Cultural consonance and body morphology: estimates with longitudinal data from an Amazonian society.
Researchers have hypothesized that the degree to which an individual's actual behavior approximates the culturally valued lifestyle encoded in the dominant cultural model has consequences for physical and mental health. We contribute to this line of research by analyzing data from a longitudinal study composed of five annual surveys (2002-2006 inclusive) from 791 adults in one society of foragers-farmers in the Bolivian Amazon, the Tsimane'. We estimate the association between a standard measure of individual achievement of the cultural model, cultural consonance, and three indicators of body morphology. Drawing on research suggesting that in societies in the early stages of economic development an increase in socioeconomic status is associated with an increase in mean body mass, we expect to find a positive association between cultural consonance and three anthropometric measures. We found the expected positive association between cultural consonance and anthropometric measures-especially for men-only when using ordinary least square (OLS) regression models, but not when using fixed-effects regression models. The real magnitude of the association was low. The comparison of estimates from OLS and fixed-effect regression models suggests that previous findings on the effects of cultural consonance on body morphology using cross-sectional data should be read with caution because the association might be largely explained by fixed characteristics of individuals not accounted in OLS models.


Improved Safety and Efficacy of Small-Bore Feeding Tube Confirmation Using an Electromagnetic Placement Device.
Early enteral nutrition has been shown to decrease complications and improve patient outcomes. Post pyloric feeding is recommended for patients with gastric intolerance or at high risk for aspiration. Feeding tube placement can be challenging and pose risk of pulmonary complications. Reliance on radiographic confirmation for feeding tube placement exposes the patient to radiation. Electromagnetic placement device (EMPD) may offer a method to minimize pulmonary complications, increase successful placement, and decrease radiation exposure to the patient. The purpose of this study was to evaluate the safety and efficacy of using EMPD verification, instead of routine abdominal radiographic confirmation, for small-bore feeding tube placement. Variables evaluated were adverse events, utilization of radiographs for confirmation, and success rate of feeding tube placement in the ordered location. Two time frames were reviewed. In a 1-year period, 3754 small-bore feeding tubes were placed using EMPD, with zero adverse events noted. Radiographic confirmation was utilized in 0%-29.2% of the EMPD placed tubes. Successful placement of feeding tubes using EMPD ranged from 94%-99.6%. During a 5-year period, 7081 EMPD feeding tubes were evaluated. One adverse event, pneumothorax, occurred during the placement of these 7081 tubes, for a rate of 0.014%. Feeding tube placement confirmation is safe and efficacious via EMPD providing an effective method of feeding tube placement with a success rate >94% into the desired location. EMPD is an accurate verification method of distal tip location, eliminating the need for routine abdominal radiographic confirmation.


Oxidized phospholipids reduce ventilator-induced vascular leak and inflammation in vivo.
Mechanical ventilation at high tidal volume (HTV) may cause pulmonary capillary leakage and acute lung inflammation resulting in ventilator-induced lung injury. Besides blunting the Toll-like receptor-4-induced inflammatory cascade and lung dysfunction in a model of lipopolysaccharide-induced lung injury, oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) exerts direct barrier-protective effects on pulmonary endothelial cells in vitro via activation of the small GTPases Rac and Cdc42. To test the hypothesis that OxPAPC may attenuate lung inflammation and barrier disruption caused by pathologic lung distension, we used a rodent model of ventilator-induced lung injury and an in vitro model of pulmonary endothelial cells exposed to pathologic mechanochemical stimulation. Rats received a single intravenous injection of OxPAPC (1.5 mg/kg) followed by mechanical ventilation at low tidal volume (LTV) (7 mL/kg) or HTV (20 mL/kg). Bronchoalveolar lavage was performed and lung tissue was stained for histological analysis. In vitro, the effects of OxPAPC on endothelial barrier dysfunction and GTPase activation were assessed in cells exposed to thrombin and pathologic (18%) cyclic stretch. HTV induced profound increases in bronchoalveolar lavage and tissue neutrophils and in lavage protein. Intravenous OxPAPC markedly attenuated HTV-induced protein and inflammatory cell accumulation in bronchoalveolar lavage fluid and lung tissue. In vitro, high-magnitude stretch enhanced thrombin-induced endothelial paracellular gap formation associated with Rho activation. These effects were dramatically attenuated by OxPAPC and were associated with OxPAPC-induced activation of Rac. OxPAPC exhibits protective effects in these models of ventilator-induced lung injury.


Composition of incubation solution impacts in vitro protein uptake to silicone hydrogel contact lenses.
To determine the impact of incubation solution composition on protein deposition to silicone hydrogel (SH) contact lenses using a simplistic and a complex model of the tear film. Three SH materials--senofilcon A (SA), lotrafilcon B (LB), and balafilcon A (BA)--were incubated in two different solutions; Solution A was a simplistic augmented buffered saline solution containing a single protein, whereas Solution B was a complex artificial tear solution (ATS), containing the augmented buffered saline solution in addition to proteins, lipids, and mucins (pH=7.4). The proteins of interest (lysozyme, lactoferrin, albumin) were radiolabeled with Iodine-125 (2% protein of interest) and the accumulation of the conjugated protein to the lens materials was determined after 1, 7, 14, and 28 days of incubation. Protein deposition was measured using a gamma counter and the raw data were translated into absolute amounts (µg/lens) via extrapolation from standards. After 28 days, lysozyme uptake was significantly lower on BA lenses when incubated in Solution A (33.7 μg) compared to Solution B (56.2 μg), p<0.001. SA lenses deposited similar amounts of lysozyme when incubated in either Solution A (2.6 μg) or Solution B (4.1 μg), p>0.05. LB lenses also deposited similar amounts of lysozyme for both solutions (Solution A: 5.0 μg, Solution B: 4.7 μg, p>0.05). After 28 days, BA lenses accumulated approximately twice the amount of lactoferrin than the other lens materials, with 30.3 μg depositing when exposed to Solution A and 22.0 μg with Solution B. The difference between the two solutions was statistically significant (p<0.001). LB materials deposited significantly greater amounts of lactoferrin when incubated in Solution A (16.6 μg) compared to Solution B (10.3 μg), p<0.001. Similar amounts of lactoferrin were accumulated onto SA lenses regardless of incubation solution composition (Solution A: 8.2 μg, Solution B: 11.2 μg, p>0.05). After 28 days, albumin deposition onto BA lenses was significantly greater when lenses were incubated in Solution B (1.7 μg) compared to Solution A (0.9 μg), p<0.001. Similar amounts of albumin were deposited on SA lenses when incubated in either solution (0.6 μg versus 0.7 μg, p>0.05). LB lenses incubated in Solution A deposited more albumin compared to Solution B (0.9 μg versus 0.6 μg), p=0.003. Protein deposition onto SH materials varied when contact lenses were incubated in either a complex ATS compared to a single protein solution. More lysozyme accumulated onto BA lenses incubated in a complex analog of the human tear film, whereas lactoferrin deposited onto SA lenses independent of incubation solution composition. To better mimic the ex vivo environment, future studies should use more appropriate analogs of the tear film.


Metabolomics of an in vitro liver model containing primary hepatocytes assembling around an endothelial cell network: comparative study on the metabolic stability and the effect of acetaminophen treatment.
Recently, a novel culture system consisting of primary hepatocytes structured over a network of endothelial cells on the Engelbreth-Holm-Swarm (EHS) gel has been reported. This in vitro liver model on the EHS gel (IVLEHS) has been shown to maintain the expression of hepatic genes and their functional activity. Moreover, the IVLEHS was more sensitive to xenobiotics than hepatocyte monocultures, suggesting the potential utility of this culture system for compound hepatotoxicity screening. However, the effect of this three-dimensional structure formation on the cellular metabolic profile of hepatocytes in the IVLEHS is not well understood. To address this concern, we performed metabolome analysis using capillary electrophoresis-time of flight mass spectrometry. Between the IVLEHS and mono-cultured hepatocytes on the EHS gel, there was no significant difference in the levels of metabolites of the urea cycle and the tricarboxylic acid cycle, essential amino acids, and adenylate energy charge (AEC) which is an important indicator of cellular energy status. On the other hand, acetaminophen-dependent decrease of the AEC in the IVLEHS was greater than that in the monoculture, suggesting the higher sensitivity of IVLEHS to acetaminophen-induced hepatotoxicity which is caused by metabolic activation of this drug. Further analysis showed that the levels of taurocholate, one of the major conjugated bile acids, were higher in the IVLEHS than in the monoculture. Considering that the construction of the IVLEHS did not seem to disturb the major cellular metabolism, our findings would strengthen the concept that IVLEHS would have beneficial effects on the maintenance of hepatic functions.


Evolving Role of Genomics in Genitourinary Neoplasms.
The aim of this article is to review the current role of genomic testing in the risk, prognosis, and treatment of genitourinary malignancies. The authors selected guidelines, publications, and abstracts relevant to the current and emerging role of genomics in genitourinary cancers. The risk of developing genitourinary cancer can be stratified based on genomic data. Prostate cancer has the strongest degree of heritability, with BRCA1/2 and HOXB13 mutations playing a role in familial disease. Genomic data is on the verge of informing treatment decisions across genitourinary cancers. mCRPC has diverse genomic alterations that represent potential therapeutic targets, including alterations in the AR pathway, DNA damage and repair pathways, cell cycle pathways, PI3K pathway, and Wnt signaling. Genomic alterations in clear cell renal cell carcinoma can inform prognosis and mutations in mTOR pathways predict response to mTOR inhibitors. Urothelial carcinoma can be classified into different subtypes based on gene expression profiling, which provides prognostic information and predicts response to chemotherapy and immunotherapy. Specific mutations have been identified that predict response to therapy including ERCC2 mutations and cisplatin, DNA damage and repair mutations and checkpoint inhibitors, and FGFR3 mutations and FGFR tyrosine kinase inhibitors such as erdafitinib. CONCLUSION: Genitourinary malignancies have not felt the impact of genomic data as greatly as other cancer types. The majority of benefit lies in identifying patients at high risk of genitourinary cancer. Fortunately, breakthroughs are on the horizon that will result in a greater incorporation of genomic information into treatment decisions for patients with genitourinary cancer.


An innovative approach for migraine prevention in young age: a preliminary study.
Headache is one of the commonest conditions to affect children and adolescents in industrialized countries. Effective pharmacological treatments without side effects are still lacking. Ginkgolide B, an herbal constituent extract from ginkgo biloba tree leaves, is a natural antiplatelet activating factor (PAF). PAF is a potent proinflammatory and nociceptive agent released during the inflammation process. Therefore, Ginkgolide B can be considered a promising non-pharmacological tool for treatment of migraine with and without aura. We propose to determine the efficacy of Ginkgolide B as preventive treatment in a group of young patients suffering from migraine without aura. A small sample of 24 young patients suffering from migraine without aura entered the open-label prospective trial. Migraine without aura was diagnosed according to International Headache Society criteria. The treatment was well tolerated and the compliance was good. These preliminary data show that Ginkgolide B seems to be effective as preventive treatment in reducing migraine attack frequency and in attenuating the use of symptomatic medication in our small series of children with primary headache.


An ex vivo lung model to study bronchioles infected with Pseudomonas aeruginosa biofilms.
A key aim in microbiology is to determine the genetic and phenotypic bases of bacterial virulence, persistence and antimicrobial resistance in chronic biofilm infections. This requires tractable, high-throughput models that reflect the physical and chemical environment encountered in specific infection contexts. Such models will increase the predictive power of microbiological experiments and provide platforms for enhanced testing of novel antibacterial or antivirulence therapies. We present an optimized ex vivo model of cystic fibrosis lung infection: ex vivo culture of pig bronchiolar tissue in artificial cystic fibrosis mucus. We focus on the formation of biofilms by Pseudomonas aeruginosa. We show highly repeatable and specific formation of biofilms that resemble clinical biofilms by a commonly studied laboratory strain and ten cystic fibrosis isolates of this key opportunistic pathogen.


Towards structural systems pharmacology to study complex diseases and personalized medicine.
Genome-Wide Association Studies (GWAS), whole genome sequencing, and high-throughput omics techniques have generated vast amounts of genotypic and molecular phenotypic data. However, these data have not yet been fully explored to improve the effectiveness and efficiency of drug discovery, which continues along a one-drug-one-target-one-disease paradigm. As a partial consequence, both the cost to launch a new drug and the attrition rate are increasing. Systems pharmacology and pharmacogenomics are emerging to exploit the available data and potentially reverse this trend, but, as we argue here, more is needed. To understand the impact of genetic, epigenetic, and environmental factors on drug action, we must study the structural energetics and dynamics of molecular interactions in the context of the whole human genome and interactome. Such an approach requires an integrative modeling framework for drug action that leverages advances in data-driven statistical modeling and mechanism-based multiscale modeling and transforms heterogeneous data from GWAS, high-throughput sequencing, structural genomics, functional genomics, and chemical genomics into unified knowledge. This is not a small task, but, as reviewed here, progress is being made towards the final goal of personalized medicines for the treatment of complex diseases.


Survival probability for a diffusive process on a growing domain.
We consider the motion of a diffusive population on a growing domain, 0<x<L(t), which is motivated by various applications in developmental biology. Individuals in the diffusing population, which could represent molecules or cells in a developmental scenario, undergo two different kinds of motion: (i) undirected movement, characterized by a diffusion coefficient, D, and (ii) directed movement, associated with the underlying domain growth. For a general class of problems with a reflecting boundary at x=0, and an absorbing boundary at x=L(t), we provide an exact solution to the partial differential equation describing the evolution of the population density function, C(x,t). Using this solution, we derive an exact expression for the survival probability, S(t), and an accurate approximation for the long-time limit, S=lim(t→∞)S(t). Unlike traditional analyses on a nongrowing domain, where S≡0, we show that domain growth leads to a very different situation where S can be positive. The theoretical tools developed and validated in this study allow us to distinguish between situations where the diffusive population reaches the moving boundary at x=L(t) from other situations where the diffusive population never reaches the moving boundary at x=L(t). Making this distinction is relevant to certain applications in developmental biology, such as the development of the enteric nervous system (ENS). All theoretical predictions are verified by implementing a discrete stochastic model.


Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a systematic literature research.
Review of efficacy and safety of Janus kinase (JAK) inhibition in immune-mediated inflammatory diseases (IMIDs). A systematic literature research (SLR) of all publications on JAK inhibitors (JAKi) treatment published until March 2019 using MEDLINE, EMBASE and the Cochrane Library. Efficacy and safety were assessed in randomised controlled trials (RCTs), integrating long-term extension periods additionally for safety evaluation. 3454 abstracts were screened with 85 included in the final analysis (efficacy and RCT safety: n=72; safety only: n=13). Efficacy of RCTs investigating tofacitinib (TOFA, n=27), baricitinib (BARI, n=9), upadacitinib (UPA, n=14), filgotinib (FILGO, n=7), decernotinib (DEC, n=3) and peficitinib (PEF, n=7) was evaluated. Six head-to-head trials comparing JAKi with tumour necrosis factor inhibitors (TNFi) were included. Efficacy of JAKi was shown in rheumatoid arthritis (RA) for all agents, psoriatic arthritis (TOFA, FILGO), ankylosing spondylitis (TOFA, FILGO), systemic lupus erythematosus (BARI), chronic plaque psoriasis (TOFA, BARI, PEF), ulcerative colitis (TOFA, UPA), Crohn's disease (UPA, FILGO) and atopic dermatitis (TOFA, BARI, UPA). Safety analysis of 72 RCTs, one cohort study and 12 articles on long-term extension studies showed increased risks for infections, especially herpes zoster, serious infections and numerically higher rates of venous thromboembolic events. No increased malignancy rates or major adverse cardiac events were observed. JAKi provide good efficacy compared to placebo (and to TNFi in RA and Pso) across various IMIDs with an acceptable safety profile. This SLR informed the task force on points to consider for the treatment of IMIDs with JAKi with the available evidence.


Long-term response to genomic selection: effects of estimation method and reference population structure for different genetic architectures.
Genomic selection has become an important tool in the genetic improvement of animals and plants. The objective of this study was to investigate the impacts of breeding value estimation method, reference population structure, and trait genetic architecture, on long-term response to genomic selection without updating marker effects. Three methods were used to estimate genomic breeding values: a BLUP method with relationships estimated from genome-wide markers (GBLUP), a Bayesian method, and a partial least squares regression method (PLSR). A shallow (individuals from one generation) or deep reference population (individuals from five generations) was used with each method. The effects of the different selection approaches were compared under four different genetic architectures for the trait under selection. Selection was based on one of the three genomic breeding values, on pedigree BLUP breeding values, or performed at random. Selection continued for ten generations. Differences in long-term selection response were small. For a genetic architecture with a very small number of three to four quantitative trait loci (QTL), the Bayesian method achieved a response that was 0.05 to 0.1 genetic standard deviation higher than other methods in generation 10. For genetic architectures with approximately 30 to 300 QTL, PLSR (shallow reference) or GBLUP (deep reference) had an average advantage of 0.2 genetic standard deviation over the Bayesian method in generation 10. GBLUP resulted in 0.6% and 0.9% less inbreeding than PLSR and BM and on average a one third smaller reduction of genetic variance. Responses in early generations were greater with the shallow reference population while long-term response was not affected by reference population structure. The ranking of estimation methods was different with than without selection. Under selection, applying GBLUP led to lower inbreeding and a smaller reduction of genetic variance while a similar response to selection was achieved. The reference population structure had a limited effect on long-term accuracy and response. Use of a shallow reference population, most closely related to the selection candidates, gave early benefits while in later generations, when marker effects were not updated, the estimation of marker effects based on a deeper reference population did not pay off.


Emotion at work: identifying the emotional climate of night nursing.
This paper introduces the concept of the emotional climate of the workplace and explores how it both shapes and is shaped by the emotions experienced, expressed and redefined by nurses. It extracts emotional aspects of an organizational climate framework developed by Litwin and Stringer and examines these with respect to nurse's experiences. The primary research was carried out at a general hospital NHS Trust in the East Midlands of the UK using a grounded theory methodology. The research methods included semi-structured interviews and observation. The themes identified include many of those found by Litwin and Stringer, others which represent variations upon these, and a new set, which, when combined, identify the emotional climate of the organization. The findings have confirmed that the "experiment" of using a 33-year-old positivistic framework to investigate aspects of qualitative research has enabled a robust contribution to the conceptual area of emotional climate.


A Guild-Based Protocol to Target Potential Natural Enemies of Philaenus spumarius (Hemiptera: Aphrophoridae), a Vector of Xylella fastidiosa (Xanthomonadaceae): A Case Study with Spiders in the Olive Grove.
The olive grove is a key landscape across the Mediterranean basin. This agroecosystem is threatened by Xylella fastidiosa, the causal agent of the olive tree quick decline syndrome, Philaenus spumarius being the main vector. A way to limit pest populations relies on the use of biological control agents such as arthropods. Among them, spiders are generalist predators with different hunting strategies that feed mostly on insects and can contribute to limit pests. In this work, field and laboratory data were used to provide a protocol aiming to facilitate the selection of species of spiders among different guilds that could represent potential natural enemies of P. spumarius. Sampling of spiders was conducted in olive groves in northeastern Portugal. Two species, namely the orb-weaver Araniella cucurbitina and the ambusher Synema globosum, were selected according to the dominant guilds of spiders inhabiting the olive crop. We tested the differences of potential predatory efficiency using classical functional response tests with P. spumarius as prey. A type-II functional response was found for A. cucurbitina, whereas a type-I response was found for S. globosum. This difference uncovers a different potential efficiency among the two species as natural enemies of P. spumarius with relevant implications at high prey density in the field. A conceptual workflow to follow the fieldwork and selection of species for further work (i.e., laboratory assays) is provided and discussed. Standardized methods regarding the assessment of the suitability and efficiency of potential natural enemies are essential for the integration of results at different geographical extents and crops. Selecting functional counterparts such as different species of predators occurring at different locations that use the same prey (e.g., a pest) in the same way (e.g., hunting strategy) would facilitate developing biological control schemes.


Measurement of longitudinal flow decorrelations in Pb+Pb collisions at s NN = 2.76 and 5.02 TeV with the ATLAS detector.
Measurements of longitudinal flow correlations are presented for charged particles in the pseudorapidity range | η | < 2.4 using 7 and 470 μ b - 1 of Pb+Pb collisions at s NN = 2.76 and 5.02 TeV, respectively, recorded by the ATLAS detector at the LHC. It is found that the correlation between the harmonic flow coefficients v n measured in two separated η intervals does not factorise into the product of single-particle coefficients, and this breaking of factorisation, or flow decorrelation, increases linearly with the η separation between the intervals. The flow decorrelation is stronger at 2.76 TeV than at 5.02 TeV. Higher-order moments of the correlations are also measured, and the corresponding linear coefficients for the k th -moment of the v n are found to be proportional to k for v 3 , but not for v 2 . The decorrelation effect is separated into contributions from the magnitude of v n and the event-plane orientation, each as a function of η . These two contributions are found to be comparable. The longitudinal flow correlations are also measured between v n of different order in n. The decorrelations of v 2 and v 3 are found to be independent of each other, while the decorrelations of v 4 and v 5 are found to be driven by the nonlinear contribution from v 2 2 and v 2 v 3 , respectively.


Cognitive function following diabetic ketoacidosis in young children with type 1 diabetes.
Young children with type 1 diabetes (T1D) may be at particularly high risk of cognitive decline following diabetic ketoacidosis (DKA). However, studies of cognitive functioning in T1D typically examine school-age children. The goal of this study was to examine whether a single experience of DKA is associated with lower cognitive functioning in young children. We found that recently diagnosed 3- to 5-year-olds who experienced one DKA episode, regardless of its severity, exhibited lower IQ scores than those with no DKA exposure. We prospectively enrolled 46 3- to 5-year-old children, who presented with DKA at the onset of T1D, in a randomized multi-site clinical trial evaluating intravenous fluid protocols for DKA treatment. DKA was moderate/severe in 22 children and mild in 24 children. Neurocognitive function was assessed once 2-6 months after the DKA episode. A comparison group of 27 children with T1D, but no DKA exposure, was also assessed. Patient groups were matched for age and T1D duration at the time of neurocognitive testing. Children who experienced DKA, regardless of its severity, exhibited significantly lower IQ scores than children who did not experience DKA, F(2, 70) = 6.26, p = .003, partial η2 = .15. This effect persisted after accounting for socioeconomic status and ethnicity. A single DKA episode is associated with lower IQ scores soon after exposure to DKA in young children.


Online updating method with new variables for big data streams.
For big data arriving in streams, online updating is an important statistical method that breaks the storage barrier and the computational barrier under certain circumstances. In the regression context, online updating algorithms assume that the set of predictor variables does not change, and consequently cannot incorporate new variables that may become available midway through the data stream. A naive approach would be to discard all previous information and start updating with new variables from scratch. We propose a method that utilizes the information from earlier data in the online updating algorithm with bias corrections to improve efficiency. The method is developed for linear models first, and then extended to estimating equations for generalized linear models. Closed-form expressions for the efficiency gain over the naive approach are derived in a particular linear model setting. We compare the performance of our proposed bias-correcting approach and the naive approach in simulation studies with data generated from a normal linear model and a logistic regression model. The method is applied to a study on airline delay, where reasons for delays were only available more recently, starting in 2003.


Reiki therapy for pain, anxiety and quality of life.
The use of complementary and alternative therapies is growing year after year, and Reiki therapy takes a place of choice. Reiki therapy, classed as a biofield energy therapy, raises the question of validity when applied to patients, especially in palliative care. The purpose of this review is to highlight the effects of Reiki therapy on pain, anxiety/depression and quality of life of patients, specifically in palliative care. The current article indicates that Reiki therapy is useful for relieving pain, decreasing anxiety/depression and improving quality of life in several conditions. Due to the small number of studies in palliative care, we were unable to clearly identify the benefits of Reiki therapy, but preliminary results tend to show some positive effects of Reiki therapy for the end-of-life population. These results should encourage teams working in palliative care to conduct more studies to determine the benefits of Reiki therapy on pain, anxiety/depression and quality of life in palliative care.


A narrative review on classification of pain conditions of the upper extremities.
Local and regional musculoskeletal discomfort and pain in the shoulder girdle or upper extremities are often reported, especially in the working population. In this review we describe the most important problems and factors when classifying musculotendinous pain in the upper extremities and shoulders. This includes an analysis of how four common diagnoses (wrist tenosynovitis, lateral epicondylitis, rotator-cuff tendinitis, myofascial pain syndrome) fulfil basic criteria of validity. It is evident that there are some serious problems regarding the validity of the current classification of the conditions. Clinical criteria are often poorly defined and the reliability insufficiently tested. The relationship to objective pathoanatomic or physiological findings seems inconsistent. Although magnetic resonance and ultrasonographic imaging are promising, they are still only preliminary methods for evaluation of tendon and connective tissue structures. The prognosis with and without treatment also seems heterogeneous and can vary between studies. A generally accepted terminology is lacking in the pathogenetically complex regional muscle pain conditions.


Initial protocol for a national evaluation of an area-based intervention programme (A Better Start) on early-life outcomes: a longitudinal cohort study with comparison (control) cohort samples.
Pregnancy and the first few years of a child's life are important windows of opportunity in which to equalise life chances. A Better Start (ABS) is an area-based intervention being delivered in five areas of socioeconomic disadvantage across England. This protocol describes an evaluation of the impact and cost-effectiveness of ABS. The evaluation of ABS comprises a mixed-methods design including impact, cost-effectiveness and process components. It involves a cohort study in the 5 ABS areas and 15 matched comparison sites (n=2885), beginning in pregnancy in 2017 and ending in 2024 when the child is age 7, with a separate cross-sectional baseline survey in 2016/2017. Process data will include a profiling of the structure and services being provided in the five ABS sites at baseline and yearly thereafter, and data regarding the participating families and the services that they receive. Eligible participants will include pregnant women living within the designated sites, with recruitment beginning at 16 weeks of pregnancy. Data collection will involve interviewer-administered and self-completion surveys at eight time points. Primary outcomes include nutrition, socioemotional development, speech, language and learning. Data analysis will include the use of propensity score techniques to construct matched programme and comparison groups, and a range of statistical techniques to calculate the difference in differences between the intervention and comparison groups. The economic evaluation will involve a within-cohort study economic evaluation to compare individual-level costs and outcomes, and a decision analytic cost-effectiveness model to estimate the expected incremental cost per unit change in primary outcomes for ABS in comparison to usual care. Ethical approval to conduct the study has been obtained. The learning and dissemination workstream involves working within and across the sites to generate learning via communities of practice and a range of learning and dissemination events.


Match Running Performance in Young Soccer Players: A Systematic Review.
To date, athletic performance has been extensively assessed in youth soccer players through laboratory and field testing. Only recently has running performance via time-motion analysis been assessed during match play. Match running data are often useful in a practical context to aid game understanding and decision making regarding training content and prescriptions. A plethora of previous reviews have collated and appraised the literature on time-motion analysis in professional senior players, but none have solely examined youth players. The aim of the present systematic review was to provide a critical appraisal and summary of the original research articles that have evaluated match running performance in young male soccer players. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, literature searches were performed in four databases: PubMed, ISI Web of Science, SPORTDiscus and SciELO. We used the following descriptors: soccer, football, young, youth, junior, physical performance, running performance, match running performance, movement patterns, time-motion analysis, distances covered, activity profile, work rate, match analysis, and match performance. Articles were included only if they were original articles written in the English language, studied populations of male children and/or adolescents (aged ≤ 20 years), were published/ahead of print on or before 31 December 2017 and showed at least one outcome measure regarding match running performance, such as total distance covered, peak game speed or indicators of activities performed at established speed thresholds. A total of 5801 records were found. After duplicates were removed and exclusion and inclusion criteria applied, 50 articles were included (n = 2615 participants). Their outcome measures were extracted and findings were synthesized. The majority of the reviewed papers covered the European continent (62%) and used global positioning systems (GPS) (64%). Measurement error of the tools used to obtain position data and running metrics was systematically overlooked among the studies. The main aims of studies were to examine differences across playing positions (20%), age groups (26%) and match halves (36%). Consistent findings pointed to the existence of positional role and age effects on match running output (using fixed running speed thresholds), but there was no clear consensus about reductions in activity over the course of match play. Congested schedules negatively affected players' running performance. While over 32% of all studies assessed the relationships between match running performance and physical capacity, biochemical markers and body composition, ~ 70% of these did not account for playing position. This review collated scientific evidence that can aid soccer conditioning professionals in understanding external match loads across youth categories. Coaches working with youth development programs should consider that data derived from a given population may not be relevant for other populations, since game rules, match format and configuration are essentially unstandardized among studies for age-matched players. Despite limited evidence, periodization training emphasizing technical-tactical content can improve match running performance. Occurrence of acute and residual impairments in the running performance of young soccer players is common. Prescription of postmatch recovery strategies, such as cold water immersion and spa treatment, can potentially help reduce these declines, although additional research is warranted. This review also highlighted areas requiring further investigation, such as the possible influence of environmental and contextual constraints and a more integrative approach combining tactical and technical data.


Children's cortisol levels and quality of child care provision.
Cortisol levels are increasingly being used as an indicator of stress levels. Research suggests that children who attend child care demonstrate higher cortisol levels than children in their homes, suggesting that child care acts as a risk factor for poor child outcomes. However, it is also suggested that quality influences outcomes. Cortisol levels were measured through samples of saliva taken from children (3-5 years of age) attending long-day care centres in Perth, Western Australia. Quality of the programme was measured using industry national quality assurance indicators designed for child care centres. The analysis employed a 2 (time of collection: average am cortisol, average pm cortisol) by 3 (centre quality: high, satisfactory, unsatisfactory) split plot ANOVA with repeated measures on the time factor. Cortisol levels of children attending high-quality programmes demonstrated a decline across the child care day. Levels in children attending unsatisfactory programmes demonstrated an increase across the day. Although we do not yet know how high, and for how long, cortisol levels need to be elevated for risk of undesirable outcomes to increase, this research signals the importance of emphasizing the need for high-quality care for young children.


Structure formats of randomised controlled trial abstracts: a cross-sectional analysis of their current usage and association with methodology reporting.
The reporting of randomised controlled trial (RCT) abstracts is of vital importance. The primary objective of this study was to investigate the association between structure format and RCT abstracts' quality of methodology reporting, informed by the current requirement and usage of structure formats by leading general medical/internal medicine journals (secondary objective). A two-part cross-sectional study. First, through hand searches, we identified all RCTs published in the top-50 high-impact general medical/internal medicine journals during July-December 2015 (n = 370), and retrieved the 'instructions to authors' of these journals. From these, we extracted the actual usage of structure formats and headings, as well as relevant journal policies. Then, after a pilot study and sample size calculation, we assessed the methodology reporting quality of 176 IMRaD (Introduction, Methods, Results, and Discussion) and 165 HS (Highly Structured) RCT abstracts sampled from 33 of the 50 selected journals, using a 9-item checklist developed based on the CONSORT for Abstracts guidelines (primary outcome: overall quality score, OQS; score range 0 to 9). 88% (324/370) of all identified RCT abstracts were structured, among which 66% (215/324) used the IMRaD format and 34% (109/324) used HS. According to journals' 'instructions to authors', 48% (24/50) journals required IMRaD, 32% (16/50) required HS, 8% (4/50) required unstructured, while the rest did not state any requirement on structure format. According to generalised estimation equation analysis adjusting for potential confounders and clustering effects, the OQS of HS abstracts was 0.5 (95% CI 0.1 to 1.0, p = 0.028) higher than IMRaD abstracts. More HS abstracts reported study setting (adjusted odds ratio, 4.2; 95% CI: 1.7 to 10.0; p = 0.001), definition of the main outcome measure (2.5; 1.3 to 4.9; p = 0.006) and the time point for main outcome assessment (3.0; 1.5 to 6.2; p = 0.002), whereas more IMRaD abstracts described the unit of randomisation (0.4; 0.3 to 0.8; p = 0.004). For RCT abstracts, the IMRaD format is more frequently used and required by leading general medical/internal medicine journals than the HS format. Abstracts in the HS format report trial methodology more completely than those in the IMRaD format.


A protocol for applying health equity-informed implementation science models and frameworks to adapt a sleep intervention for adolescents at risk for suicidal thoughts and behaviors.
Effective and equitable strategies to prevent youth suicidal thoughts and behaviors (STB) are an urgent public health priority. Adolescent sleep disturbances are robustly linked to STB but are rarely addressed in preventive interventions or among Black and/or Hispanic/Latinx youth for whom STB risk is increasing disproportionately. This paper describes an application of health equity-informed implementation science models and frameworks to adapt and evaluate the evidence-based Transdiagnostic Sleep and Circadian (TSC) intervention for primary care implementation with adolescents of minoritized backgrounds with depression and STB risk. This multiphase study protocol uses the Assessment, Decision, Adaptation, Production, Topical Experts-Integration, Training, Testing (ADAPT-ITT) model to adapt and evaluate TSC for primary care implementation with adolescents who are depressed, at risk for STB, and of primarily Black and/or Hispanic/Latinx backgrounds. We integrate the Consolidated Framework for Implementation Research (CFIR) in an initial qualitative inquiry of adolescent, caregiver, and clinician perceptions of TSC. Subsequent ADAPT-ITT phases include systematically and iteratively testing adaptations based on the qualitative inquiry, with ongoing key informant input, and then evaluating the adapted TSC for feasibility, acceptability, and efficacy in a pilot randomized trial. Based on youth depression and sleep health disparities research, we expect that TSC adaptations will be needed to enhance intervention content for adolescents with depression, STB risk, and primarily Black and/or Hispanic/Latinx backgrounds. We also anticipate adaptations will be needed to align TSC delivery methods with primary care implementation. Adapting evidence-based interventions with end-users and contexts in mind can help ensure that intervention strategies and delivery methods are acceptable to, and feasible with, health disparate populations. Although TSC has shown effectiveness for adolescents with sleep disturbances, we expect that additional multiphase research is necessary to optimize TSC for primary care delivery with Black and/or Hispanic/Latinx adolescents with depression and STB risk.


Continuous ST-segment monitoring: nurses' attitudes, practices, and quality of patient care.
Continuous ischemia monitoring helps identify patients with acute, but often silent, myocardial ischemia. Evidence suggests nurses do not activate ischemia monitoring because they think it is difficult to use. ST-Map software incorporates graphic displays to make monitoring of ongoing ischemia easier. To determine if nurses' use of and attitude toward ischemia monitoring and the quality of patient care improve with use of ST-Map. The study included 61 nurses and 202 patients with acute coronary syndrome in a cardiac intensive care unit. Baseline data on nurses' use of and attitude toward ischemia monitoring and quality of care were obtained. Education was then provided and ST-Map software was installed on all monitors. Follow-up data were obtained 4 months later. The percentage of nurses who had ever used ischemia monitoring was 13% before ST Map and 90% afterward (P < .001). The most common reason for not using ischemia monitoring before ST Map was inadequate knowledge (62%). The most common reason for liking ischemia monitoring after ST Map was knowing when a patient has ischemia (80%). Time to acquisition of a 12-lead electrocardiogram in response to symptoms or ST-segment changes was 5 to 15 minutes before ST Map and always less than 5 minutes afterward (P < .001). Time to return to the catheterization laboratory did not differ before and after ST Map. ST Map was associated with more frequent use of ischemia monitoring, improved attitudes of nurses toward ischemia monitoring, and shorter time to obtaining 12-lead electrocardiograms.


Sex differences in the acute nasal antioxidant/antielectrophilic response of the rat to inhaled naphthalene.
Naphthalene is a nasal carcinogen, inducing respiratory adenomas in male and olfactory neuroblastomas in female rats, respectively. The reasons for the site and sex-specific tumorigenic response are unknown. Naphthalene is bioactivated to electrophilic metabolites; cytotoxicity followed by regenerative cell proliferation is likely involved in the tumorigenic response. To examine sex differences in the acute nasal response to naphthalene, male and female F344 rats were nose-only exposed to 0, 1, 3, 10, or 30 ppm naphthalene vapor for 4 or 6 h. Following exposure, respiratory/transitional mucosa (RTM) and olfactory mucosa (OM) were isolated and analyzed for markers of oxidant/electrophilic stress and/or toxicity, including reduced/oxidized glutathione levels (GSH/GSSG), mRNA levels of electrophile-responsive genes, and epithelial cytoxicity (as measured by membrane permeability to ethidium homodimer-1). Naphthalene caused significant depletion of GSH in RTM and OM with no increase in GSSG. Cytotoxicity was apparent at concentrations of 15 and 30 ppm. No consistent sex differences were observed in these responses. Sex differences were observed in the induction of antielectrophilic genes in OM: glutamyl cysteine ligase (catalytic subunit) (Gclc), NADPH quinone oxidase 1 (Nqo1), and heme oxygenase 1 (Hmox1) were all induced to a greater extent in the male OM compared with the female. No consistent sex differences were observed in the RTM. Although the mechanism of the sex difference in the RTM adenoma response remains enigmatic, sex differences in the induction of antioxidant/electrophile-responsive genes may contribute to the heightened sensitivity of the female OM to the carcinogenic effects of naphthalene.


Direct activation of cGMP-dependent channels of retinal rods by the cGMP phosphodiesterase.
The cationic conductances of purified bovine retinal rod membranes were studied by incorporation of vesicles into planar lipid bilayers. When the membranes were stripped of all peripheral proteins [guanine nucleotide-binding protein (G protein) and cGMP phosphodiesterase (3',5'-cyclic-GMP 5'-nucleotidohydrolase), EC 188.8.131.52], sodium and calcium fluxes were almost only observed in the presence of cGMP. Reconstitution experiments in which purified cGMP phosphodiesterase alone or with G protein were reassociated to the vesicles in proportions similar to those found in the native rod provide evidence for a direct interaction between the cGMP-dependent channel protein and the phosphodiesterase. (i) In its inhibited state, phosphodiesterase markedly stimulates the activity of the channels in the presence of cGMP (situation in the dark-adapted rod) but is not capable of activating the channels in the absence of cGMP. (ii) In the absence of cGMP, activation of the phosphodiesterase by G protein with GTP bound (equivalent to photoexcitation) induces the opening of cation channels that have the same conductance for sodium ions as cGMP-activated channels (20-22 pS, with two sublevels of about 7 pS and 13 pS).


ESTIMATING WITHIN-SCHOOL CONTACT NETWORKS TO UNDERSTAND INFLUENZA TRANSMISSION.
Many epidemic models approximate social contact behavior by assuming random mixing within mixing groups (e.g., homes, schools, and workplaces). The effect of more realistic social network structure on estimates of epidemic parameters is an open area of exploration. We develop a detailed statistical model to estimate the social contact network within a high school using friendship network data and a survey of contact behavior. Our contact network model includes classroom structure, longer durations of contacts to friends than non-friends and more frequent contacts with friends, based on reports in the contact survey. We performed simulation studies to explore which network structures are relevant to influenza transmission. These studies yield two key findings. First, we found that the friendship network structure important to the transmission process can be adequately represented by a dyad-independent exponential random graph model (ERGM). This means that individual-level sampled data is sufficient to characterize the entire friendship network. Second, we found that contact behavior was adequately represented by a static rather than dynamic contact network. We then compare a targeted antiviral prophylaxis intervention strategy and a grade closure intervention strategy under random mixing and network-based mixing. We find that random mixing overestimates the effect of targeted antiviral prophylaxis on the probability of an epidemic when the probability of transmission in 10 minutes of contact is less than 0.004 and underestimates it when this transmission probability is greater than 0.004. We found the same pattern for the final size of an epidemic, with a threshold transmission probability of 0.005. We also find random mixing overestimates the effect of a grade closure intervention on the probability of an epidemic and final size for all transmission probabilities. Our findings have implications for policy recommendations based on models assuming random mixing, and can inform further development of network-based models.


Report from the second international symposium on animal genomics for animal health: critical needs, challenges and potential solutions.
The second International Symposium on Animal Genomics for Animal Health held in Paris, France 31 May-2 June, 2010, assembled more than 140 participants representing research organizations from 40 countries. The symposium included a roundtable discussion on critical needs, challenges and opportunities, and a forward look at the potential applications of animal genomics in animal health research. The aim of the roundtable discussion was to foster a dialogue between scientists working at the cutting edge of animal genomics research and animal health scientists. Importantly, stakeholders were included to provide input on priorities and the potential value of animal genomics to the animal health community. In an effort to facilitate the roundtable discussion, the organizers identified four priority areas to advance the use of genome-enabled technologies in animal health research. Contributions were obtained through open discussions and a questionnaire distributed at the start of the symposium. This report provides the outcome of the roundtable discussion for each of the four priority areas. For each priority, problems are identified, including potential solutions and recommendations. This report captures key points made by symposium participants during the roundtable discussion and serves as a roadmap to steer future research priorities in animal genomics research.


Three-dimensional in vitro modeling of malignant bone disease recapitulates experimentally accessible mechanisms of osteoinhibition.
Malignant bone disease (MBD) occurs when tumors establish in bone, causing catastrophic tissue damage as a result of accelerated bone destruction and inhibition of repair. The resultant so-called osteolytic lesions (OL) take the form of tumor-filled cavities in bone that cause pain, fractures, and associated morbidity. Furthermore, the OL microenvironment can support survival of tumor cells and resistance to chemotherapy. Therefore, a deeper understanding of OL formation and MBD progression is imperative for the development of future therapeutic strategies. Herein, we describe a novel in vitro platform to study bone-tumor interactions based on three-dimensional co-culture of osteogenically enhanced human mesenchymal stem cells (OEhMSCs) in a rotating wall vessel bioreactor (RWV) while attached to micro-carrier beads coated with extracellular matrix (ECM) composed of factors found in anabolic bone tissue. Osteoinhibition was recapitulated in this model by co-culturing the OEhMSCs with a bone-tumor cell line (MOSJ-Dkk1) that secretes the canonical Wnt (cWnt) inhibitor Dkk-1, a tumor-borne osteoinhibitory factor widely associated with several forms of MBD, or intact tumor fragments from Dkk-1 positive patient-derived xenografts (PDX). Using the model, we observed that depending on the conditions of growth, tumor cells can biochemically inhibit osteogenesis by disrupting cWnt activity in OEhMSCs, while simultaneously co-engrafting with OEhMSCs, displacing them from the niche, perturbing their activity, and promoting cell death. In the absence of detectable co-engraftment with OEhMSCs, Dkk-1 positive PDX fragments had the capacity to enhance OEhMSC proliferation while inhibiting their osteogenic differentiation. The model described has the capacity to provide new and quantifiable insights into the multiple pathological mechanisms of MBD that are not readily measured using monolayer culture or animal models.


Driving drug discovery: the fundamental role of academic labs.
Academic labs have been responsible for virtually all of the basic science discoveries that translate into the discovery and development of innovative new medicines. There is a growing concern that large pharmaceutical and biotechnology companies are not able to sustain research pipelines that bring new compounds into drug development that translate into innovative new medicines, especially in areas with high unmet medical need. To address the needs of patients, caregivers, and society, academic labs have played and can continue to play an important role at one or more stages in the development of innovative medicines, both directly and through collaborations with researchers in pharmaceutical and biotechnology companies. Collaboration is in the best interests of patients and society if it accelerates the translation of basic science discoveries to new medicines that address unmet medical needs.


Proteogenomic analysis reveals alternative splicing and translation as part of the abscisic acid response in Arabidopsis seedlings.
In eukaryotes, mechanisms such as alternative splicing (AS) and alternative translation initiation (ATI) contribute to organismal protein diversity. Specifically, splicing factors play crucial roles in responses to environment and development cues; however, the underlying mechanisms are not well investigated in plants. Here, we report the parallel employment of short-read RNA sequencing, single molecule long-read sequencing and proteomic identification to unravel AS isoforms and previously unannotated proteins in response to abscisic acid (ABA) treatment. Combining the data from the two sequencing methods, approximately 83.4% of intron-containing genes were alternatively spliced. Two AS types, which are referred to as alternative first exon (AFE) and alternative last exon (ALE), were more abundant than intron retention (IR); however, by contrast to AS events detected under normal conditions, differentially expressed AS isoforms were more likely to be translated. ABA extensively affects the AS pattern, indicated by the increasing number of non-conventional splicing sites. This work also identified thousands of unannotated peptides and proteins by ATI based on mass spectrometry and a virtual peptide library deduced from both strands of coding regions within the Arabidopsis genome. The results enhance our understanding of AS and alternative translation mechanisms under normal conditions, and in response to ABA treatment.


Sunlight decatungstate photoinduced trifluoromethylations of (hetero)aromatics and electron-poor olefins.
Tetrabutylammonium decatungstate has been exploited to photoinduce the trifluoromethylation of (hetero)aromatics and electron-poor olefins. The process made use of the cheap Langlois' reagent (CF3SO2Na) and occurred under sunlight irradiation in an acetonitrile/water mixture. The trifluoromethylation of (hetero)aromatics required the use of potassium persulfate as an additive and the mono- or bis-trifluoromethylated adducts were obtained, depending on the actual reaction conditions and the chosen substrate.


Genome-wide SNP and CNV analysis identifies common and low-frequency variants associated with severe early-onset obesity.
Common and rare variants associated with body mass index (BMI) and obesity account for <5% of the variance in BMI. We performed SNP and copy number variation (CNV) association analyses in 1,509 children with obesity at the extreme tail (>3 s.d. from the mean) of the BMI distribution and 5,380 controls. Evaluation of 29 SNPs (P < 1 × 10(-5)) in an additional 971 severely obese children and 1,990 controls identified 4 new loci associated with severe obesity (LEPR, PRKCH, PACS1 and RMST). A previously reported 43-kb deletion at the NEGR1 locus was significantly associated with severe obesity (P = 6.6 × 10(-7)). However, this signal was entirely driven by a flanking 8-kb deletion; absence of this deletion increased risk for obesity (P = 6.1 × 10(-11)). We found a significant burden of rare, single CNVs in severely obese cases (P < 0.0001). Integrative gene network pathway analysis of rare deletions indicated enrichment of genes affecting G protein-coupled receptors (GPCRs) involved in the neuronal regulation of energy homeostasis.


Chonggu Granules Improve Cartilage Matrix Metabolism in Knee Osteoarthritis via the miR-148a-3p/Wnt/β-Catenin Pathway.
This study aims to explore the effect and underlying mechanism of Chonggu Granules (CGG) in knee osteoarthritis (KOA) in rats. A papain-induced KOA model was established in rats. The pathological alterations of extracellular matrix in rat cartilage tissues were observed through hematoxylin and eosin (H&E) staining, followed by Mankin score for quantitative scoring. The ultrastructure of cartilage extracellular matrix was examined under a transmission electron microscopy (TEM). ELISA was used to measure the levels of IL-6, TNF-α, and IL-1β in rat serum. Immunofluorescence was performed for assessing the levels of MMP-3, MMP-13, and Col2al in rat cartilage. Western blot was used to identify the protein expressions of wnt1, GSK-3β, β-catenin, and Aggrecan in rat cartilage. The mRNA relative expressions of miR-148a-3p, wnt1, β-catenin, and GSK-3β in rat cartilage were detected by RT-PCR. Luciferase reporter gene was used to detect the target genes of miR-148a-3p. CGG significantly improved articular cartilage tissue and extracellular matrix metabolism compared to the model group as indicated by H&E, Mankin score, and TEM data. Moreover, low, medium, and high doses of CGG reduced the levels of IL-6, TNF-α, IL-1β, MMP-3, and MMP-13 in serum to varying degrees but increased the levels of Col2al and Aggrecan. Mechanistically, CGG targeted wnt1 by increasing the expression of miR-148a-3p in a dose-dependent manner, thereby downregulating the mRNA and protein expressions of β-catenin in cartilage tissue and upregulating the mRNA and protein expressions of GSK-3β. CGG may control the miR-148a-3p/wnt/β-catenin signaling pathway to decrease the levels of its downstream target genes MMP-13 and MMP-3, increase the expressions of Col2al and Aggrecan, and downregulate the contents of inflammatory cytokines IL-6, TNF-α, and IL-1β, thereby improving the metabolism of cartilage extracellular matrix and alleviating the degeneration of articular cartilage in KOA.


Glucose administration prior to a divided attention task improves tracking performance but not word recognition: evidence against differential memory enhancement?
The cognition-enhancing effects of glucose administration to humans have been well-documented; however, it remains unclear whether this effect preferentially targets episodic memory or other cognitive domains. The effect of glucose on the allocation of attentional resources during memory encoding was assessed using a sensitive dual-attention paradigm. One hundred and twenty volunteers (mean age 21.60, SD 4.89, 77 females) took part in this randomised, double-blind, placebo-controlled, parallel groups study where each consumed a 25-g glucose drink or a placebo. Half of the participants in each drink condition attempted to track a moving on-screen target during auditory word presentation. The distance between the cursor and the tracking target was used as an index of attentional cost during encoding. Effects of drink and tracking on recognition memory and drink on tracking performance were assessed. Self-rated appetite and mood were co-monitored. Co-performing the tracking task significantly impaired memory performance irrespective of drink condition. In the placebo-tracking condition, there was a cost to tracking manifest as greater deviation from target during and immediately following word presentation. Compared with placebo, the glucose drink significantly improved tracking performance during encoding. There were significant time-related changes in thirst and alertness ratings but these were not differentially affected by drink or tracking conditions. Tracking but not memory was enhanced by glucose. This finding suggests that, under certain task conditions, glucose administrations does not preferentially enhance memory performance. One mechanism through which glucose acts as a cognition enhancer is through allowing greater allocation of attentional resources.


Lower limb intracast pressures generated by different types of immobilisation casts.
To determine if complete, split casts and backslabs [plaster of Paris (POP) and fiberglass] generate different intracast pressures and pain. Increased swelling within casts was modeled by a closed water system attached to an expandable bag placed directly under different types of casts applied to a healthy lower limb. Complete fiberglass and POP casts, split casts and backslabs were applied. Twenty-five milliliter aliquots of saline were injected into the system and the generated intracast pressures were measured using a sphygmomanometer. The subject was blinded to the pressure scores to avoid bias. All casts were applied to the same right limb on the same subject to avoid the effects of variations in anatomy or physiology on intracast pressures. Pain levels were evaluated using the Visual Analogue Score after each sequential saline injection. Each type of cast was reapplied four times and the measurements were repeated on four separate occasions. Sample sizes were determined by a pre-study 90% power calculation to detect a 20% difference in intracast pressures between cast groups. A significant difference between the various types of casts was noted when the saline volume was greater than 100 mL (P = 0.009). The greatest intracast pressure was generated by complete fiberglass casts, which were significantly higher than complete POP casts or backslabs (P = 0.018 and P = 0.008 respectively) at intracast saline volumes of 100 mL and higher. Backslabs produced a significantly lower intracast pressure compared to complete POP only once the saline volume within casts exceeded 225 mL (P = 0.009). Intracast pressures were significantly lower in split casts (P = 0.003). Split POP and fiberglass casts produced the lowest intracast pressures, even compared to backslabs (P = 0.009). Complete fiberglass casts generated the highest pain levels at manometer pressures of 75 mmHg and greater (P = 0.001). Split fiberglass casts had significantly reduced pain levels (P = 0.001). In contrast, a split complete POP cast did not produce significantly reduced pain levels at pressures between 25-150 mmHg. There was no difference in pain generated by complete POP and backslabs at manometer pressures of 200 mmHg and lower. Fibreglass casts generate significantly higher intracast pressures and pain than POP casts. Split casts cause lower intracast pressures regardless of material, than complete casts and backslabs.


In pursuit of virtual lead optimization: the role of the receptor structure and ensembles in accurate docking.
Accurate ranking during in silico lead optimization is critical to drive the generation of new ligands with higher affinity, yet it is especially difficult because of the subtle changes between analogs. In order to assess the role of the structure of the receptor in delivering accurate lead ranking results, we docked a set of forty related inhibitors to structures of one species of dihydrofolate reductase (DHFR) derived from crystallographic, NMR solution data, and homology models. In this study, the crystal structures yielded the superior results: the compounds were placed in the active site in the conserved orientation and the docking scores for 80% percent of the compounds clustered into the same bins as the measured affinity. Single receptor structures derived from NMR data or homology models did not serve as accurate docking receptors. To our knowledge, these are the first experiments that assess ranking of homologous lead compounds using a variety of receptor structures. We then extended the study to investigate whether ensembles, either computationally or experimentally derived, of all of the single starting structures aid, hinder or have no effect on the performance of the starting template. Impressively, when ensembles of receptor structures derived from NMR data or homology models were employed, docking accuracy improved to a level equal to that of the high resolution crystal structures. The same experiments using a second species of DHFR and set of ligands confirm the results. A comparison of the structures of the individual ensemble members to the starting structures shows that the effect of the ensembles can be ascribed to protein flexibility in addition to absorption of computational error.


Inferring synteny between genome assemblies: a systematic evaluation.
Genome assemblies across all domains of life are being produced routinely. Initial analysis of a new genome usually includes annotation and comparative genomics. Synteny provides a framework in which conservation of homologous genes and gene order is identified between genomes of different species. The availability of human and mouse genomes paved the way for algorithm development in large-scale synteny mapping, which eventually became an integral part of comparative genomics. Synteny analysis is regularly performed on assembled sequences that are fragmented, neglecting the fact that most methods were developed using complete genomes. It is unknown to what extent draft assemblies lead to errors in such analysis. We fragmented genome assemblies of model nematodes to various extents and conducted synteny identification and downstream analysis. We first show that synteny between species can be underestimated up to 40% and find disagreements between popular tools that infer synteny blocks. This inconsistency and further demonstration of erroneous gene ontology enrichment tests raise questions about the robustness of previous synteny analysis when gold standard genome sequences remain limited. In addition, assembly scaffolding using a reference guided approach with a closely related species may result in chimeric scaffolds with inflated assembly metrics if a true evolutionary relationship was overlooked. Annotation quality, however, has minimal effect on synteny if the assembled genome is highly contiguous. Our results show that a minimum N50 of 1 Mb is required for robust downstream synteny analysis, which emphasizes the importance of gold standard genomes to the science community, and should be achieved given the current progress in sequencing technology.


Spatial distribution of some microbial trophic groups in a plug-flow-type anaerobic bioreactor treating swine manure.
Anaerobic digestion of swine manure is carried out by a consortium of microbial species, including volatile fatty acid (VFA) producers, VFA-degraders and methanogens. The distribution of five phylogenetic groups within a plug-flow-type anaerobic bioreactor consisting of eight serially-connected tanks was examined through the sequential digestion of swine manure. Quantification was carried out using reverse transcription real-time PCR (RT-Q-PCR) assays targeting the 16S rRNA of Clostridium (cluster XIVa), Peptostreptococcus, Syntrophomonas, Methanosaeta, and Methanosarcina spp. The VFA producers Peptostreptococcus spp. and Clostridium spp. were found predominantly in compartments where hydrolysis/acidogenesis took place. The spatial distribution of the aceticlastic methanogens, Methanosaeta and Methanosarcina, within the bioreactor was not correlated with methanogenic activity. In contrast the VFA-degrading genus Syntrophomonas spp. was more abundant in compartments with elevated methanogenic activity. Multivariate statistical analyses of the RT-Q-PCR data have provided new insights into our understanding of how the various trophic groups were distributed within this bioreactor system. While the distribution of clostridia, peptostreptococci and Syntrophomonas corresponded to their known metabolic functions, aceticlastic methanogens were not apparently linked to the methanogenesis stage occurring in latter compartments, suggesting that hydrogenotrophic methanogens were the primary methane generators in this bioreactor. However, aceticlastic methanogens could be involved in compartments related to the hydrolysis/acidogenesis stage.


Calibration of wafer surface inspection systems using spherical silica nanoparticles.
Silica nanospheres with diameters ranging from 60 nm to 269 nm are investigated as an alternative to polystyrene spheres for calibrating laser-scattering-based wafer surface inspection systems, since they are less susceptible to changes upon ultraviolet exposure. Polystyrene and silica spheres were classified by differential mobility analysis before being deposited onto bare silicon wafers, and scattered signals were measured by two commercial tools using 488 nm and 355 nm laser light. The instrument signals were modeled by integrating a theoretically-determined differential cross section over the collection geometry of each tool, and the predicted signals were compared to the measured signals. The resulting calibrations, whether performed using the polystyrene spheres, the silica spheres, or both, were found to be equivalent and to meet industry requirements, provided the index of refraction of the silica spheres was allowed to be a floating parameter. The indices were found to be 1.413 and 1.421 at 488 nm and 355 nm, respectively, consistent with a void fraction of 11.4%.


Inhalation anesthesia of rats: influence of the fraction of inspired oxygen on limb ischemia/reperfusion injury.
Inhalation anesthesia with isoflurane is a well-established and safe method used in small laboratory animals. In most cases oxygen is used as a carrier gas for isoflurane, but room air or mixtures of oxygen with air or nitrous oxide are also being used. Anesthesia is therefore administered using different fractions of inspired oxygen (FiO2), and this may have consequences for the outcome of experiments. The aim of the present study was to investigate the influence of FiO2 on rat hind limb ischemia/reperfusion injury and to refine the used inhalation anesthesia. Male Wistar rats were subjected to 3.5 h of ischemia and 2 h of reperfusion, and divided into three groups according to FiO2 in the O2/air/isoflurane anesthesia gas mixture: 40%, 60%, and 100% O2 Normal, healthy rats were used as controls. Muscle edema and creatine kinase MM, a marker for myocyte necrosis, were significantly increased with 40% FiO2 as compared with 100% FiO2 (P < 0.05). Partial pressure of oxygen, oxygen saturation, and oxyhemoglobin were significantly higher in the 100% O2 group as compared with 40% O2 No significant differences were detected for other parameters, such as the oxidative stress markers malondialdehyde and superoxide dismutase. We conclude that a refined inhalation anesthesia setting using 40% FiO2, reflecting more or less the clinical situation, leads to a more severe and more physiologically relevant reperfusion injury than higher FiO2. Oxidative stress did not correlate with FiO2 and seemed to have no influence on reperfusion injury.


Effect of caffeic acid phenethyl ester (CAPE) on H₂O₂ induced oxidative and inflammatory responses in human middle ear epithelial cells.
Acute otitis media (OM) is a common pediatric disease. Recent research into the pathogenesis of OM has focused on oxidative damage, induced by oxygen free radicals, to the middle ear mucosa along with inflammation. Caffeic acid phenethyl ester (CAPE) is a biologically active ingredient of propolis honey bees, with antioxidative and anti-inflammatory activities. The effect of CAPE on hydrogen peroxide (H(2)O(2))-induced inflammatory and oxidative reactions in the middle ear is still not known. The aim of this study was to evaluate the anti-inflammatory and antioxidative effects of CAPE on cultured human middle ear epithelial cells (HMEECs). The inflammatory injury of H(2)O(2) and the anti-inflammatory effect of CAPE were determined by measuring levels of pro-inflammatory cytokines (tumor necrosis factor (TNF)-α and COX-2) with real-time reverse transcription polymerase chain reaction and Western blot analysis. Oxidative stress induced by H(2)O(2) and antioxidative effects of CAPE were evaluated directly by reactive oxygen species (ROS) production using flow cytometric analysis of 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H(2)DCFDA), and indirectly by the expression of superoxide dismutase (SOD) using Western blot analysis. The effect of CAPE was compared with N-acetyl cysteine (NAC) which has well-known antioxidative and anti-inflammatory effects. CAPE significantly inhibited H(2)O(2)-induced upregulation of TNF-α and COX-2 expression in a dose and time dependent manner. ROS accumulation induced by H(2)O(2) stimulation was decreased by CAPE pretreatment. Induced SOD expression after H(2)O(2) stimulation was diminished by CAPE pretreatment. The anti-inflammatory and antioxidative effects of CAPE were similar to those of NAC. These findings suggest that inflammation induced by H(2)O(2) can be inhibited by CAPE via inhibition of the expression of pro-inflammatory cytokines such as TNF-α and COX-2. Furthermore, CAPE has antioxidative effects, which decreases the need for endogenous SOD expression.


Maternal epigenetic pathways control parental contributions to Arabidopsis early embryogenesis.
Defining the contributions and interactions of paternal and maternal genomes during embryo development is critical to understand the fundamental processes involved in hybrid vigor, hybrid sterility, and reproductive isolation. To determine the parental contributions and their regulation during Arabidopsis embryogenesis, we combined deep-sequencing-based RNA profiling and genetic analyses. At the 2-4 cell stage there is a strong, genome-wide dominance of maternal transcripts, although transcripts are contributed by both parental genomes. At the globular stage the relative paternal contribution is higher, largely due to a gradual activation of the paternal genome. We identified two antagonistic maternal pathways that control these parental contributions. Paternal alleles are initially downregulated by the chromatin siRNA pathway, linked to DNA and histone methylation, whereas transcriptional activation requires maternal activity of the histone chaperone complex CAF1. Our results define maternal epigenetic pathways controlling the parental contributions in plant embryos, which are distinct from those regulating genomic imprinting.


Favourable changes in economic well-being and self-rated health among the elderly.
Adverse economic shocks exert an influence on health perceptions, but little is known about the effect of sudden positive changes in a person's financial situation on self-rated health, particularly among low income people. This paper explores the association between an increase in the amount of non-contribution pensions, public cash transfers given to Costa Rican elderly of low socio-economic status (SES) and changes in self-rated health over time. The analysis is based on data from CRELES, the "Costa Rican Study on Longevity and Healthy Aging", which is based on a probabilistic sample of people born in 1945 or earlier, and living in Costa Rica by 2002. The fieldwork for the first and second waves of CRELES was conducted from 2004 to 2006, and from 2006 to 2008, respectively. The Costa Rican Government raised the amount of the non-contribution pension for the poor 100% before July 2007, and an additional 100% after that date. Due to the CRELES fieldwork schedule, the data have a natural quasi-experimental design, given that approximately half of CRELES respondents were interviewed before July 2007, independently of their status in receiving the public cash transfers. Using random effects ordered probit regression models, we find that people who experienced such increase report a greater improvement in self-rated health between waves than those who experienced a smaller increase and than the rest of the interviewees. Results suggest that increases in income may lead to a greater improvement in self-rated health.


Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production.
Bruton's tyrosine kinase (Btk), the gene mutated in the human immunodeficiency X-linked agammaglobulinemia, is activated by LPS and is required for LPS-induced TNF production. In this study, we have investigated the role of Btk both in signaling via another TLR (TLR2) and in the production of other proinflammatory cytokines such as IL-1beta, IL-6, and IL-8. Our data show that in X-linked agammaglobulinemia PBMCs, stimulation with TLR4 (LPS) or TLR2 (N-palmitoyl-S-[2, 3-bis(palmitoyloxy)-(2R)-propyl]-(R)-cysteine) ligands produces significantly less TNF and IL-1beta than in normal controls. In contrast, a lack of Btk has no impact on the production of IL-6, IL-8, or the anti-inflammatory cytokine, IL-10. Our previous data suggested that Btk lies within a p38-dependent pathway that stabilizes TNF mRNA. Accordingly, TaqMan quantitative PCR analysis of actinomycin D time courses presented in this work shows that overexpression of Btk is able to stabilize TNF, but not IL-6 mRNA. Furthermore, using the p38 inhibitor SB203580, we show that the TLR4-induced production of TNF, but not IL-6, requires the activity of p38 MAPK. These data provide evidence for a common requirement for Btk in TLR2- and TLR4-mediated induction of two important proinflammatory cytokines, TNF and IL-1beta, and reveal important differences in the TLR-mediated signals required for the production of IL-6, IL-8, and IL-10.


Adequate sample size for developing prediction models is not simply related to events per variable.
The choice of an adequate sample size for a Cox regression analysis is generally based on the rule of thumb derived from simulation studies of a minimum of 10 events per variable (EPV). One simulation study suggested scenarios in which the 10 EPV rule can be relaxed. The effect of a range of binary predictors with varying prevalence, reflecting clinical practice, has not yet been fully investigated. We conducted an extended resampling study using a large general-practice data set, comprising over 2 million anonymized patient records, to examine the EPV requirements for prediction models with low-prevalence binary predictors developed using Cox regression. The performance of the models was then evaluated using an independent external validation data set. We investigated both fully specified models and models derived using variable selection. Our results indicated that an EPV rule of thumb should be data driven and that EPV ≥ 20  generally eliminates bias in regression coefficients when many low-prevalence predictors are included in a Cox model. Higher EPV is needed when low-prevalence predictors are present in a model to eliminate bias in regression coefficients and improve predictive accuracy.


Bonobos respond to distress in others: consolation across the age spectrum.
How animals respond to conflict provides key insights into the evolution of socio-cognitive and emotional capacities. Evidence from apes has shown that, after social conflicts, bystanders approach victims of aggression to offer stress-alleviating contact behavior, a phenomenon known as consolation. This other-orientated behavior depends on sensitivity to the other's emotional state, whereby the consoler acts to ameliorate the other's situation. We examined post-conflict interactions in bonobos (Pan paniscus) to identify the determinants of consolation and reconciliation. Thirty-six semi-free bonobos of all ages were observed at the Lola ya Bonobo Sanctuary, DR Congo, using standardized Post-conflict/Matched Control methods. Across age and sex classes, bonobos consoled victims and reconciled after conflicts using a suite of affiliative and socio-sexual behaviors including embracing, touching, and mounting. Juveniles were more likely to console than adults, challenging the assumption that comfort-giving rests on advanced cognitive mechanisms that emerge only with age. Mother-reared individuals were more likely to console than orphans, highlighting the role of rearing in emotional development. Consistent with previous studies, bystanders were more likely to console relatives or closely bonded partners. Effects of kinship, affiliation and rearing were similarly indicated in patterns of reconciliation. Nearby bystanders were significantly more likely to contact victims than more distal ones, and consolation was more likely in non-food contexts than during feeding. The results did not provide convincing evidence that bystander contacts served for self-protection or as substitutes for reconciliation. Overall, results indicate that a suite of social, developmental and contextual factors underlie consolation and reconciliation in bonobos and that a sensitivity to the emotions of others and the ability to provide appropriate consolatory behaviors emerges early in development.


[Current management of imported severe malaria].
Severe malaria is a diagnostic and therapeutic emergency with great impact worldwide for incidence and mortality. The clinical presentation of severe malaria can be very polymorphic and rapidly progressing. Therefore a correct diagnosis and an early and adequate antiparasitic and support therapy are essential. This paper attempts to outline the diagnosis frame and the treatment of severe malaria for adults, paediatric patients and for pregnant.


Preconditioned endothelial progenitor cells reduce formation of melanoma metastases through SPARC-driven cell-cell interactions and endocytosis.
Tumor progression is associated with the release of signaling substances from the primary tumor into the bloodstream. Tumor-derived cytokines are known to promote the mobilization and the recruitment of cells from the bone marrow, including endothelial progenitor cells (EPC). Here, we examined whether such paracrine influence could also influence the capacity of EPC to interfere with circulating metastatic cells. We therefore consecutively injected EPC prestimulated by tumor-conditioned medium (EPC-CM) and luciferase-expressing B16 melanoma cells to mice. A net decrease in metastases spreading (vs. nonstimulated EPC) led us to carry out a 2-dimensional difference gel electrophoresis (2D-DIGE) proteomic study to identify possible mediators of EPC-driven protection. Among 33 proteins exhibiting significant changes in expression, secreted protein, acidic and rich in cysteine (SPARC) presented the highest induction after EPC exposure to CM. We then showed that contrary to control EPC, SPARC-silenced EPC were not able to reduce the extent of metastases when injected with B16 melanoma cells. Using adhesion tests and the hanging drop assay, we further documented that cell-cell interactions between EPC-CM and melanoma cells were promoted in a SPARC-dependent manner. This interaction led to the engulfment of melanoma cells by EPC-CM, a process prevented by SPARC silencing and mimicked by recombinant SPARC. Finally, we showed that contrary to melanoma cells, the prometastatic human breast cancer cell line MDA-MB231-D3H2 reduced SPARC expression in human EPC and stimulated metastases spreading. Our findings unravel the influence of tumor cells on EPC phenotypes through a SPARC-driven accentuation of macrophagic capacity associated with limitations to metastatic spread.


Time varying association between deprivation, ethnicity and SARS-CoV-2 infections in England: A population-based ecological study.
Ethnically diverse and socio-economically deprived communities have been differentially affected by the COVID-19 pandemic in the UK. Using a multilevel regression model we assessed the time-varying association between SARS-CoV-2 infections and areal level deprivation and ethnicity from 1st of June 2020 to the 19th of September 2021. We separately considered weekly test positivity rate and estimated debiased prevalence at the Lower Tier Local Authority (LTLA) level, adjusting for confounders and spatio-temporal correlation structure. Comparing the least deprived and predominantly White areas with most deprived and predominantly non-White areas over the whole study period, the weekly positivity rate increases from 2·977% (95% CrI 2.913%-3.029%) to 3·347% (95% CrI 3.300%-3.402%). Similarly, prevalence increases from 0·369% (95% CrI 0.361%-0.375%) to 0·405% (95% CrI 0.399%-0.412%). Deprivation has a stronger effect until October 2020, while the effect of ethnicity becomes more pronounced at the peak of the second wave and then again in May-June 2021. In the second wave of the pandemic, LTLAs with large South Asian populations were the most affected, whereas areas with large Black populations did not show increased values for either outcome during the entire period under analysis. Deprivation and proportion of non-White populations are both associated with an increased COVID-19 burden in terms of disease spread and monitoring, but the strength of association varies over the course of the pandemic and for different ethnic subgroups. The consistency of results across the two outcomes suggests that deprivation and ethnicity have a differential impact on disease exposure or susceptibility rather than testing access and habits. EPSRC, MRC, The Alan Turing Institute, NIH, UKHSA, DHSC.


A statistical approach to determining responses to individual peptides from pooled-peptide ELISpot data.
To investigate in detail the effect of infection or vaccination on the human immune system, ELISpot assays are used to simultaneously test the immune response to a large number of peptides of interest. Scientists commonly use "peptide pools", where, instead of an individual peptide, a test well contains a group of peptides. Since the response from a well may be due to any or many of the peptides in the pool, pooled assays usually need to be followed by confirmatory assays of a number of individual peptides. We present a statistical method that enables estimation of individual peptide responses from pool responses using the Expectation Maximization (EM) algorithm for "incomplete data". We demonstrate the accuracy and precision of these estimates in simulation studies of ELISpot plates with 90 pools of 6 or 7 peptides arranged in three dimensions and three Mock wells for the estimation of background. In analysis of real pooled data from 6 subjects in a HIV-1 vaccine trial, where 199 peptides were arranged in 80 pools if size 9 or 10, our estimates were in very good agreement with the results from individual-peptide confirmatory assays. Compared to the classical approach, we could identify almost all the same peptides with high or moderate response, with less than half the number of confirmatory tests. Our method facilitates efficient use of the information available in pooled ELISpot data to avoid or reduce the need for confirmatory testing. We provide an easy-to-use free online application for implementing the method, where on uploading two spreadsheets with the pool design and pool responses, the user obtains the estimates of the individual peptide responses.


Evaluation of a project to enhance knowledge of hereditary diseases and management.
During 1992 and 1993, in a designated suburban area of Perth, Western Australia, information on hereditary disease was provided for health professionals and the general community. This information was in the form of posters, pamphlets, postal flyers and return letter cards, a static display, newspaper articles, advertisements and radio broadcasts, and professional seminars. The aim of this project was to evaluate the effectiveness of combined strategies to convey practical information about hereditary disease to the community and health professionals. Multiple measures of response evaluation were used, which included structured questionnaire surveys of health professionals and members of the community before and after the project. In the community surveys, respondents who were female, married, middle aged, and parents, and had a higher level of education or were born in Australia, New Zealand, or the United Kingdom were generally better informed about hereditary diseases. This intervention resulted in only meagre changes in community knowledge about hereditary disease, even though promotional materials were shown to be appropriate. General Practitioners (GPs) and Child Health Nurses (CHNs) were supportive of clinical genetic services and recognised a need for continuation of education in this field. There is a rapidly increasing need for community and health professional comprehension of the applications of the new genetic technology. This project indicates that routine educational and health promotion strategies will not be enough to achieve desired levels of knowledge and attitude change.


Neutralization of lethal potency and inhibition of enzymatic activity of a phospholipase A2 neurotoxin, crotoxin, by non-precipitating antibodies (Fab).
Rabbit antibodies were prepared against both purified catalytic (component-B) and purified non-catalytic (component-A) subunits of crotoxin, the major phospholipase A2 neurotoxin from the South American rattlesnake. They cross-react with crotoxin-like toxins from the venom of several Crotalus species as well as with single-chain phospholipase A2 neurotoxins from Crotalid and Viperid venoms (agkistrodontoxin and ammodytoxin A) but not from Elapid venoms (notexin). Immunological cross-reactions of anti-component-A and anti-component-B sera with crotoxin and with its isolated components A and B showed that component-A exposes determinants of low immunogenicity which are present on component-B, whereas the major antigenic determinants of component-B are not present on component-A. Anti-component-B antibodies, but not anti-component-A antibodies, neutralize the lethal potency of crotoxin and inhibit its enzymatic activity. Furthermore, non-precipitating anti-component-B Fab fragments were as potent as antibodies, indicating that crotoxin neutralization results from the binding of the antibodies to the catalytic subunit, rather than the formation of an immunoprecipitate.


Comparison of outcomes of perinatal care in Slovakia and the UK.
To investigate whether there are differences in maternal and perinatal outcomes between Slovakia and the UK, and whether any observed variations can be attributed to differences in perinatal care. Data on outcomes of perinatal care in Slovakia and the UK between 2006 and 2010 were compared. Perinatal mortality figures included stillbirths weighing 1000g or more and early neonatal deaths. In Slovakia, the perinatal mortality rate was significantly higher than that in the UK (RR 1.12; 95% CI, 1.06-1.18). Cesarean delivery was significantly more frequent in Slovakia (RR 1.05; 95% CI, 1.05-1.06); instrumental vaginal delivery was less frequent (ventouse delivery, RR 0.20; 95% CI, 0.19-0.21; forceps delivery, RR 0.09; 95% CI, 0.09-0.10). Episiotomy and peripartum hysterectomy were performed more often in Slovakia (episiotomy, RR 4.10; 95% CI, 4.07-4.12; peripartum hysterectomy, RR 2.02; 95% CI 1.65-2.47). The incidence of eclampsia was significantly higher in Slovakia (RR 1.60; 95% CI, 1.26-2.04). There were no significant differences in the rates of maternal death. Perinatal care outcomes and intervention rates differ between Slovakia and UK. This may be explained by differences in outcome definitions, perinatal care, and official encouragement of medical complaints.


Expression of AQP1 Was Associated with Apoptosis and Survival of Patients in Gastric Adenocarcinoma.
Recently, interest in the role of aquaporin 1 (AQP1) in human gastrointestinal carcinogenesis has developed. However, to date no studies have examined relationships between AQP1 expression and specific characteristics of gastric adenocarcinoma. We investigated 109 specimens of primary gastric adenocarcinoma and their corresponding normal gastric mucosa using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) to determine AQP1 expression. We then evaluated disease free survival (DFS) and overall survival (OS) in these patients in association with AQP1 expression. Both immunohistochemical and RT-PCR analyses identified increased AQP1 expression in tumors from patients with gastric adenocarcinoma (p < 0.001). The 3-year DFS and OS rates were higher in the AQP1-negative group than in the positive group (DFS: 77.2 vs. 52.8%, p < 0.001; OS: 85.1 vs. 70.7%, p < 0.001). The 5-year DFS and OS rates exhibited a similar trend (p < 0.001). Subgroup analysis of patients with early gastric adenocarcinoma (stages I and II) revealed a total 5-year OS of 90.0%, with 5-year OS being higher in the AQP1-negative group than in the positive group (95.2 vs. 84.2%). Furthermore, incidence of tumor recurrence following surgical treatment was significantly higher in the AQP1-positive group (4/19, 21.1%) compared with the negative group (0/21, 0%). Our study demonstrates that AQP1 plays an important role in gastric adenocarcinoma and may therefore represent a novel therapeutic target and prognostic marker in this disease.


The update on transcriptional regulation of autophagy in normal and pathologic cells: A novel therapeutic target.
Autophagy is a genetically programmed, evolutionarily conserved catabolic process that occurs in response to stress. While short-lived proteins are degraded via the ubiquitin/proteasome pathway in higher eukaryotes, autophagy refers to intracellular pathway for development, differentiation, survival, and homeostasis through the lysosomal-dependent machinery, which regulates the synthesis, degradation, and recycling of long-lived proteins and even whole cytoplasmic organelles. The newly discovery shows that autophagy plays an important role in recycling nutrients upon starvation and maintaining cellular energy homeostasis. Recent basic and clinical investigations further demonstrate that autophagic abnormalities have been considered underlying reasons for lots of human diseases, including liver disease, cardiovascular and cerebrovascular diseases, neurodegenerative diseases, neoplastic diseases, and cancers. Pharmacological modulation of autophagy might point to possible therapeutic strategies for combating a broad range of diseases. Regrettably, although the mechanisms underlying the regulation of autophagy have long been attracted extensive concern of numerous scholars and its acute regulation by nutrient-sensing signaling pathways is well described, the overview on longer-term transcriptional regulation of autophagy is still filled with confusion. This review summarizes current knowledge on transcriptional regulation of autophagy and expands our horizons on the autophagy repertoire. On the other hand, it also offers a glimpse into different strategies that have been used in experimental models to counteract excessive pathological autophagy via transcriptional regulation mechanism in the prevention and treatment of disease.


MINI-AC: inference of plant gene regulatory networks using bulk or single-cell accessible chromatin profiles.
Gene regulatory networks (GRNs) represent the interactions between transcription factors (TF) and their target genes. Plant GRNs control transcriptional programs involved in growth, development, and stress responses, ultimately affecting diverse agricultural traits. While recent developments in accessible chromatin (AC) profiling technologies make it possible to identify context-specific regulatory DNA, learning the underlying GRNs remains a major challenge. We developed MINI-AC (Motif-Informed Network Inference based on Accessible Chromatin), a method that combines AC data from bulk or single-cell experiments with TF binding site (TFBS) information to learn GRNs in plants. We benchmarked MINI-AC using bulk AC datasets from different Arabidopsis thaliana tissues and showed that it outperforms other methods to identify correct TFBS. In maize, a crop with a complex genome and abundant distal AC regions, MINI-AC successfully inferred leaf GRNs with experimentally confirmed, both proximal and distal, TF-target gene interactions. Furthermore, we showed that both AC regions and footprints are valid alternatives to infer AC-based GRNs with MINI-AC. Finally, we combined MINI-AC predictions from bulk and single-cell AC datasets to identify general and cell-type specific maize leaf regulators. Focusing on C4 metabolism, we identified diverse regulatory interactions in specialized cell types for this photosynthetic pathway. MINI-AC represents a powerful tool for inferring accurate AC-derived GRNs in plants and identifying known and novel candidate regulators, improving our understanding of gene regulation in plants.