anchorage site of axonemal microtubules with the dense epiplasmic layer of the tentacle shaft. Obiously, this filamentous layer is engaged in positioning the haptocysts at the plasma membrane and in holding the membrane itself under tension. The putative contractile nature of microfilaments and the epiplasmic layer is argued from ATP-sensitive glycerol models of tentacles and from the results of halothane treatment of native tentacles. Halothane treatment of resting tentacles also gave indications of the presence of differentially stable intermicrotubule-bridges. The role of micro-filaments and halothane-resistant dynein-like inter-row bridges in tentacle movement is discussed. As soon as the plasma membrane of the knob is 'sealed' with the prey pellicle during feeding, the microtubules of the sleeve region slide into the knob where they bend back and outwards. The microtubules now appear decorated and sometimes cross-connected by microfilaments which adhere closely to the plasma membrane- now acting as a peritrophic membrane-lining the prey cytoplasm against the microtubules of the inner tube. These microfilaments which show a close association with the microtubules of the active knob area, are thought to be engaged in microtubular bending and stretching during feeding. They may also be involved in the transport of the peritrophic membrane in distal tentacle regions. Microinematographically recorded oscillations in tentacle diameter in these regions are in agreement with the electron-microscopic findings of various states of collapsed tentacle axonemes. These observations, as well as the occurrence of helically twisted tentacles during feeding, suggest microfilament mediated sequential back and forth movements of sleeve microtubules in the knob region which generate a proximally migrating helical wave.


Recognition of motor imagery electroencephalography using independent component analysis and machine classifiers.
Motor imagery electroencephalography (EEG), which embodies cortical potentials during mental simulation of left or right finger lifting tasks, can be used to provide neural input signals to activate a brain computer interface (BCI). The effectiveness of such an EEG-based BCI system relies on two indispensable components: distinguishable patterns of brain signals and accurate classifiers. This work aims to extract two reliable neural features, termed contralateral and ipsilateral rebound maps, by removing artifacts from motor imagery EEG based on independent component analysis (ICA), and to employ four classifiers to investigate the efficacy of rebound maps. Results demonstrate that, with the use of ICA, recognition rates for four classifiers (fisher linear discriminant (FLD), back-propagation neural network (BP-NN), radial-basis function neural network (RBF-NN), and support vector machine (SVM)) improved significantly, from 54%, 54%, 57% and 55% to 70.5%, 75.5%, 76.5% and 77.3%, respectively. In addition, the areas under the receiver operating characteristics (ROC) curve, which assess the quality of classification over a wide range of misclassification costs, also improved from .65, .60, .62, and .64 to .74, .76, .80 and .81, respectively.


Multiple sclerosis incidence associated with the soil lead and arsenic concentrations in Taiwan.
Few studies in the world have assessed the incidence of multiple sclerosis (MS) with soil heavy metal concentrations. We explored the association of soil heavy metal factors and the MS incidence in Taiwan. There were 1240 new MS cases from the National Health Insurance Research Database and were verified with serious disabling disease certificates, 1997-2008. Soil heavy metal factors records included arsenic, mercury, cadmium, chromium, copper, nickel, lead and zinc in Taiwan from 1986 to 2002. Spatial regression was used to reveal the association of soil heavy metals and age- and gender-standardized incidence ratios for townships by controlling sunlight exposure hours, smoking prevalence and spatial autocorrelation. The lead (Pb) concentration in the soil positively correlated with the township incidence; on the other hand, the arsenic (As) concentration in soil negatively correlated with the township incidence and when found together controlled each other. The positive correlation of lead (Pb) predominated in males, whereas the negative correlation of arsenic (As) in soil predominated in females. We conclude that exposure to lead (Pb) in soil positive associated with incidence of MS in Taiwan, especially in males. Exposure to arsenic (As) in soil negative associated with MS in Taiwan, especially in females.


Tendon-Derived Mesenchymal Stem Cells (TDSCs) as an In Vitro Model for Virological Studies in Wild Birds.
The use of wild animals in research is complicated due to the capture and housing conditions, as well as to legal aspects, making it difficult to develop in vivo and in vitro models for the study of pathologies that affect these species. Here we validate an in vitro model of tendon-derived mesenchymal cells (TDSC) from Eurasian blackbird (Turdus merula) cadaveric samples. Through the expression of surface markers and the ability to differentiate into multiple lineages, the nature of the cells was confirmed. We then evaluated Mesenchymal Stem Cells (MSCs) as an infection model for the Usutu Flavivirus. To this aim, blackbird TDSCs were compared to Vero E6 cells, commonly used in Flavivirus studies. Both cells showed permissiveness to USUV infection as confirmed by immunocytochemistry. Moreover, TDSCs exhibited replication kinetics similar to, although slightly lower than, Vero E6, confirming these cells as a pertinent study model for the study of the pathogenesis of USUV. In this work, we isolated and characterized tendon-derived mesenchymal stem cells, which represent an interesting and convenient in vitro model for the study of wildlife species in laboratories.


The Effects of Dexamethasone on the Time to Pain Resolution in Dental Periapical Abscess.
Dental infections are frequently encountered in the emergency department (ED), with periapical abscesses being among the most painful. Traditional pain management strategies include local anesthetic injections, oral analgesics, and intravenous opioids. We sought to identify an alternative pain management strategy with early use of dexamethasone as adjunct to conventional therapies for inflammation and pain at the site of infection. We conducted a prospective, randomized, double-blind, placebo-controlled study comparing the analgesic effect of dexamethasone and placebo in ED patients with periapical abscess during a 2-year timeframe at two urban academic EDs. Adult patients presenting with physical examination findings consistent with a diagnosis of periapical abscess were randomized to receive oral dexamethasone or an identical placebo. Pain was assessed using the verbal numeric scale in person at discharge and via telephone at 12, 24, 48, and 72 h after discharge from the ED. Seventy-three patients were enrolled, with 37 receiving dexamethasone and 36 receiving placebo. Follow-up pain scores were obtained for 52 patients at 12, 24, 48, and 72 h. Ten patients from the dexamethasone group and 11 from placebo group were lost to follow-up. Patients who received dexamethasone reported a greater reduction in pain at 12 h compared with the placebo group (p = 0.029). Changes in pain scores from baseline and at 24, 48, and 72 h were not statistically significant. No adverse events were reported. Single-dose dexamethasone as adjunct to conventional medical management for pain caused by periapical abscess demonstrated a significant reduction in pain 12 h post treatment compared with placebo.


Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells.
The bulk of the human genome (~98%) is comprised of non-coding sequences. Cis-regulatory elements (CREs) are non-coding DNA sequences that contain binding sites for transcriptional regulators to modulate gene expression. Alterations of CREs have been implicated in various diseases including cancer. While promoters and enhancers have been the primary CREs for studying gene regulation, very little is known about the role of silencer, which is another type of CRE that mediates gene repression. Originally identified as an adaptive immunity system in prokaryotes, CRISPR/Cas9 has been exploited to be a powerful tool for eukaryotic genome editing. Here, we present the use of this technique to delete an intronic silencer in the human RUNX1 gene and investigate the impacts on gene expression in OCI-AML3 leukemic cells. Our approach relies on electroporation-mediated delivery of two preassembled Cas9/guide RNA (gRNA) ribonucleoprotein (RNP) complexes to create two double-strand breaks (DSBs) that flank the silencer. Deletions can be readily screened by fragment analysis. Expression analyses of different mRNAs transcribed from alternative promoters help evaluate promoter-dependent effects. This strategy can be used to study other CREs and is particularly suitable for hematopoietic cells, which are often difficult to transfect with plasmid-based methods. The use of a plasmid- and virus-free strategy allows simple and fast assessments of gene regulatory functions.


Hyphomycetes on the Vochysiaceae from the Brazilian cerrado.
New hyphomycetes are described in association with leaves of native plants of the family Vochysiaceae, as part of studies of cerrado fungi. Six new species are described belonging to genera Alternaria (A. qualeae sp. nov.), Janetia (J. salvertiae sp. nov.), Passalora (P. qualeae sp. nov.) and Periconiella (P. longispora sp. nov., P. qualeae-grandiflorae sp. nov. and P. campo-grandensis sp. nov.). A key to the species of Periconiella on Qualea is provided.


Recent advances in the application of capillary electromigration methods for food analysis and Foodomics.
This review work presents and discusses the main applications of capillary electromigration methods in food analysis and Foodomics. Papers that were published during the period February 2015-February 2017 are included following the previous review by Acunha et al. (Electrophoresis 2016, 37, 111-141). The paper shows the large variety of food related molecules that have been analyzed by CE including amino acids, biogenic amines, carbohydrates, chiral compounds, contaminants, DNAs, food additives, heterocyclic amines, lipids, peptides, pesticides, phenols, pigments, polyphenols, proteins, residues, toxins, vitamins, small organic and inorganic compounds, as well as other minor compounds. This work describes the last results on food quality and safety, nutritional value, storage, bioactivity, as well as uses of CE for monitoring food interactions and food processing including recent microchips developments and new applications of CE in Foodomics.


Physician Practices Regarding SIDS in Kansas.
Sudden infant death syndrome (SIDS) is the leading cause of death among infants aged 1 to 12 months. The purpose of this study was to assess prenatal and postnatal physicians' knowledge about SIDS in a county with high rates of SIDS deaths. A cross-sectional survey was conducted of pediatricians, family practitioners, and obstetricians in Sedgwick County, Kansas. Most physicians reported correctly that there were effective measures to reduce SIDS. Most respondents agreed it was important to discuss SIDS with parents. Pediatricians were more likely than family practitioners and obstetricians to recognize that pacifier use is important for infants in their first year to reduce SIDS and 2 to 4 months is the age range for peak incidence of SIDS. Pediatricians, family practitioners, and obstetricians are knowledgeable about SIDS and SIDS risk reduction. However, they are not allocating adequate time for discussing SIDS and SIDS reduction efforts with patients.


Neuropsychological adverse drug reactions of Remdesivir: analysis using VigiBase, the WHO global database of individual case safety reports.
Although remdesivir (GS-5734) has recently demonstrated clinical benefits against the pandemic outbreak of coronavirus disease 2019 (COVID-19), neuropsychological adverse reactions (ADRs) remain to be examined in real-world settings. Therefore, we aimed to identify and characterize the neuropsychological ADRs associated with remdesivir use. We obtained data for this international pharmacovigilance cohort study from individual case safety reports (ICSRs) in a World Health Organization database (VigiBase) from the first report on remdesivir on February 17, 2020, until August 30, 2020 (n=1,403,532). ADRs reported to be relevant to remdesivir were compared with the full database by using a Bayesian neural network method to calculate the information component (IC). A total of 2,107 reported cases of neuropsychological ADRs suspected to be associated with remdesivir were identified from among all ICSRs in the database during the observation period. Although 108 neuropsychological ADRs (64 neurologic events and 44 psychologic events) were reported in association with the medication, no statistically significant pharmacovigilance signal could be detected; the IC025 value was negative for all of the neuropsychological dysfunctions (anxiety [n=13, 0.62%], seizures [n=12, 0.57%], lethargy [n=6, 0.28%], agitation [n=5, 0.25%], cerebral infarction [n=3, 0.14%], ischemic stroke [n=3, 0.14%], and hemiparesis [n=3, 0.14%]). Our study demonstrates that remdesivir, a novel drug applied to the treatment of COVID-19, does not have a significant association with adverse neurologic or psychiatric reactions in the real-world setting.


All optical dynamic nanomanipulation with active colloidal tweezers.
Manipulation of colloidal objects with light is important in diverse fields. While performance of traditional optical tweezers is restricted by the diffraction-limit, recent approaches based on plasmonic tweezers allow higher trapping efficiency at lower optical powers but suffer from the disadvantage that plasmonic nanostructures are fixed in space, which limits the speed and versatility of the trapping process. As we show here, plasmonic nanodisks fabricated over dielectric microrods provide a promising approach toward optical nanomanipulation: these hybrid structures can be maneuvered by conventional optical tweezers and simultaneously generate strongly confined optical near-fields in their vicinity, functioning as near-field traps themselves for colloids as small as 40 nm. The colloidal tweezers can be used to transport nanoscale cargo even in ionic solutions at optical intensities lower than the damage threshold of living micro-organisms, and in addition, allow parallel and independently controlled manipulation of different types of colloids, including fluorescent nanodiamonds and magnetic nanoparticles.


Childhood adversities and adult-onset chronic pain: Results from the World Mental Health Survey, Japan.
Childhood adversities (CAs) have been associated with adult-onset chronic pain. However, to date, most single country studies on this association have been undertaken in Western countries. This study examined the association in Japan where information is scarce. Data were drawn from the World Mental Health Survey Japan, a population-based cross-sectional survey undertaken in 11 areas of Japan in 2002-2006. We analyzed data from adults aged ≥20 years who provided information on CAs occurring before age 18 years and chronic pain (n = 1740). Cox proportional hazard models were used to estimate the risk for different forms of adult-onset chronic pain (arthritis/rheumatism, neck/back pain, headache and any pain) as a function of the presence of 11 different types of CA and the number of CAs. In the adjusted models, significant associations were observed between: physical abuse and neck/back pain (HR 2.55) and any pain (HR 1.88); sexual abuse and any pain (HR 2.84). Significant dose-dependent relationships were also observed between a greater number of CAs and some adult-onset chronic pain conditions (neck/back and any pain). The results of this study suggest that in Japan, some forms of CA may be associated with certain types of adult-onset chronic pain, in particular neck/back pain.


The SEB-1 Transcription Factor Binds to the STRE Motif in Neurospora crassa and Regulates a Variety of Cellular Processes Including the Stress Response and Reserve Carbohydrate Metabolism.
When exposed to stress conditions, all cells induce mechanisms resulting in an attempt to adapt to stress that involve proteins which, once activated, trigger cell responses by modulating specific signaling pathways. In this work, using a combination of pulldown assays and mass spectrometry analyses, we identified the Neurospora crassa SEB-1 transcription factor that binds to the Stress Response Element (STRE) under heat stress. Orthologs of SEB-1 have been functionally characterized in a few filamentous fungi as being involved in stress responses; however, the molecular mechanisms mediated by this transcription factor may not be conserved. Here, we provide evidences for the involvement of N. crassa SEB-1 in multiple cellular processes, including response to heat, as well as osmotic and oxidative stress. The Δseb-1 strain displayed reduced growth under these conditions, and genes encoding stress-responsive proteins were differentially regulated in the Δseb-1 strain grown under the same conditions. In addition, the SEB-1-GFP protein translocated from the cytosol to the nucleus under heat, osmotic, and oxidative stress conditions. SEB-1 also regulates the metabolism of the reserve carbohydrates glycogen and trehalose under heat stress, suggesting an interconnection between metabolism control and this environmental condition. We demonstrated that SEB-1 binds in vivo to the promoters of genes encoding glycogen metabolism enzymes and regulates their expression. A genome-wide transcriptional profile of the Δseb-1 strain under heat stress was determined by RNA-seq, and a broad range of cellular processes was identified that suggests a role for SEB-1 as a protein interconnecting these mechanisms.


Sylvatic Canine Morbillivirus in Captive Panthera Highlights Viral Promiscuity and the Need for Better Prevention Strategies.
Canine Distemper Virus (CDV) is a multi-host morbillivirus that infects virtually all Carnivora and a few non-human primates. Here we describe a CDV outbreak in an exotic felid rescue center that led to the death of eight felids in the genus Panthera. Similar to domestic dogs and in contrast to previously described CDV cases in Panthera, severe pneumonia was the primary lesion and no viral antigens or CDV-like lesions were detected in the central nervous system. Four tigers succumbed to opportunistic infections. Viral hemagglutinin (H)-gene sequence was up to 99% similar to strains circulating contemporaneously in regional wildlife. CDV lesions in raccoons and skunk were primarily encephalitis. A few affected felids had at least one previous vaccination for CDV, while most felids at the center were vaccinated during the outbreak. Panthera sharing a fence or enclosure with infected conspecifics had significantly higher chances of getting sick or dying, suggesting tiger-tiger spread was more likely than recurrent spillover. Prior vaccination was incomplete and likely not protective. This outbreak highlights the need for further understanding of CDV epidemiology for species conservation and public health.


Multifocal and metastatic hepatic hemangioendothelioma: case report and literature review.
Epithelioid hemangioendothelioma is a rare neoplasm of vascular origin whose involvement of organs such as lung, spleen, bone, breast and liver has already been reported. The clinical signs and the prognosis of this tumor are quite variable. From the present case report, the authors have sought to contribute with literature data, by reviewing clinical and radiological features which may be useful to include such a condition in the differential diagnosis of liver lesions.


Current options in the management of apnea of prematurity.
Apnea of prematurity (AOP) is a common problem that affects premature infants and, to a lesser degree, term infants. Apnea of prematurity appears to be due to immaturity of the infant's neurologic and respiratory systems. Apnea of prematurity is a diagnosis of exclusion that can be made only when other possible infectious, cardiologic, physiologic, and metabolic causes of apnea have been ruled out. The fundamental principles for managing apnea of prematurity include monitoring the infant closely while instituting supportive care measures such as tactile stimulation, continuous positive airway pressure, or mechanical ventilation. When necessary, pharmacologic therapy may be used to stimulate breathing. The first-line agents of choice for the management of AOP are the methylxanthines. And, for second-line therapy, a switch to a different class of agent, such as the respiratory stimulant doxapram, is an option. Of the methylxanthines, theophylline is the most extensively used. However, a review of the literature suggests that caffeine citrate may be the agent of choice for AOP. Comparative clinical studies have demonstrated that caffeine is at least as effective as theophylline, has a longer half-life, is associated with fewer adverse events, and, in addition, has a greater ease of administration. Caffeine stimulates the respiratory and central nervous systems more effectively and penetrates into the cerebrospinal fluid more readily than theophylline. In addition, because of stable plasma levels, caffeine has a wide therapeutic margin and few side effects. In contrast, theophylline plasma levels may fluctuate widely, which necessitates frequent monitoring and has a higher incidence of adverse events than caffeine. Before the FDA approval of caffeine citrate (Cafcit) for administration either intravenously and/or orally, caffeine preparations were "homemade." A few studies suggest that use of pharmacotherapy to treat AOP is not generally associated with long-term sequelae, although more data are needed before this can be definitively concluded.


Analysis of Recovery Methods' Efficacy Applied up to 72 Hours Postmatch in Professional Football: A Systematic Review With Graded Recommendations.
Sleep, nutrition, active recovery, cold-water immersion, and massage were recently reported as the most used postmatch recovery methods in professional football. However, the recommendations concerning the effect of these methods remain unclear. To systematically review the literature regarding the effectiveness of the most common recovery methods applied to male and female football players (or other team sports) 72 hours postmatches and to provide graded recommendations for their use. A systematic search of the literature was performed, and the level of evidence of randomized and nonrandomized studies was classified as 1 or 2, respectively, with additional ++, +, and - classification according to the quality of the study and risk of bias. Graded recommendations were provided regarding the effectiveness of recovery methods for physical, physiological, and perceptive variables. From the 3472 articles identified, 39 met the inclusion criteria for analysis. The studies' levels of evidence varied among methods (sleep: 2+ to 1++; nutrition: 2- to 1+; cold-water immersion: 2- to 1++; active recovery: 2- to 1+; and massage: 1- to 1+). Different graded recommendations were attributed, and none of them favored the effective use of recovery methods for physiological and physical parameters, whereas massage and cold-water immersion were recommended as beneficial for perceptive variables. Cold-water immersion and massage can be recommended to recover up to 72 hours postmatch at a perceptive level. However, there is a current need for high-quality research that identifies effective recovery strategies that enhance recovery at the physical and physiological levels.


Plasminogen activation by airway smooth muscle is regulated by type I collagen.
Plasmin, the activated protease product of plasminogen, is involved in collagen remodeling, and is strongly implicated in asthma pathophysiology by recent genome-wide association studies. This study examines plasminogen "activation" by airway smooth muscle cells, and its regulation in a fibrotic environment created by culture on type I collagen and incubation with transforming growth factor (TGF)-β. Urokinase plasminogen activator (uPA) activity was detected in the supernatants of human airway smooth muscle cell cultures maintained in serum-free conditions. Incubation with plasminogen (1.5-50.0 μg/ml, 24 h) increased plasmin activity in a concentration-dependent manner (P < 0.001). uPA activity was higher in cultures maintained on fibrillar type I collagen substrata than in those on plastic, as was plasmin activity after incubation with plasminogen (20 μg/ml). Pretreatment with TGF-β (100 pM) for 18 hours inhibited plasminogen activation by airway smooth muscle cells maintained on plastic, but not on collagen. TGF-β stimulated an increase in the level of uPA mRNA in airway smooth muscle cells grown on collagen, but not on plastic. Reducing the levels of β1-integrin collagen receptor, using interference RNA, attenuated plasmin formation by airway smooth muscle cells grown on collagen, and restored the inhibitory effect of TGF-β. This study shows that airway smooth muscle activation of plasminogen by uPA is accelerated in a collagen-rich environment in which the inhibitory effect of TGF-β is attenuated in association with greater uPA expression induced via β1-integrin signaling. These findings suggest that the plasminogen-activation system involving uPA has the potential to contribute to airway wall remodeling in asthma.


The cosmetic ingredient review: a status report.
The cosmetic industry, with the advice of individuals familiar with food and drug safety assessment, set up a Cosmetic Ingredient Review panel of experts and an attendant staff in the fall of 1976, which began to function in July 1977. Its structure and role were carefully developed by a steering committee to assure the independence and credibility of the expert panel's deliberations and decisions and the ultimate publication of a final report on each of many ingredients. That report must conclude 1) that there is reasonable certainty that the ingredient is safe under conditions of use, 2) that it is unsafe, or 3) that the evidence is inadequate to make such a judgment. There is considerable variability in the adequacy of the safety assessments or the assessments of safety in the literature and unpublished reports on ingredients that have been reviewed to date.


Exhaled nitric oxide in healthy children: variability and a lack of correlation with atopy.
Nitric oxide (NO) is a free radical produced by several lung cells via the enzyme nitric oxide synthetase (NOS) and can be easily measured in exhaled air by chemiluminescence analysis. As the iso-enzyme iNOS may be induced by cytokines and endotoxin, NO is elevated in several chronic inflammatory airway diseases. Prior to using exhaled nitric oxide (eNO) as a non-invasive marker of airway inflammation in daily routine, the role of possibly influencing factors such as age, time of the day, smoking exposure and intra-individual variability have to be clarified. NO concentrations were measured in 107 healthy children aged 4-18 years at an expiratory flow of 184 ml/s. Spirometry and a skin-prick test were performed and a questionnaire on family history of atopy, personal symptoms of atopic disease and smoke exposure was completed. For intra-individual variability nitric oxide was measured in six children three times daily on 6 consecutive days. Median eNO concentration was 5.7 p.p.b., and increased significantly with age but did not vary with gender. No correlation was found between eNO and smoke exposure, positive skin-prick test, FEV1, MEF25 and time of the day. There was no circadian rhythm found in the six children measured on 6 consecutive days, but the eNO showed an intra-individual coefficient of variation of 25.9%. With the help of a two-compartment model of the lung the alveolar NO concentration was estimated to be 4.1 p.p.b and was shown to be constant with age, whereas the airway part of NO steadily increased with age. When comparing eNO values with standardized measurement techniques, the age of the children and the large intra-subject coefficient of variation have to be taken into account, whereas in healthy children subject-specific factors such as atopic history, gender and skin test reactivity did not affect eNO measurement.


Features indicative of cervical abnormality. A factor to be reckoned with in clinical headache work and research?
The current criteria for cervicogenic headache (CEH) contain an anamnestic and a physical examination part. The latter consists of: 1) range of motion in the cervical spine (1+); 2) mechanical precipitation of head pain (uppermost score: 1.5+). These two factors are included in "Features indicative of cervical abnormality", outlined in the present context, with a view to possibly facilitating CEH diagnosis. These "features" have a wider scope, containing not only the two original factors (1 and 2), but also three additional factors--their relative contribution to the totality also given in parentheses: 3) facet joint tenderness (0.5+); 4) neck muscle tenderness (0.5+); and 5) skin-roll test (1.0+). The sum of the solitary features is, accordingly, 4.5+. An extra 0.5+ can be added if there is extreme positivity of one of the factors, i.e., a maximum of 5.0+. This coarse system concerning cervical function has also been tested out in 1834 parishioners in the Vågå study of headache epidemiology (irrespective of headache diagnoses). The mean number of features increased with increasing intensity of head pain (by a factor of almost 3). In headache-free individuals (n.=246), the mean was 0.42+, against a mean in the whole series of 0.79+. Reproducibility tests demonstrated relatively high consistency.


Glucocorticoid-induced cell-derived matrix modulates transforming growth factor β2 signaling in human trabecular meshwork cells.
Aberrant remodeling of trabecular meshwork (TM) extracellular matrix (ECM) may induce ocular hypertensive phenotypes in human TM (hTM) cells to cause ocular hypertension, via a yet unknown mechanism. Here, we show that, in the absence of exogenous transforming growth factor-beta2 (TGFβ2), compared with control matrices (VehMs), glucocorticoid-induced cell-derived matrices (GIMs) trigger non-Smad TGFβ2 signaling in hTM cells, correlated with overexpression/activity of structural ECM genes (fibronectin, collagen IV, collagen VI, myocilin), matricellular genes (connective tissue growth factor [CTGF], secreted protein, acidic and rich in cysteine), crosslinking genes/enzymes (lysyl oxidase, lysyl oxidase-like 2-4, tissue transglutaminase-2), and ECM turnover genes/enzymes (matrix metalloproteinases-MMP2,14 and their inhibitors-TIMP2). However, in the presence of exogenous TGFβ2, VehMs and GIMs activate Smad and non-Smad TGFβ2 signaling in hTM cells, associated with overexpression of α-smooth muscle actin (α-SMA), and differential upregulation of aforementioned ECM genes/proteins with new ones emerging (collagen-I, thrombospondin-I, plasminogen activator inhibitor, MMP1, 9, ADAMTS4, TIMP1); with GIM-TGFβ2-induced changes being mostly more pronounced. This suggests dual glaucomatous insults potentiate profibrotic signaling/phenotypes. Lastly, we demonstrate type I TGFβ receptor kinase inhibition abrogates VehM-/GIM- and/or TGFβ2-induced upregulation of α-SMA and CTGF. Collectively, pathological TM microenvironments are sufficient to elicit adverse cellular responses that may be ameliorated by targeting TGFβ2 pathway.