xiSPEC: web-based visualization, analysis and sharing of proteomics data.
We present xiSPEC, a standard compliant, next-generation web-based spectrum viewer for visualizing, analyzing and sharing mass spectrometry data. Peptide-spectrum matches from standard proteomics and cross-linking experiments are supported. xiSPEC is to date the only browser-based tool supporting the standardized file formats mzML and mzIdentML defined by the proteomics standards initiative. Users can either upload data directly or select files from the PRIDE data repository as input. xiSPEC allows users to save and share their datasets publicly or password protected for providing access to collaborators or readers and reviewers of manuscripts. The identification table features advanced interaction controls and spectra are presented in three interconnected views: (i) annotated mass spectrum, (ii) peptide sequence fragmentation key and (iii) quality control error plots of matched fragments. Highlighting or selecting data points in any view is represented in all other views. Views are interactive scalable vector graphic elements, which can be exported, e.g. for use in publication. xiSPEC allows for re-annotation of spectra for easy hypothesis testing by modifying input data. xiSPEC is freely accessible at http://spectrumviewer.org and the source code is openly available on https://github.com/Rappsilber-Laboratory/xiSPEC.


The feasibility of a web-based counselling program for occupational physicians and employees on sick leave due to back or neck pain.
The objective of this feasibility study was to gain insight into occupational physicians' (OPs) and employees' use of, and attitudes towards, 'Snelbeter' (Get Well Fast), a new web-based counselling program for employees on sick leave due to non-specific back or neck pain and their OPs. Registered user information was collected from the website to get insight in the use of the program by employees (n = 24). Qualitative information was obtained through semi-structured in-depth interviews with 19 OPs and nine employees in order to get insight in the actual use of the provided information, the attitudes towards the program and possible improvements of the program. Actual use of the program among OPs was low. The majority of OPs, eight out of 11 (73%), never or only occasionally signed in. The greatest obstacle for OPs to use the program was the low number of eligible employees involved. Employees appreciated the program but their use was moderate. A small majority of the employees who used the program, 14 out of 24 (58%), opened 50% to 100% of the provided documents, a majority of the interviewed employees, seven out of nine (78%), used the provided information sometimes or regularly. The absence of personal contact was found to be a major barrier towards use of the program by employees. Although both OPs and employees appreciated the idea of the program and employees appreciated using it, program utilization was moderate to low. The discussion section reveals that before implementation can be started to any extent, the program will need adaptations that make it more attractive to use. The program should be considered for both return to work (RTW) and the prevention of sick leave. Adding personal contact (e.g. involving physiotherapists) to the program may also be promising.


Detecting Novel Ototoxins and Potentiation of Ototoxicity by Disease Settings.
Over 100 drugs and chemicals are associated with permanent hearing loss, tinnitus, and vestibular deficits, collectively known as ototoxicity. The ototoxic potential of drugs is rarely assessed in pre-clinical drug development or during clinical trials, so this debilitating side-effect is often discovered as patients begin to report hearing loss. Furthermore, drug-induced ototoxicity in adults, and particularly in elderly patients, may go unrecognized due to hearing loss from a variety of etiologies because of a lack of baseline assessments immediately prior to novel therapeutic treatment. During the current pandemic, there is an intense effort to identify new drugs or repurpose FDA-approved drugs to treat COVID-19. Several potential COVID-19 therapeutics are known ototoxins, including chloroquine (CQ) and lopinavir-ritonavir, demonstrating the necessity to identify ototoxic potential in existing and novel medicines. Furthermore, several factors are emerging as potentiators of ototoxicity, such as inflammation (a hallmark of COVID-19), genetic polymorphisms, and ototoxic synergy with co-therapeutics, increasing the necessity to evaluate a drug's potential to induce ototoxicity under varying conditions. Here, we review the potential of COVID-19 therapies to induce ototoxicity and factors that may compound their ototoxic effects. We then discuss two models for rapidly detecting the potential for ototoxicity: mammalian auditory cell lines and the larval zebrafish lateral line. These models offer considerable value for pre-clinical drug development, including development of COVID-19 therapies. Finally, we show the validity of in silico screening for ototoxic potential using a computational model that compares structural similarity of compounds of interest with a database of known ototoxins and non-ototoxins. Preclinical screening at in silico, in vitro, and in vivo levels can provide an earlier indication of the potential for ototoxicity and identify the subset of candidate therapeutics for treating COVID-19 that need to be monitored for ototoxicity as for other widely-used clinical therapeutics, like aminoglycosides and cisplatin.


Soyasaponins: A New Class of Root Exudates in Soybean (Glycine max).
Root exudates are plant metabolites secreted from the roots into the soil. These exudates are involved in many important biological processes, including acquisition of nutrients, defense and signaling to rhizosphere bacteria, such as isoflavones of soybean crucial for the symbiosis with rhizobium. Less is known, however, about other types of root exudates. This study shows that soybean roots secrete large amounts of soyasaponins (triterpenoid glycosides) as root exudates. The soyasaponins are classified into four groups, with group A being the most secreted of these compounds, whereas DDMP (2,3-dihydro-2,5-dihydroxy-6-methyl-4H-pyran-4-one) soyasaponins is the group showing greatest accumulation in root tissues, suggesting a selection system for secreted compounds. Time-course experiments showed that the soyasaponin secretion peaked during early vegetative stages. In particular, soyasaponin Ah was the major compound secreted by soybean roots, whereas the deacetylated derivative Af was the major compound secreted specifically during the VE stage. The secretion of soyasaponins containing glycosyl moieties is an apparent loss of photosynthates. This phenomenon has been also observed in other legume species, although the composition of secreted soyasaponins is plant species dependent. The identification of triterpenoid saponins as major metabolites in legume root exudates will provide novel insights into chemical signaling in the rhizosphere between plants and other organisms.


Aspergillus caespitosus ASEF14, an oleaginous fungus as a potential candidate for biodiesel production using sago processing wastewater (SWW).
Oleaginous microorganisms are sustainable alternatives for the production of biodiesel. Among them, oleaginous fungi are known for their rapid growth, short life cycles, no light requirement, easy scalability, and the ability to grow in cheap organic resources. Among all the sources used for biodiesel production, industrial wastewater streams have been least explored. We used oleaginous fungi to decontaminate sago processing wastewater and produce biodiesel. Among the 15 isolates screened for lipid production and starch utilization using the Nile red staining assay and amylase plate screening, three isolates accumulated > 20% (w/w) of their dry cell mass as lipids. The isolate ASEF14 exhibited the highest lipid accumulation (> 40%) and was identified as Aspergillus caespitosus based on the 28S rRNA gene sequencing. The maximum lipid content of 54.4% in synthetic medium (SM) and 37.2% in sago processing wastewater (SWW) was produced by the strain. The Fourier-transform infrared (FTIR) spectroscopy of the fungal oil revealed the presence of functional peaks corresponding to major lipids. Principal component analysis (PCA) of the FTIR data revealed major changes in the fatty acid composition during the transition from the growth phase (Days 1-3) to the lipid accumulation phase (Days 4-7). The fatty acid methyl esters (FAME) analysis of fungal oil from SWW contained 43.82% and 9.62% of saturated and monounsaturated fatty acids, respectively. The composition and percentage of individual FAME derived from SWW were different from SM, indicating the effect of nutrient and fermentation time. The fuel attributes of the SM- and SWW-grown fungal biodiesel (kinematic viscosity, iodine value, cetane number, cloud and pour point, linolenic acid content, FA > 4 double bonds) met international (ASTM D6751, EN 14214) and national (IS 15607) biodiesel standards. In addition to biodiesel production, the strain removed various contaminants such as total solids (TS), total suspended solids (TSS), total dissolved solids (TDS), dissolved oxygen (DO), chemical oxygen demand (COD), biological oxygen demand (BOD), total nitrogen (TN), total phosphorus (TP), and cyanide up to 58.6%, 53.0%, 35.2%, 94.5%, 89.3%, 91.3%, 74.0%, 47.0%, and 53.84%, respectively, from SWW. These findings suggested that A. caespitosus ASEF14 is a potential candidate with high lipid accumulating ability (37.27%), capable of using SWW as the primary growth medium. The medium and incubation time alter the FAME profile of this fungus. The physical properties of fungal oil were in accordance with the biodiesel standards. Moreover, it decontaminated SWW by reducing several polluting nutrients and toxicants. The fungal biodiesel produced by this cost-effective method could serve as an alternate path to meet global energy demand.


Advancing a multilevel framework for epidemiologic research on asthma disparities.
Our understanding of asthma epidemiology is growing increasingly complex. Asthma outcomes are clearly socially patterned, with asthma ranking as a leading cause of health disparities among minority and low socioeconomic groups. Yet, the increasing prevalence and marked disparities in asthma remain largely unexplained by known risk factors. In the United States, asthma disproportionately affects nonwhite children living in urban areas and children living in poverty. Low socioeconomic status (SES), ethnic minority group status, and residence in an inner-city environment are closely intertwined in the United States, making it a challenge to fully disentangle the independent effects of each of these characteristics on asthma morbidity. In addition, studies show geographic variation in asthma outcomes across large cities and neighborhoods within cities that cannot be explained by economic factors alone. Although more limited data are available, studies in rural areas also suggest the stratification of risk based on SES and the proportion of minorities. Among low-SES areas, those with predominantly minority, segregated populations seem especially burdened. Marginalized populations of lower socioeconomic position are disproportionately exposed to irritants (eg, tobacco smoke), pollutants (eg, diesel-related particles), and indoor allergens (eg, cockroach and mouse allergen). Moreover, these marginalized individuals may also live in communities that are increasingly socially toxic, which, in turn, may be related to the increased experience of psychosocial stress that may influence asthma morbidity. Epidemiologic trends suggest that asthma may provide an excellent paradigm for understanding the role of community-level contextual factors in disease. Specifically, a multilevel approach that includes an ecological perspective may help to explain heterogeneities in asthma expression across socioeconomic and geographic boundaries that, to date, remain largely unexplained. Traditionally, asthma epidemiology has focused on individual-level risk factors and family factors. Far less attention has been given to the broader social context in which individuals live. A multilevel approach that explicitly recognizes the embedding of asthma within its biological, psycho-socioeconomic, environmental, and community contexts, is likely to provide a better understanding of asthma disparities at different stages in the life course. Is it simply asthma disparities or is it social disparities in asthma?


Tempo and mode of multicellular adaptation in experimentally evolved Saccharomyces cerevisiae.
Multicellular complexity is a central topic in biology, but the evolutionary processes underlying its origin are difficult to study and remain poorly understood. Here we use experimental evolution to investigate the tempo and mode of multicellular adaptation during a de novo evolutionary transition to multicellularity. Multicelled "snowflake" yeast evolved from a unicellular ancestor after 7 days of selection for faster settling through liquid media. Over the next 220 days, snowflake yeast evolved to settle 44% more quickly. Throughout the experiment the clusters evolved faster settling by three distinct modes. The number of cells per cluster increased from a mean of 42 cells after 7 days of selection to 114 cells after 227 days. Between days 28 and 65, larger clusters evolved via a twofold increase in the mass of individual cells. By day 227, snowflake yeast evolved to form more hydrodynamic clusters that settle more quickly for their size than ancestral strains. The timing and nature of adaptation in our experiment suggests that costs associated with large cluster size favor novel multicellular adaptations, increasing organismal complexity.


Neuropsychological performance in advanced age: influences of demographic factors and Apolipoprotein E: findings from the Cache County Memory Study.
The Cache County Study of Memory in Aging (CCMS) is an epidemiological study of Alzheimer's disease (AD), mild cognitive disorders, and aging in a population of exceptionally long-lived individuals (7th to 11th decade). Observation of population members without dementia provides an opportunity for establishing the range of normal neurocognitive performance in a representative sample of the very old. We examined neurocognitive performance of the normal participants undergoing full clinical evaluations (n = 507) and we tested the potential modifying effects of apolipoprotein E (APOE) genotype, a known genetic risk factor for the later development of AD. The results indicate that advanced age and low education are related to lower test scores across nearly all of the neurocognitive measures. Gender and APOE epsilon4 both had negligible and inconsistent influences, affecting only isolated measures of memory and expressive speech (in case of gender). The gender and APOE effects disappeared once age and education were controlled. The study of this exceptionally long-lived population provides useful normative information regarding the broad range of "normal" cognition seen in advanced age. Among elderly without dementia or other cognitive impairment, APOE does not appear to exert any major effects on cognition once other demographic influences are controlled.


Complement Receptor C5aR1 Plays an Evolutionarily Conserved Role in Successful Cardiac Regeneration.
Defining conserved molecular pathways in animal models of successful cardiac regeneration could yield insight into why adult mammals have inadequate cardiac regeneration after injury. Insight into the transcriptomic landscape of early cardiac regeneration from model organisms will shed light on evolutionarily conserved pathways in successful cardiac regeneration. Here we describe a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration: axolotl, neonatal mice, and zebrafish. Apical resection to remove ≈10% to 20% of ventricular mass was carried out in these model organisms. RNA-sequencing analysis was performed on the hearts harvested at 3 time points: 12, 24, and 48 hours after resection. Sham surgery was used as internal control. Genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors (activated by complement components, part of the innate immune system) were found to be highly upregulated in all 3 species. This approach revealed induction of gene expression for complement 5a receptor 1 in the regenerating hearts of zebrafish, axolotls, and mice. Inhibition of complement 5a receptor 1 significantly attenuated the cardiomyocyte proliferative response to heart injury in all 3 species. Furthermore, after left ventricular apical resection, the cardiomyocyte proliferative response was diminished in mice with genetic deletion of complement 5a receptor 1. These data reveal that activation of complement 5a receptor 1 mediates an evolutionarily conserved response that promotes cardiomyocyte proliferation after cardiac injury and identify complement pathway activation as a common pathway of successful heart regeneration.


Copy number variation of the gene NCF1 is associated with rheumatoid arthritis.
The aim of this study was to investigate genetic variants in the gene neutrophil cytosolic factor 1 (NCF1) for association with rheumatoid arthritis (RA). In rodent models, a single-nucleotide polymorphism (SNP) in Ncf1 has been shown to be a major locus regulating severity of arthritis. Ncf1 encodes one of five subunits of the NADPH oxidase complex. In humans the genomic structure of NCF1 is complex, excluding it from genome-wide association screens and complicating genetic analysis. In addition to copy number variation of NCF1, there are also two nonfunctional pseudogenes, nearly identical in sequence to NCF1. We have characterized copy number variation and SNPs in NCF1, and investigated these variants for association with RA. We find that RA patients are less likely to have an increased copy number of NCF1, 7.6%, compared with 11.6% in controls; p=0.037. We also show that the T-allele of NCF1-339 (rs13447) is expressed in NCF1 and significantly reduces reactive oxygen species production. This is the first finding of genetic association of NCF1 with RA. The detailed characterization of genetic variants in NCF1 also helps elucidate the complexity of the NCF1 gene. These data suggest that an increased copy number of NCF1 can be protective against developing RA and add support to previous findings of a role of NCF1 and the phagocyte NADPH oxidase complex in RA pathogenesis.


Associations of sodium intake with obesity, metabolic disorder, and albuminuria according to age.
Sodium intake is associated with obesity and metabolic disorder in the general population. However, sodium intake is significantly reduced according to the decrease of energy intake in older adults although the prevalence of obesity is higher than younger adults. We evaluate the association of sodium excretion (UNa) with blood pressure, obesity, metabolic disorders, and albuminuria according to age. An observational study using data from the Korean National Health and Nutrition Examination Survey IV-V (2008-2011) was performed (N = 18,146). The 24 hour UNa was estimated from a single fasting urine sample.Participants aged≥75 years showed the highest risk for hypertension (HTN) in the highest quartile of UNa (1.769, 95% CI, 1.174-2.665), and the risks for HTN increased with advancing age. Obesity was not associated with UNa in participants aged≥75 years, and hypertriglyceridemia and body fat were not related to UNa in participants aged≥65 years, although these values were significantly associated with UNa in participants aged<65 years. Impaired fasting glucose (IFG) and insulin resistance (IR) were associated with UNa only in participants aged 20-39 years. The highest quartile of UNa showed a 3.777 fold increased risk for albuminuria in those aged 20-39 years (95% CI, 1.130-12.630), and a 1.885 fold increased risk (95% CI, 1.156-3.075) among participants aged 40-64 years. In participants aged≥65 years, albuminuria was not associated with UNa. In contrast with HTN, UNa was not associated with albuminuria, obesity, hypertriglyceridemia, IFG, and IR in older adults despite a strong association in younger adults.


Modeling early retinal development with human embryonic and induced pluripotent stem cells.
Human pluripotent stem cells have the potential to provide comprehensive model systems for the earliest stages of human ontogenesis. To serve in this capacity, these cells must undergo a targeted, stepwise differentiation process that follows a normal developmental timeline. Here we demonstrate the ability of both human embryonic stem cells (hESCs) and induced pluripotent stem (iPS) cells to meet these requirements for human retinogenesis. Upon differentiation, hESCs initially yielded a highly enriched population of early eye field cells. Thereafter, a subset of cells acquired features of advancing retinal differentiation in a sequence and time course that mimicked in vivo human retinal development. Application of this culture method to a human iPS cell line also generated retina-specific cell types at comparable times in vitro. Lastly, altering endogenous signaling during differentiation affected lineage-specific gene expression in a manner consistent with established mechanisms of early neural and retinal cell fate determination. These findings should aid in the investigation of the molecular events governing retinal specification from human pluripotent stem cells.


Reliable Positioning and mmWave Communication via Multi-Point Connectivity.
One of the key elements of future 5G and beyond mobile technology is millimeter-wave (mmWave) communications, which is targeted to extreme high-data rate services. Furthermore, combining the possibility of a wideband signal transmission with the capability of pencil-beamforming, mmWave technology is key for accurate cellular-based positioning. However, it is also well-known that at the mmWave frequency band the radio channel is very sensitive to line-of-sight blockages giving rise to unstable connectivity and inefficient communication. In this paper, we tackle the blockage problem and propose a solution to increase the communication reliability by means of a coordinated multi-point reception. We also investigate the advantage of this solution in terms of positioning quality. More specifically, we describe a robust hybrid analog⁻digital receive beamforming strategy to combat the unavailability of dominant links. Numerical examples are provided to validate the efficiency of our proposed method.


Novel male mice show gradual decline in the capacity to disrupt early pregnancy and in urinary excretion of testosterone and 17 beta-estradiol during the weeks immediately following castration.
Novel male mice can disrupt intrauterine implantation of fertilized ova in inseminated females. Evidence indicates mediation by androgen-dependent excretions. This study was designed to examine the time course of males' ability to disrupt pregnancy following castration and relate this to their urinary excretion of testosterone and 17 beta-estradiol. During days 1-5 of pregnancy, previously inseminated females were housed underneath castrated novel males at various intervals after the surgery. Castrated males generally continued to disrupt pregnancy during the initial weeks after surgery. Progressively, the probability of retention of pregnancy increased as a linear function of time since castration. There was an apparent asymptote, where the majority of females remained pregnant, beginning at about 6 weeks following surgery. Males' excretion of testosterone and 17 beta-estradiol in urine, measured via ELISA procedures, diminished gradually during the weeks after castration.


Cytotoxic T-lymphocyte response to autologous human squamous cell cancer of the lung: epitope reconstitution with peptides extracted from HLA-Aw68.
Cytotoxic T-lymphocytes (CTLs) specific for autologous human squamous cell cancer of the lung were generated by stimulation of peripheral blood lymphocytes with autologous tumor cells in vitro. The CTL line was >97% CD3+, CD8+, CD16- and produced tumor necrosis factor-alpha, gamma-interferon, and granulocyte-macrophage colony-stimulating factor after stimulation with autologous tumor. The CTLs lysed autologous tumor but failed to recognize autologous or histocompatibility leukocyte antigen-matched lymphoid cells, K562, or allogeneic tumor cells of several histological types. Antibody-blocking studies suggested that the CTLs recognized one or more antigens presented by the class I major histocompatibility complex molecule Aw68. To characterize these antigens further, histocompatibility leukocyte antigen Aw68 molecules were extracted from the squamous cell cancer of the lung tumor line by immunoaffinity chromatography, and the associated peptides were eluted in acid and separated by reversed-phase high-performance liquid chromatography. Reconstitution of the CTL epitope was evaluated by adding these peptides to autologous Epstein-Barr virus-transformed B-cells. Two peaks of reconstituting activity were observed, suggesting that these CTLs recognize at least two Aw68-associated peptides. This study confirms the existence of a CTL response against autologous human squamous cell cancer of the lung and suggests that this CTL response is directed against peptide epitopes presented by the class I major histocompatibility complex molecules. It is anticipated that this approach will permit identification of peptide epitopes for lung cancer-specific CTLs.


Protocol For An Adjuvant Alpha-Fetoprotein-Derived Peptide After Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma: Safety Study.
Hepatocellular carcinoma (HCC) is a worldwide health concern because of a continued increase in cases globally; furthermore, the prognosis for patients with HCC remains poor. Transarterial chemoembolization (TACE) has been established as the standard of care for the intermediate stage of HCC; however, no therapeutic agents are available to reduce the high rate of recurrence. This study aims to evaluate the safety of alpha-fetoprotein (AFP)-derived peptides for patients with HCC post-TACE. This will be an open-label, single-arm, multicenter study to evaluate the safety of AFP-derived peptides (AFP 357 and AFP 403), which contain histocompatibility antigen-A24-restricted cytotoxic T lymphocyte epitopes from tumor antigens expressed in HCC and is recognized at a high rate by lymphocytes in patients with HCC. Protocol treatment will consist of six courses of the subcutaneous administration of 3 mg each of AFP 357 and AFP 403. A total of 14 patients will be included in this study, the first 6 as a main analysis target group and an additional 8 as an extended cohort from three institutions in Japan. The primary endpoint will be the occurrence of serious adverse events (safety profile). The secondary endpoints will include time to progression, overall survival, completion rate, and adverse events (efficacy profile). We have recruited 14 patients with HCC as of December 2019. The final follow-up will be completed by March 2020. In this study, we will evaluate the safety profile of AFP-derived peptides for patients with HCC post-TACE. We believe that this study will provide useful information and will help to design a subsequent phase II trial based on the results. Japan Registry of Clinical Trials jRCTs041180155; https://jrct.niph.go.jp/latest-detail/jRCTs041180155. DERR1-10.2196/17082.


Analysis of Reported Health Care Use by Sexual Orientation Among Youth.
In the United States, adolescents who are lesbian, gay, or bisexual (LGB) face disparities across physical and mental health outcomes compared with non-LGB youth, yet few studies have looked at patterns of health care utilization by sexual orientation. To compare health care utilization indicators for LGB and non-LGB youth. This cohort study analyzed wave 3 data from Healthy Passages, a longitudinal observational study of diverse public school students in Birmingham, Alabama; Houston, Texas; and Los Angeles County, California. Multivariable logistic regression models tested sexual-orientation differences in the past 12-month health care utilization measures, controlling for youth age, gender, race and ethnicity, household education, income, and marital status. Data collection began in 2010 when students were in the 5th grade (mean [SE] age, 11.13 [0.01] years) (wave 1) and continued 2 years later (wave 2, 7th grade) and 5 years later (wave 3, 10th grade). Permission to be contacted was provided for 6663 children, and 5147 (77%) participated in audio computer-assisted self-administered interviews. This study included 4256 youth (640 LGB, 3616 non-LGB) who completed interviews at wave 1 and wave 3 and answered key items used in this analysis. Analyses were completed in June 2021. Sexual orientation (LGB vs non-LGB). Health care utilization and communication difficulty with a physician in the past 12 months. Among 4256 youths included in the study at baseline in 5th grade (wave 1), 2171 (48.9%) were female; 1502 (44.5%) were Hispanic or Latino; 1479 (28.9%) were Black; the mean (SE) age was 11.19 (0.03) years; and 640 (14.5%) were LGB at wave 3. Compared with non-LGB youth, a higher proportion of LGB youth reported not receiving needed medical care in the last 12 months (adjusted odds ratio [aOR], 1.68; 95% CI,1.38-2.05), most commonly for sexually transmitted infections, contraception, and substance use. LGB youth more frequently reported difficulty communicating with their physician (aOR, 1.71; 95% CI, 1.27-2.30) than non-LGB youth. This study's results found that health care utilization differs by sexual orientation for youth. These findings suggest that clinician training is needed to address the health care needs of LGB youth. Routinely capturing sexual orientation data might enable tracking of health care utilization indicators for LGB youth.


Do Polymicrobial Intra-Abdominal Infections Have Worse Outcomes than Monomicrobial Intra-Abdominal Infections?
Numerous studies have demonstrated microorganism interaction through signaling molecules, some of which are recognized by other bacterial species. This interspecies synergy can prove detrimental to the human host in polymicrobial infections. We hypothesized that polymicrobial intra-abdominal infections (IAI) have worse outcomes than monomicrobial infections. Data from the Study to Optimize Peritoneal Infection Therapy (STOP-IT), a prospective, multicenter, randomized controlled trial, were reviewed for all occurrences of IAI having culture results available. Patients in STOP-IT had been randomized to receive four days of antibiotics vs. antibiotics until two days after clinical symptom resolution. Patients with polymicrobial and monomicrobial infections were compared by univariable analysis using the Wilcoxon rank sum, χ(2), and Fisher exact tests. Culture results were available for 336 of 518 patients (65%). The durations of antibiotic therapy in polymicrobial (n = 225) and monomicrobial IAI (n = 111) were equal (p = 0.78). Univariable analysis demonstrated similar demographics in the two populations. The 37 patients (11%) with inflammatory bowel disease were more likely to have polymicrobial IAI (p = 0.05). Polymicrobial infections were not associated with a higher risk of surgical site infection, recurrent IAI, or death. Contrary to our hypothesis, polymicrobial IAI do not have worse outcomes than monomicrobial infections. These results suggest polymicrobial IAI can be treated the same as monomicrobial IAI.


The association between health risk behaviors and sexual orientation among a school-based sample of adolescents.
This study is one of the first to examine the association between sexual orientation and health risk behaviors among a representative, school-based sample of adolescents. This study was conducted on an anonymous, representative sample of 4159 9th- to 12th-grade students in public high schools from Massachusetts' expanded Centers for Disease Control and Prevention 1995 Youth Risk Behavior Survey. Sexual orientation was determined by the following question: "Which of the following best describes you?" A total of 104 students self-identified as gay, lesbian, or bisexual (GLB), representing 2.5% of the overall population. Of GLB youth, 66.7% were male and 70% were white (not Hispanic). Health risk and problem behaviors were analyzed comparing GLB youth and their peers. Those variables found to be significantly associated with GLB youth were then analyzed by multiple logistic regression models. GLB youth were more likely than their peers to have been victimized and threatened and to have been engaged in a variety of risk behaviors including suicidal ideation and attempts, multiple substance use, and sexual risk behaviors. Four separate logistic regression models were constructed. Model I, Onset of Behaviors Before Age 13, showed use of cocaine before age 13 years as strongly associated with GLB orientation (odds ratio [OR]: 6.10; 95% confidence interval [CI] = 2.45-15.20). Early initiation of sexual intercourse (2.15; 10.6-4.38), marijuana use (1.98; 1.04-4.09), and alcohol use (1.82; 1.03-3.23) also was associated with GLB orientation. Model II, Lifetime Frequencies of Behaviors, showed that frequency of crack cocaine use (1.38; 1.06-1.79), inhalant use (1.30; 1.05-1.61), and number of sexual partners (1.27; 1.06-1.43) was associated with GLB orientation. Model III, Frequency of Recent Behaviors, showed smokeless tobacco use in the past 30 days (1.38; 1. 20-1.59) and number of sexual partners in the previous 3 months (1. 47; 1.31-1.65) were associated with GLB orientation. Model IV, Frequency of Behaviors at School, showed having one's property stolen or deliberately damaged (1.23; 1.08-1.40) and using marijuana (1.29; 1.05-1.59) and smokeless tobacco (1.53; 1.30-1.81) were associated with GLB orientation. Overall, GLB respondents engaged disproportionately in multiple risk behaviors, reporting an increased mean number of risk behaviors (mean = 6.81 +/- 4.49) compared with the overall student population (mean = 3.45 +/- 3.15). GLB youth who self-identify during high school report disproportionate risk for a variety of health risk and problem behaviors, including suicide, victimization, sexual risk behaviors, and multiple substance use. In addition, these youth are more likely to report engaging in multiple risk behaviors and initiating risk behaviors at an earlier age than are their peers. These findings suggest that educational efforts, prevention programs, and health services must be designed to address the unique needs of GLB youth.


Increased Inflammatory Markers Detected in Nasal Lavage Correlate with Paranasal Sinus Abnormalities at MRI in Adolescent Patients with Cystic Fibrosis.
Chronic rhinosinusitis (CRS) is a characteristic feature of cystic fibrosis (CF) multiorgan disease and develops early in the life of patients with CF. The study aimed to correlate the inflammatory markers and the presence of structural abnormalities detected by MRI in the paranasal sinuses of patients with CF. Methods: Nasal lavage and MRI of the paranasal sinuses was performed in a cohort of 30 CF patients (median age 14 y; range 7-20 y). Morphological abnormalities characteristic of CF were evaluated with a dedicated CRS MRI scoring system and correlated with different inflammation parameters measured in nasal lavage. Inflammation of the paranasal sinuses was positively associated with structural abnormalities in MRI. The concentration of the pro-inflammatory markers neutrophil elastase (NE) and the neutrophil elastase/alpha1-antitrypsin (NE/A1AT) complex correlated significantly with CRS-MRI sum score (p < 0.05, r = 0.416 and p < 0.05, r = 0.366, respectively). S. aureus infection was associated with the increased pro-inflammatory cytokine activity of IL-6 and IL-8, and increased levels of NE/A1AT complex in our patients (p < 0.05, respectively). CRS-MRI sum score and individual sinus MRI scores were positively associated with inflammatory activity as a sign of CRS pathology present in CF.


COVARIANCE ASSISTED SCREENING AND ESTIMATION.
Consider a linear model Y = X β + z, where X = Xn,p and z ~ N(0, In ). The vector β is unknown and it is of interest to separate its nonzero coordinates from the zero ones (i.e., variable selection). Motivated by examples in long-memory time series (Fan and Yao, 2003) and the change-point problem (Bhattacharya, 1994), we are primarily interested in the case where the Gram matrix G = X'X is non-sparse but sparsifiable by a finite order linear filter. We focus on the regime where signals are both rare and weak so that successful variable selection is very challenging but is still possible. We approach this problem by a new procedure called the Covariance Assisted Screening and Estimation (CASE). CASE first uses a linear filtering to reduce the original setting to a new regression model where the corresponding Gram (covariance) matrix is sparse. The new covariance matrix induces a sparse graph, which guides us to conduct multivariate screening without visiting all the submodels. By interacting with the signal sparsity, the graph enables us to decompose the original problem into many separated small-size subproblems (if only we know where they are!). Linear filtering also induces a so-called problem of information leakage, which can be overcome by the newly introduced patching technique. Together, these give rise to CASE, which is a two-stage Screen and Clean (Fan and Song, 2010; Wasserman and Roeder, 2009) procedure, where we first identify candidates of these submodels by patching and screening, and then re-examine each candidate to remove false positives. For any procedure β̂ for variable selection, we measure the performance by the minimax Hamming distance between the sign vectors of β̂ and β. We show that in a broad class of situations where the Gram matrix is non-sparse but sparsifiable, CASE achieves the optimal rate of convergence. The results are successfully applied to long-memory time series and the change-point model.


[Study of mortality due to myocardial infarction and alcoholism on the basis of the WHO MONICA and Acute Myocardial Infarction Registry programs].
To study trends of mortality due to alcoholism (A) and cardiovascular diseases (CVD) in Novosibirsk in 1981 to 1998. The WHO MONICA and Acute Myocardial Infarction Register programmes were used to survey the population of 3 Novosibirsk districts. There were notified 9016 cases of nonviolent death, by exclusing another pathology, with the exception of CVD and alcoholic intoxication. Mortality rates due to myocardial infarction (MI) were relatively stable throughout the observation period, except for 1988, 1994, and 1998 (a significant increase). Those due to A showed the following trend: stabilization in 1981-1982, a significant increase in 1983-1987, stabilization in 1988-1991, a significant increase in 1992-1994, and a decrease in 1995-1998. Mortality rate from MI were 2-3 times greater than that from A, with the exception of 1994-1995 when they were equal, i.e. the trends of mortality from MI and A did not coincide. Social stress is a factor that greatly influences MI death rates, mainly due to prehospital mortality. As social stress increases, younger age groups, both males and females, are afflicted, which is extremely hazardous for the population. By taking into account the mortality trends, it may be stated that A hardly affects death rates from MI. In the pattern of mortality from CVD, death rates from MI and A were 50-70% in males and 35-60% and females; those from MI were 35-55 and 30-45%, respectively. The increase in alcoholism mortality is associated with the population's addictive behavior in the period of social upheavals in the community. According to official statistics, the mortality trends do not reflect the actual state of things. This may be done only by stringently standardized programmes with their schemes of data collection and diagnosis verification. The WHO MONICA and Acute Myocardial Infarction programmes belong to such programmes.


Determination of Rifampin Concentrations by Urine Colorimetry and Mobile Phone Readout for Personalized Dosing in Tuberculosis Treatment.
Individual pharmacokinetic variability is a driver of poor tuberculosis (TB) treatment outcomes. We developed a method for measurement of rifampin concentrations by urine colorimetry and a mobile phone photographic application to predict clinically important serum rifampin pharmacokinetic measurements in children treated for TB. Among spiked urine samples, colorimetric assay performance was tested with conventional spectrophotometric and the mobile phone/light box methods under various environmental and biologic conditions. Urine rifampin absorbance (Abs) was then determined from timed specimens from children treated for TB in Tanzania, and compared to serum pharmacokinetic measurements collected throughout the dosing interval. Both the mobile phone/light box and spectrophotometry demonstrated excellent correlation across a wide range of urine rifampin concentrations (7.8-1000 mg/L) in intra- and interday trials, 24-hour exposure to ambient light or darkness, and varying urinalysis profiles (all r ≥ 0.98). In 12 Tanzanian children, the urine mobile phone/light box measurement and serum peak concentration (Cmax) were significantly correlated (P = .004). Using a Cmax target of 8 mg/L, the area under the receiver operating characteristic curve was 80.1% (range, 47.2%-100%). A urine mobile phone/light box threshold of 50 Abs correctly classified all patients (n = 6) with serum measurements below target. The urine colorimetry with mobile phone/light box assay accurately measured rifampin absorbance in varying environmental and biological conditions that may be observed clinically. Among children treated for TB, the assay was sensitive for detection of low rifampin serum concentrations. Future work will identify the optimal timing for urine collection, and operationalize use in TB-endemic settings.


Occupational injuries in workers of a Spanish bank.
In 2017, 69 108 work-related traffic injuries with medical leave were documented, constituting 12% of all occupational injuries (OI) in Spain. The aim of this study was to describe OI within a Spanish bank company during 2017. A cross-sectional analysis was conducted using the company's mandatory OI records, presenting data in both absolute (n) and relative (%) frequencies. The chi-square test was employed for comparisons. Among the company's 10 399 employees, 176 OI cases were recorded. Most were minor musculoskeletal incidents, with one severe myocardial infarction and one mild anxiety episode. Lower limb injuries were the most prevalent. Injuries of the trunk (P < 0.001), neck (P < 0.05), and upper limbs (P < 0.001) were linked to workplace factors. Approximately 62% of OI occurred outside the workplace and resulted in more extended medical leave (P < 0.01). Traffic-related injuries accounted for 39% of OI cases and caused 49% of days lost due to OI (P < 0.001).Female gender (P < 0.001) and age over 40 years (P < 0.05) were significantly associated with OI. In our study, musculoskeletal injuries were the most common, with a single cardiovascular event being the most severe. OI occurring outside the workplace was more frequent and led to longer medical leaves. Notably, traffic-related injuries were especially significant, exceeding official statistics 4-fold.


Characterization of semiconductor-laser phase noise and estimation of bit-error rate performance with low-speed offline digital coherent receivers.
We develop a systematic method for characterizing semiconductor-laser phase noise, using a low-speed offline digital coherent receiver. The field spectrum, the FM-noise spectrum, and the phase-error variance measured with such a receiver can completely describe phase-noise characteristics of lasers under test. The sampling rate of the digital coherent receiver should be much higher than the phase-fluctuation speed. However, 1 GS/s is large enough for most of the single-mode semiconductor lasers. In addition to such phase-noise characterization, interpolating the taken data at 1.25 GS/s to form a data stream at 10 GS/s, we can predict the bit-error rate (BER) performance of multi-level modulated optical signals at 10 Gsymbol/s. The BER degradation due to the phase noise is well explained by the result of the phase-noise measurements.


The Canadian Study of Health and Aging: risk factors for Alzheimer's disease in Canada.
To study risk factors for Alzheimer's disease (AD) based on data from the Canadian Study of Health and Aging. Population-based case-control study. Communities and institutions in 10 Canadian provinces. Two hundred fifty-eight cases clinically diagnosed with probable AD, with onset of symptoms within 3 years of diagnosis, and 535 controls, frequency matched on age group, study center, and residence in community or institution, clinically confirmed to be cognitively normal. Odds ratios (ORs) were calculated using unconditional logistic regression for previously hypothesized and potential risk factors for AD. The OR for family history of dementia was significantly elevated (2.62; 95% confidence interval [CI], 1.53 to 4.51) and increased with the number of relatives with dementia. Those with less education were at higher risk of AD, with an OR of 4.00 (95% CI, 2.49 to 6.43) for those with 0 to 6 years, in comparison with those with 10 or more years. Head injury achieved borderline significance. A history of arthritis resulted in a low risk of AD (OR = 0.54; 95% CI, 0.36 to 0.81), as did a history of use of nonsteroidal anti-inflammatory drugs. Initial analyses showed an increased risk of AD for occupational exposure to glues as well as to pesticides and fertilizers; the increased risk was greater in those with less education. This study confirmed a number of previously reported risk factors for AD, but provided little support for others. A new finding was an increased risk for those with occupational exposure to glues as well as pesticides and fertilizers, but this needs further study.


Relationship between organizational structure and creativity in teaching hospitals.
Organization structure and manpower constitute two basic components of anorganization and both are necessary for stablishing an organization. The aim of this survey was to investigate the type of the organization structure (mechanic and organic) from viewpoint of senior and junior managers in Shiraz teaching hospitals and creativity in each of these two structures. In this cross-sectional and descriptive-analytic study, organization structure and organizational creation questionnaires were filled out by hospital managers. According to the statistical consultation and due to limited target population, the entire study population was considered as sample. Thus, the sample size in this study was 84 (12 hospitals and every hospital, n = 7). For data analysis, SPSS 14 was used and Spearman correlation coefficient and t-test were used. RESULTS showed that there is a negative association between centralization and complexity with organizational creation and its dimensions. Also there was a negative association between formalization and 4 organizational creation dimensions: reception change, accepting ambiguity, abet new view and less control outside (p=0.001). The results of this study showed that the creation in hospitals with organic structure is more than that in hospitals with mechanic structure.


Biomarkers for severe eosinophilic asthma.
The last decade has seen the approval of several new biologics for the treatment of severe asthma-targeting specific endotypes and phenotypes. This review will examine how evidence generated from the mepolizumab clinical development program showed that blood eosinophil counts, rather than sputum or tissue eosinophil counts, evolved as a pharmacodynamic and predictive biomarker for the efficacy of treatment with mepolizumab in patients with severe eosinophilic asthma. Based on the available evidence and combined with clinical judgement, a baseline blood eosinophil threshold of 150 cells/μL or greater or a historical blood eosinophil threshold of 300 cells/μL or greater will allow selection of patients with severe eosinophilic asthma who are most likely to achieve clinically significant reductions in the rate of exacerbations with mepolizumab treatment.


A method for topical dosing of invertebrates with pesticide for use in feeding experiments.
The ability to produce large numbers of pesticide-exposed insects (e.g. crickets) is important for feeding studies into the effects of pesticides on key predatory species. House crickets (Acheta domesticus L. 1758) were submersed in serial dilutions of the pesticides, fenitrothion and fipronil, used for the control of locusts in Australia, and then rapidly frozen for residue analysis. Good correlations were found between increasing concentrations of serial pesticide dilutions and the resultant residual concentrations of the parent compounds in crickets, with R2 values of 0.949 (fenitrothion) and 0.946 (fipronil). R2 values for the much less abundant fipronil metabolites were lower 0.858 (sulfone), 0.368 (desulfinyl) and 0.785 (sulfide). This method enables insecticide exposure mimicking the field conditions to be assessed, and can be done immediately prior to an experiment. This ensures locusts remain alive when introduced to the feeding chambers, and enables multiple prey items to be dosed with a known pesticide burden.


An investigation of auditory contagious yawning.
Despite a widespread familiarity with the often compelling urge to yawn after perceiving someone else yawn, an understanding of the neural mechanism underlying contagious yawning remains incomplete. In the present auditory fMRI study, listeners used a 4-point scale to indicate how much they felt like yawning following the presentation of a yawn, breath, or scrambled yawn sound. Not only were yawn sounds given significantly higher ratings, a trait positively correlated with each individual's empathy measure, but relative to control stimuli, random effects analyses revealed enhanced hemodynamic activity in the right posterior inferior frontal gyrus (pIFG) in response to hearing yawns. Moreover, pIFG activity was greatest for yawn stimuli associated with high as opposed to low yawn ratings and for control sounds associated with equally high yawn ratings. These results support a relationship between contagious yawning and empathy and provide evidence for pIFG involvement in contagious yawning. A supplemental figure for this study may be downloaded from http://cabn.psychonomic-journals.org/content/supplemental.


Differential expression pattern of extracellular matrix molecules during chondrogenesis of mesenchymal stem cells from bone marrow and adipose tissue.
Adipose-derived adult stem cells (ADASCs) or bone marrow-derived mesenchymal stem cells (BMSCs) are considered as alternative cell sources for cell-based cartilage repair due to their ability to produce cartilage-specific matrix. This article addresses the differential expression pattern of extracellular matrix (ECM) molecules in BMSCs or ADASCs following chondrogenic differentiation. Human BMSCs or ADASCs were encapsulated in alginate and cultured in TGF-beta1-containing medium for 2 or 3 weeks. Chondrospecific mRNA expression was analyzed and alternative splicing of alpha(1)-procollagen type II mRNA was monitored via reverse transcriptase-polymerase chain reaction (RT-PCR). Corresponding ECM synthesis was demonstrated using immunohistochemistry. After chondroinduction, expression of collagen type II, type X, COMP and aggrecan mRNA was 3-15-fold higher than in ADASCs. The type IIA splicing form of alpha(1)-procollagen type II was expressed in both populations, and the type IIB splicing form was exclusively detected in BMSCs. In response to TGF-beta, collagen type II and X were secreted more strongly by BMSCs than by ADASCs. BMSCs express a more mature phenotype than ADASCs after chondroinduction. TGF-beta1 induces alternative splicing of the alpha(1)-procollagen type II transcript in BMSCs, but not in ADASCs. These findings may direct the development of a cell-specific culture environment either to prevent hypertrophy in BMSCs or to promote chondrogenic maturation in ADASCs.


Oral anticoagulation among atrial fibrillation patients with anaemia: an observational cohort study.
To investigate the risk of stroke/thromboembolism (TE) and major bleeding associated with anaemia among patients with atrial fibrillation (AF). Also, to assess the effects of oral anticoagulation (OAC) and time in therapeutic range (TTR) with vitamin K antagonists according to level of haemoglobin (Hb). Through administrative registry databases, we identified all Danish patients diagnosed with AF from 1997 to 2012. We included 18 734 AF patients with recent available data on Hb. Multiple Cox regression analyses were used to estimate hazard ratios and to compute standardized absolute 1-year risks of stroke/TE and major bleeding. Among included patients, 3796 (20%) had mild anaemia (Hb 6.83-7.45 mmol/L for women and Hb 6.83-8.03 mmol/L for men) and 2562 (14%) had moderate/severe anaemia (Hb <6.83 mmol/L). Moderate/severe anaemia was associated with increased risk of major bleeding and 9.1% lower median TTR compared with no anaemia. Use of OAC was associated with reduced risk of stroke/TE among patients without anaemia [standardized absolute 1-year difference -2.5%, 95% confidence interval (CI) -3.8 to -1.7%] or with mild anaemia (-2.3%, 95% CI -2.8 to -1.8%), but not with moderate/severe anaemia, (0.03%, -1.8 to +2.8%, interaction P = 0.01). Oral anticoagulation was associated with a 5.3% (95% CI 2.1-8.7%) increased standardized absolute risk of major bleeding among AF patients with moderate/severe anaemia. Anaemia was common in patients with AF and associated with major bleeding and lower TTR. Oral anticoagulation was associated with more major bleeding, but no reduction in risk of stroke/TE among AF patients with moderate/severe anaemia.


Predicting Survival After Irradiation of Metastases from Transitional Carcinoma of the Bladder.
For patients with metastatic bladder cancer, radiotherapy is a good option to control symptoms and improve outcomes. Potential prognostic factors for survival including the radiation dose were investigated. Ten factors were evaluated in 63 patients for association with survival after irradiation namely age, gender, performance status, initial T-category, initial N-category, metastases at initial diagnosis, number of metastases, metastatic sites, radiation dose and time from diagnosis of metastases to irradiation. On univariate analysis, survival was negatively associated with Karnofsky performance score (KPS) ≤70 (p=0.033), initial N-category ≥1 (p=0.026) and radiation doses given as equivalent dose in 2-Gy fractions (EQD2) <20 Gy. Doses >30 Gy were slightly superior to 20-30 Gy. On multivariate analysis, EQD2 (p=0.015) maintained its significance; a trend was found for N-category (p=0.063) and KPS (p=0.073). Predictors for survival after irradiation of metastases from bladder cancer were identified. Radiation doses ≥20 Gy should be used.


Guidelines for the Management of a Pregnant Trauma Patient.
Physical trauma affects 1 in 12 pregnant women and has a major impact on maternal mortality and morbidity and on pregnancy outcome. A multidisciplinary approach is warranted to optimize outcome for both the mother and her fetus. The aim of this document is to provide the obstetric care provider with an evidence-based systematic approach to the pregnant trauma patient. Significant health and economic outcomes considered in comparing alternative practices. Published literature was retrieved through searches of Medline, CINAHL, and The Cochrane Library from October 2007 to September 2013 using appropriate controlled vocabulary (e.g., pregnancy, Cesarean section, hypotension, domestic violence, shock) and key words (e.g., trauma, perimortem Cesarean, Kleihauer-Betke, supine hypotension, electrical shock). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English between January 1968 and September 2013. Searches were updated on a regular basis and incorporated in the guideline to February 2014. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). This guideline is expected to facilitate optimal and uniform care for pregnancies complicated by trauma. Summary Statement Specific traumatic injuries At this time, there is insufficient evidence to support the practice of disabling air bags for pregnant women. (III) Recommendations Primary survey 1. Every female of reproductive age with significant injuries should be considered pregnant until proven otherwise by a definitive pregnancy test or ultrasound scan. (III-C) 2. A nasogastric tube should be inserted in a semiconscious or unconscious injured pregnant woman to prevent aspiration of acidic gastric content. (III-C) 3. Oxygen supplementation should be given to maintain maternal oxygen saturation > 95% to ensure adequate fetal oxygenation. (II-1B) 4. If needed, a thoracostomy tube should be inserted in an injured pregnant woman 1 or 2 intercostal spaces higher than usual. (III-C) 5. Two large bore (14 to 16 gauge) intravenous lines should be placed in a seriously injured pregnant woman. (III-C) 6. Because of their adverse effect on uteroplacental perfusion, vasopressors in pregnant women should be used only for intractable hypotension that is unresponsive to fluid resuscitation. (II-3B) 7. After mid-pregnancy, the gravid uterus should be moved off the inferior vena cava to increase venous return and cardiac output in the acutely injured pregnant woman. This may be achieved by manual displacement of the uterus or left lateral tilt. Care should be taken to secure the spinal cord when using left lateral tilt. (II-1B) 8. To avoid rhesus D (Rh) alloimmunization in Rh-negative mothers, O-negative blood should be transfused when needed until cross-matched blood becomes available. (I-A) 9. The abdominal portion of military anti-shock trousers should not be inflated on a pregnant woman because this may reduce placental perfusion. (II-3B) Transfer to health care facility 10. Transfer or transport to a maternity facility (triage of a labour and delivery unit) is advocated when injuries are neither life- nor limb-threatening and the fetus is viable (≥ 23 weeks), and to the emergency room when the fetus is under 23 weeks' gestational age or considered to be non-viable. When the injury is major, the patient should be transferred or transported to the trauma unit or emergency room, regardless of gestational age. (III-B) 11. When the severity of injury is undetermined or when the gestational age is uncertain, the patient should be evaluated in the trauma unit or emergency room to rule out major injuries. (III-C) Evaluation of a pregnant trauma patient in the emergency room 12. In cases of major trauma, the assessment, stabilization, and care of the pregnant women is the first priority; then, if the fetus is viable (≥ 23 weeks), fetal heart rate auscultation and fetal monitoring can be initiated and an obstetrical consultation obtained as soon as feasible. (II-3B) 13. In pregnant women with a viable fetus (≥ 23 weeks) and suspected uterine contractions, placental abruption, or traumatic uterine rupture, urgent obstetrical consultation is recommended. (II-3B) 14. In cases of vaginal bleeding at or after 23 weeks, speculum or digital vaginal examination should be deferred until placenta previa is excluded by a prior or current ultrasound scan. (III-C) Adjunctive tests for maternal assessment 15. Radiographic studies indicated for maternal evaluation including abdominal computed tomography should not be deferred or delayed due to concerns regarding fetal exposure to radiation. (II-2B) 16. Use of gadolinium-based contrast agents can be considered when maternal benefit outweighs potential fetal risks. (III-C) 17. In addition to the routine blood tests, a pregnant trauma patient should have a coagulation panel including fibrinogen. (III-C) 18. Focused abdominal sonography for trauma should be considered for detection of intraperitoneal bleeding in pregnant trauma patients. (II-3B) 19. Abdominal computed tomography may be considered as an alternative to diagnostic peritoneal lavage or open lavage when intra-abdominal bleeding is suspected. (III-C) Fetal assessment 20. All pregnant trauma patients with a viable pregnancy (≥ 23 weeks) should undergo electronic fetal monitoring for at least 4 hours. (II-3B) 21. Pregnant trauma patients (≥ 23 weeks) with adverse factors including uterine tenderness, significant abdominal pain, vaginal bleeding, sustained contractions (> 1/10 min), rupture of the membranes, atypical or abnormal fetal heart rate pattern, high risk mechanism of injury, or serum fibrinogen < 200 mg/dL should be admitted for observation for 24 hours. (III-B) 22. Anti-D immunoglobulin should be given to all rhesus D-negative pregnant trauma patients. (III-B) 23. In Rh-negative pregnant trauma patients, quantification of maternal-fetal hemorrhage by tests such as Kleihauer-Betke should be done to determine the need for additional doses of anti-D immunoglobulin. (III-B) 24. An urgent obstetrical ultrasound scan should be undertaken when the gestational age is undetermined and need for delivery is anticipated. (III-C) 25. All pregnant trauma patients with a viable pregnancy who are admitted for fetal monitoring for greater than 4 hours should have an obstetrical ultrasound prior to discharge from hospital. (III-C) 26. Fetal well-being should be carefully documented in cases involving violence, especially for legal purposes. (III-C) Obstetrical complications of trauma 27. Management of suspected placental abruption should not be delayed pending confirmation by ultrasonography as ultrasound is not a sensitive tool for its diagnosis. (II-3D) Specific traumatic injuries 28. Tetanus vaccination is safe in pregnancy and should be given when indicated. (II-3B) 29. Every woman who sustains trauma should be questioned specifically about domestic or intimate partner violence. (II-3B) 30. During prenatal visits, the caregiver should emphasize the importance of wearing seatbelts properly at all times. (II-2B) Perimortem Caesarean section 31. A Caesarean section should be performed for viable pregnancies (≥ 23 weeks) no later than 4 minutes (when possible) following maternal cardiac arrest to aid with maternal resuscitation and fetal salvage. (III-B).


[Quality of life assessment in pancreatic carcinoma: results of an European multicentric study].
Quality of life (Qol) assessment is a mandatory endpoint of cancer clinical trials. Little research has been conducted on pancreatic cancer (Pc) and no disease specific Qol questionnaire exists. We report on the development of the European Organization for Research and Treatment of Cancer (EORTC) Pc Qol module to supplement the core cancer module (QLQ-C30). Literature research and qualitative interviews with 6 specialists and 34 patients in the UK were followed by construction of a questionnaire, a peer review by international specialists and EORTC. Administration of the QLQ-C 30, a provisional Pc module and a qualitative debriefing interview was performed on 78 patients in 8 countries stratified into groups by disease stage and treatment intention. Pretesting identified that 23/26 questions had an adequate internal reliability (Cronbach's alpha > 0.7) and construct validity (Pearson's r 0.4-0.6). The median time of completion was 12 mins. Qualitative analysis indicates that the module is easy to complete and cross culturally applicable. The EORTC QLO-PAN 26 includes 26 items covering symptoms, body image, sexuality and the emotional and social consequences of Pc. It is intended for use in patients undergoing clinical trials for pancreatic cancer including surgery, chemotherapy and radiotherapy and will allow the detection of small but clinically meaningful differences in clinical trials for Pc.


Integrative analysis of outer membrane vesicles proteomics and whole-cell transcriptome analysis of eravacycline induced Acinetobacter baumannii strains.
Acinetobacter baumannii is a multidrug-resistant (MDR) hazardous bacterium with very high antimicrobial resistance profiles. Outer membrane vesicles (OMVs) help directly and/or indirectly towards antibiotic resistance in these organisms. The present study aims to look on the proteomic profile of OMV as well as on the bacterial transcriptome upon exposure and induction with eravacycline, a new synthetic fluorocycline. RNA sequencing analysis of whole-cell and LC-MS/MS proteomic profiling of OMV proteome abundance were done to identify the differential expression among the eravacycline-induced A. baumannii ATCC 19606 and A. baumannii clinical strain JU0126. The differentially expressed genes from the RNA sequencing were analysed using R package and bioinformatics software and tools. Genes encoding drug efflux and membrane transport were upregulated among the DEGs from both ATCC 19606 and JU0126 strains. As evident with the induction of eravacycline resistance, ribosomal proteins were upregulated in both the strains in the transcriptome profiles and also resistance pumps, such as MFS, RND, MATE and ABC transporters. High expression of stress and survival proteins were predominant in the OMVs proteome with ribosomal proteins, chaperons, OMPs OmpA, Omp38 upregulated in ATCC 19606 strain and ribosomal proteins, toluene tolerance protein, siderophore receptor and peptidases in the JU0126 strain. The induction of resistance to eravacycline was supported by the presence of upregulation of ribosomal proteins, resistance-conferring factors and stress proteins in both the strains of A. baumannii ATCC 19606 and JU0126, with the whole-cell gene transcriptome towards both resistance and stress genes while the OMVs proteome enriched more with survival proteins. The induction of resistance to eravacycline in the strains were evident with the increased expression of ribosomal and transcription related genes/proteins. Apart from this resistance-conferring efflux pumps, outer membrane proteins and stress-related proteins were also an essential part of the upregulated DEGs. However, the expression profiles of OMVs proteome in the study was independent with respect to the whole-cell RNA expression profiles with low to no correlation. This indicates the possible role of OMVs to be more of back-up additional protection to the existing bacterial cell defence during the antibacterial stress.


Exercise order in resistance training.
Resistance training (RT) is now an integral component of a well rounded exercise programme. For a correct training prescription, it is of the utmost importance to understand the interaction among training variables, such as the load, volume, rest interval between sets and exercises, frequency of sessions, exercise modality, repetition velocity and, finally, exercise order. Sports medicine research has indicated that exercise order is an important variable that affects both acute responses and chronic adaptations to RT programmes. Therefore, the purpose of this review was to analyse and discuss exercise order with relevance to acute responses (e.g. repetition performance) and also the expression of chronic adaptable characteristics (e.g. maximal strength and hypertrophy). To accomplish this purpose, the Scielo, Science Citation Index, National Library of Medicine, MEDLINE, Scopus, SPORTDiscus™ and CINAHL® databases were accessed to locate previously conducted original scientific investigations. The studies reviewed examined both acute responses and chronic adaptations with exercise order as the experimental variable. Generally, with relevance to acute responses, a key finding was that exercise order affects repetition performance over multiple sets, indicating that the total repetitions, and thus the volume, is greater when an exercise is placed at the beginning of an RT session, regardless of the relative amount of muscle mass involved. The pre-exhaustion method might not be an effective technique to increase the extent of neuromuscular recruitment for larger muscle groups (e.g. pectoralis major for the bench press) when preceded by a single-joint movement (e.g. pec-deck fly). With relevance to localized muscular endurance performance, oxygen consumption and ratings of perceived exertion, the limited amount of research conducted thus far indicates that exercise order does not appear to impact the acute expression of these variables. In terms of chronic adaptations, greater strength increases were evident by untrained subjects for the first exercise of a given sequence, while strength increases were inhibited for the last exercise of a given sequence. Additionally, based on strength and hypertrophy (i.e. muscle thickness and volume) effect-size data, the research suggests that exercises be ordered based on priority of importance as dictated by the training goal of a programme, irrespective of whether the exercise involves a relatively large or small muscle group. In summary, exercise order is an important variable that should receive greater attention in RT prescription. When prescribed appropriately with other key prescriptive variables (i.e. load, volume, rest interval between sets and exercises), the exercise order can influence the efficiency, safety and ultimate effectiveness of an RT programme.


The consequences of sample pooling in proteomics: an empirical study.
Pooling of samples in proteomics experiments might help overcome resource constraints when many individuals are analysed. The measured biological variation should be reduced giving increased power to detect treatment differences. Pooling has been advocated in microarray work but there are few tests of its potential in proteomics. In this study, we examine three issues on which the success of the pooling approach might hinge and provide evidence that: (i) the protein expression in a pool matches the mean expression of the individuals making up the pool for the majority of proteins, although for some proteins the pool expression is different; (ii) the biological variance between pools is reduced compared with that between individuals, as predicted in theory, but this reduction is not as large as expected. A practical consequence of this is that power could be reduced; (iii) proteins detectable in individual samples are usually but not always visible when samples are pooled. We conclude that pooling of samples in proteomics work is a valid and potentially valuable procedure but consideration should be given to these issues in experimental design.


Pulmonary hypertension in chronic obstructive pulmonary disease: current theories of pathogenesis and their implications for treatment.
The development of pulmonary hypertension is a poor prognostic sign in patients with chronic obstructive pulmonary disease (COPD), affecting both mortality and quality of life. Although pulmonary hypertension in COPD is traditionally viewed as a result of emphysematous destruction of the vascular bed and/or hypoxia, recent studies indicate that neither of these factors correlates very well with pulmonary artery pressures. New human and animal experimental data are beginning to show that pulmonary hypertension in this setting is probably a result of the direct effect of tobacco smoke on the intrapulmonary vessels with abnormal production of mediators that control vasoconstriction, vasodilatation, and vascular cell proliferation, ultimately leading to aberrant vascular remodelling and aberrant vascular physiology. These changes are in many ways similar to those seen in other forms of pulmonary hypertension and suggest that the treatments used for primary pulmonary hypertension may be beneficial in patients with COPD.


Injury-induced suppression of effector T cell immunity requires CD1d-positive APCs and CD1d-restricted NKT cells.
Overwhelming infection remains the leading cause of death from serious burn injury despite recent advances in the care of burn patients and a better understanding of immune and inflammatory consequences of injury. In this study, we report a critical requirement for CD1d-restricted NKT cells and CD1d expression by APCs in the immune dysfunction that occurs early after burn injury. Using a well-established murine scald injury model with BALB/c and BALB/c CD1d knockout mice, we investigated whether peripheral T cell immunity was affected by the presence or absence of CD1d-restricted NKT cells in the early stages after injury. Using Ag-specific delayed-type hypersensitivity, T cell proliferation, and cytokine production as indices of immune responsiveness, we observed that both CD1d expression by APCs and CD1d-restricted NKT cells are required for immune suppression after injury. Via adoptive transfer of splenocytes from injured mice to uninjured recipients, we found injury-induced suppression of immunity to be Ag specific, long lasting, and critically dependent on cell surface expression of CD1d by APCs. Together, our results suggest that the defects in T cell responsiveness that occur subsequent to severe burn injury are not merely the result of global or passive suppression, but instead represent an active form of CD1d/NKT cell-dependent immunologic tolerance.


An isozyme-specific selective system for the recovery of mammalian cells deficient in hepatic alcohol dehydrogenase activity.
A selective system toxic towards mammalian cells expressing the liver-specific isozyme of alcohol dehydrogenase (L-ADH) has been developed. A number of alpha-unsaturated primary and secondary alcohols were assayed for their ability to serve as substrates for rat liver ADH and were screened for cytotoxicity towards L-ADH+ and L-ADH- cells. 1-Propen-3-ol and 1-penten-3-ol were identified as agents showing selective cytotoxicity. Reconstruction experiments demonstrated that 1-propen-3-ol at a concentration of 15 microM could be used to recover L-ADH- clones from mixed populations of L-ADH+ and L-ADH cells. Cells expressing the non-allelic S-ADH isozyme were not killed under these conditions. The selective system defined in this report is thus isozyme-specific.


Vitamin D3 and zinc synergistically induce regulatory T cells and suppress interferon-γ production in mixed lymphocyte culture.
Although vitamin D3 (cholecalciferol) and zinc are known to individually shift the immune response towards tolerance, little is known about the effect of their combined administration. This work contributes to understanding the combined action of zinc and vitamin D3 in different in vitro models for immune reactions. Zinc and vitamin D3 in combination boosted the differentiation into Foxp3+CD4+ T cells (Treg). Vitamin D3 alone reduced the percentage of CD4+T-bet+ T cells (TH1). In mixed lymphocyte culture (MLC), therapeutic concentrations of vitamin D3 and zinc in combination suppressed interferon-γ (IFN-γ) secretion more strongly than the single agent treatment. This effect was also detected for a combination of subtherapeutic concentrations of both vitamin D3 and zinc. Vitamin D3, even at nanomolar concentrations, increased intracellular zinc levels. PBMC (peripheral blood mononuclear cells) of individuals at risk of zinc deficiency responded to vitamin D3 treatment with a higher mRNA expression of Zip13. In PBMC, both agents reduced activation-induced IL-17 secretion. In summary, this study shows, for the first time, a vitamin D3-induced upregulation of CD4+Foxp3+ T cells in MLC. The data propose a model where zinc augments the effect of vitamin D3 in certain therapeutic and subtherapeutic concentrations. Lower concentrations of both vitamin D3 and zinc could be used for effective treatment, thus reducing possible side effects from vitamin D3 and zinc. Vitamin D3 and zinc in combination may be a promising and cheap option to treat dysregulated immune response in various conditions.


Prophage induction by alkylating ethyl methylaminosulfonate.
Treatment of the lysogenic strain M. lysodeikticus 53-40 (N5) with ethyl methylaminosulfonate results in a slight increase in infective center concentration of N5 phages which is only detectable once disturbing cells had been eliminated by lysozyme. After conversion of ethyl methylaminosulfonate with radioactive labelled guanosine at 37 degrees C, N7-ethyl-guanine could be ascertained. Therefore the biological activity of the drug may be due to an ethylation of DNA.


MRI study of brain myelination.
Brain development in infants is characterized by growth and myelination. Myelin is a cell membrane devoid of MRI signal; the MRI images obtained at different stages of myelination result from changes in brain tissue water content, from the multiplication of glial cells which precedes myelination (the so-called myelination gliosis), and from the accumulation of lipid myelin precursors contained in cells. T1-weighted sequences are used for the "premyelination" process and T2-weighted sequences for myelination proper. The development of myelination in the white matter is sequential, precisely determined, identical in all individuals, and it has been well studied by histologists. In vivo, myelination in infants is shown at MRI as the same precise sequence but with some changes in time towards the end. The myelination process takes place at different times and different speeds in different brain regions, and for any given structure the speed of myelination varies in relation to time.


Bindarit, an inhibitor of monocyte chemotactic protein synthesis, protects against bone loss induced by chikungunya virus infection.
The recent global resurgence of arthritogenic alphaviruses, in particular chikungunya virus (CHIKV), highlights an urgent need for the development of therapeutic intervention strategies. While there has been significant progress in defining the pathophysiology of alphaviral disease, relatively little is known about the mechanisms involved in CHIKV-induced arthritis or potential therapeutic options to treat the severe arthritic symptoms associated with infection. Here, we used microcomputed tomographic (μCT) and histomorphometric analyses to provide previously undescribed evidence of reduced bone volume in the proximal tibial epiphysis of CHIKV-infected mice compared to the results for mock controls. This was associated with a significant increase in the receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) ratio in infected murine joints and in the serum of CHIKV patients. The expression levels of the monocyte chemoattractant proteins (MCPs), including MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7, were also highly elevated in joints of CHIKV-infected mice, accompanied by increased cellularity within the bone marrow in tibial epiphysis and ankle joints. Both this effect and CHIKV-induced bone loss were significantly reduced by treatment with the MCP inhibitor bindarit. Collectively, these findings demonstrate a unique role for MCPs in promoting CHIKV-induced osteoclastogenesis and bone loss during disease and suggest that inhibition of MCPs with bindarit may be an effective therapy for patients affected with alphavirus-induced bone loss. Arthritogenic alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), cause worldwide outbreaks of polyarthritis, which can persist in patients for months following infection. Previous studies have shown that host proinflammatory soluble factors are associated with CHIKV disease severity. Furthermore, it is established that chemokine (C-C motif) ligand 2 (CCL2/MCP-1) is important in cellular recruitment and inducing bone-resorbing osteoclast (OC) formation. Here, we show that CHIKV replicates in bone and triggers bone loss by increasing the RANKL/OPG ratio. CHIKV infection results in MCP-induced cellular infiltration in the inflamed joints, and bone loss can be ameliorated by treatment with an MCP-inhibiting drug, bindarit. Taken together, our data reveal a previously undescribed role for MCPs in CHIKV-induced bone loss: one of recruiting monocytes/OC precursors to joint sites and thereby favoring a pro-osteoclastic microenvironment. This suggests that bindarit may be an effective treatment for alphavirus-induced bone loss and arthritis in humans.


Life and space.
The studies dealing with the detection of life on planets and in space will have two periods. The first period will be associated with the application of automatical devices, which will detect living creatures, whereas the second, more late, period will be concerned with the investigations provided by man himself. In these studies one should proceed from the idea of life on the Earth, and, consequently, look for living creatures containing no water, no carbon dioxide, etc. only after obtaining negative results in searching for creatures similar to those living on the Earth. The whole course of "chemical evolution" on the Earth proves the necessity of the detection on other planets of heterotrophic microorganisms at first, and only afterwards to look for specialized forms, i.e. chemo- and photoautotrophs. It is usually underestimated that as a result of adaptation to certain ecological conditions existing on planets living creatures may appear, which will distinctly differ in their biological properties from terrestrial forms. At present there is no faultless investigation which is able to prove to existence of cosmobionts in meteorites. The appropriate experiments convince us that soil bacteria. may penetrate into the central parts of meteorites, which have been lying in the ground. Samplings at high altitudes with the aid of aerostats or the rockets are difficult to provide because of the possibility of pollution of samples by terrestrial microbes. It is therefore necessary to elaborate special devices and new methods for sampling. The most perfect instrument for the detection of microorganisms will be a device, which will record the multiplication rate of microbes in the liquid media simultaneously by means of different methods: manometry, nephelometry, potentiometry and the determination of radioactive carbon dioxide which is extracted during the breakdown of organic substances.


Hydrogen molecules (H2) improve perfusion recovery via antioxidant effects in experimental peripheral arterial disease.
Reactive oxygen species (ROS) impair neovascularization and perfusion recovery following limb ischemia in patients with peripheral arterial disease (PAD). Hydrogen molecules (H2) comprise an antioxidant gas that has been reported to neutralize cytotoxic ROS. The present study investigated whether H2 may serve as a novel therapeutic strategy for PAD. H2‑saturated water or dehydrogenized water was supplied to mice with experimental PAD. Laser Doppler perfusion imaging demonstrated that H2‑saturated water improved perfusion recovery, decreased the rate of necrosis, increased the capillary density in the gastrocnemius muscle and increased the artery density in the abductor muscle in the ischemic limbs, at 14 and 21 days post‑hindlimb ischemia. Ischemic muscle tissue was harvested 7 days after experimental PAD for biochemical testing and H2 was observed to reduce the levels of malondialdehyde and increase the levels of cyclic guanine monophosphate (cGMP). In cultured endothelial cells, H2‑saturated culture medium resulted in reduced ROS levels, increased tube formation and increased cGMP levels. In macrophages, H2 decreased cellular ROS levels and promoted M2 polarization. H2‑saturated water increases angiogenesis and arteriogenesis and subsequently improves perfusion recovery in a mouse PAD model via reduction of ROS levels.


Transcriptional reprogramming and phenotypic switching associated with the adaptation of Lactobacillus plantarum C2 to plant niches.
Lactobacillus plantarum has been isolated from a large variety of ecological niches, thus highlighting its remarkable environmental adaptability as a generalist. Plant fermentation conditions markedly affect the functional features of L. plantarum strains. We investigated the plant niche-specific traits of L. plantarum through whole-transcriptome and phenotypic microarray profiles. Carrot (CJ) and pineapple (PJ) juices were chosen as model systems, and MRS broth was used as a control. A set of 3,122 genes was expressed, and 21 to 31% of genes were differentially expressed depending on the plant niche and cell physiological state. L. plantarum C2 seemed to specifically respond to plant media conditions. When L. plantarum was cultured in CJ, useful pathways were activated, which were aimed to sense the environment, save energy and adopt alternative routes for NAD(+) regeneration. In PJ the acidic environment caused a transcriptional switching, which was network-linked to an acid tolerance response involving carbohydrate flow, amino acid and protein metabolism, pH homeostasis and membrane fluidity. The most prominent phenotypic dissimilarities observed in cells grown in CJ and PJ were related to carbon and nitrogen metabolism, respectively. Summarising, a snapshot of a carrot and pineapple sensing and adaptive regulation model for L. plantarum C2 was proposed.


Soy sterol esters and beta-sitostanol ester as inhibitors of cholesterol absorption in human small bowel.
Plant sterols are natural dietary components with serum cholesterol-lowering properties. The lowering of serum cholesterol by plant sterols is believed to be the result of an inhibition of cholesterol absorption in the small bowel, although increased bile acid excretion has also been suggested. The difference in effect of saturated and unsaturated plant sterols on cholesterol absorption needs to be elucidated further. The primary aim of this study was to measure small-bowel cholesterol absorption and sterol excretion in addition to hepatic cholesterol synthesis after intake of soy sterol esters and beta-sitostanol ester corresponding to 1.5 g plant sterols/d. Seven ileostomy subjects were studied during a control period and 2 intervention periods when either soy sterol esters or beta-sitostanol ester was added to a basal diet. Ileostomy bags were collected every other hour and frozen immediately for analysis of nutrients and sterols. Cholesterol absorption was 56% (43-65%) in the control period and decreased to 38% (32-46%) in the soy sterol ester period (P = 0.00) and to 39% (30-48%) in the beta-sitostanol ester period (P = 0.00). Esterified soy sterols and beta-sitostanol inhibited cholesterol absorption equally, despite the different structures of the plant sterols.


The Care and Management of Children and Young People with Ataxia Telangiectasia Provided by Nurses and Allied Health Professionals: a Scoping Review.
Ataxia telangiectasia (A-T) is a rare, multisystem progressive condition that typically presents in early childhood. In the absence of cure, people with A-T require coordinated multidisciplinary care to manage their complex array of needs and to minimize the disease burden. Although symptom management has proven benefits for this population, including improved quality of life and reduced complications, there is a need for guidance specific to the nursing and allied healthcare teams who provide care within the community. A scoping review, adopting the Joanna Briggs Institute methodology, was undertaken. It aimed to identify and map the available expertise from nursing and allied healthcare and management of children and young people with A-T ≤ 18 years of age. A rigorous search strategy was employed which generated a total of 21,118 sources of evidence, of which 50 were selected for review following screening by experts. A range of interventions were identified that reported a positive impact on A-T-related impairments, together with quality of life, indicating that outcomes can be improved for this population. Most notable interventions specific to A-T include therapeutic exercise, inspiratory muscle training, and early nutritional assessment and intervention. Further research will be required to determine the full potential of the identified interventions, including translatability to the A-T setting for evidence related to other forms of ataxia. Large gaps exist in the nursing and allied health evidence-base, highlighting a need for robust research that includes children and young people with A-T and their families to better inform and optimize management strategies.


SPRR3 Contributes to Aggressiveness of Pancreatic Cancer Cells via NF-κB Signaling Pathway.
Pancreatic cancer remains a deadly solid tumor with worst survival, and a better understanding of the mechanisms of carcinogenesis of pancreatic cancer is critical to promote the survival of patients with pancreatic cancer. qPCR and western blot assay were used to determine the expression of SPRR3 in pancreatic cancer. Anchorage-independent growth ability, BrdU labeling, Transwell assay, and in vivo experiment were used to examine the functions of SPRR3 in aggressiveness of pancreatic cancer. Luciferase reporter assay, nucleoplasmic-separation technique, qPCR, and western blot assay were used to investigate the mechanism of SPRR3 regulating aggressiveness of pancreatic cancer. Our results showed that SPRR3 was significantly increased in pancreatic cancer, which resulted in poor survival for patients with pancreatic cancer. Further analysis showed that overexpression of SPRR3 contributed to anchorage-independent growth ability, growth rate, and invasion ability of pancreatic cancer cells. While, knockdown of SPRR3 showed the reverse results. Mechanistically, overexpression of SPRR3 can promote the transcription of NF-κB pathway, nuclear accumulation of p65, and mRNA levels of NF-κB pathway downstream genes. But, knockdown of SPRR3 induced the reverse results. The above findings clarified the important roles of SPRR3 in the progression of pancreatic cancer through NF-κB pathway. And targeting SPRR3 might be an effective strategy to therapy pancreatic cancer.


Exploring preterm birth as a polymicrobial disease: an overview of the uterine microbiome.
Infection is a leading cause of preterm birth (PTB). A focus of many studies over the past decade has been to characterize microorganisms present in the uterine cavity and document any association with negative pregnancy outcome. A range of techniques have been used to achieve this, including microbiological culture and targeted polymerase chain reaction assays, and more recently, microbiome-level analyses involving either conserved, phylogenetically informative genes such as the bacterial 16S rRNA gene or whole shotgun metagenomic sequencing. These studies have contributed vast amounts of data toward characterization of the uterine microbiome, specifically that present in the amniotic fluid, fetal membranes, and placenta. However, an overwhelming emphasis has been placed on the bacterial microbiome, with far less data produced on the viral and fungal/yeast microbiomes. With numerous studies now referring to PTB as a polymicrobial condition, there is the need to investigate the role of viruses and fungi/yeasts in more detail and in particular, look for associations between colonization with these microorganisms and bacteria in the same samples. Although the major pathway by which microorganisms are believed to colonize the uterine cavity is vertical ascension from the vagina, numerous studies are now emerging suggesting hematogenous transfer of oral microbiota to the uterine cavity. Evidence of this has been produced in mouse models and although DNA-based evidence in humans appears convincing in some aspects, use of methodologies that only detect viable cells as opposed to lysed cells and extracellular DNA are needed to clarify this. Such techniques as RNA analyses and viability polymerase chain reaction are likely to play key roles in the clinical translation of future microbiome-based data, particularly in confined environments such as the uterus, as detection of viable cells plays a key role in diagnosis and treatment of infection.


PKU-3: An HCl-Inclusive Aluminoborate for Strecker Reaction Solved by Combining RED and PXRD.
A novel microporous aluminoborate, denoted as PKU-3, was prepared by the boric acid flux method. The structure of PKU-3 was determined by combining the rotation electron diffraction and synchrotron powder X-ray diffraction data with well resolved ordered Cl(-) ions in the channel. Composition and crystal structure analysis showed that there are both proton and chlorine ions in the channels. Part of these protons and chlorine ions can be washed away by basic solutions to activate the open pores. The washed PKU-3 can be used as an efficient catalyst in the Strecker reaction with yields higher than 90%.


British family heart study: its design and method, and prevalence of cardiovascular risk factors.
The aim of this paper is to describe the prevalence of cardiovascular risk factors in families screened systematically by nurses in British general practice, and in subgroups with reported hypertension, hypercholesterolaemia, diabetes and coronary heart disease. Twenty six general practices (13 intervention and 13 control practices) in 13 towns in England, Wales and Scotland were involved in a randomized control trial. Randomly ordered invitations were sent for a family health check to 4158 households (men aged 40-59 years and their partners) registered with the 13 intervention practices. One or more adult members from 2373 households (57%) were screened; in 1477 visits the selected man and his female partner attended of whom 98% were married. In all, 3850 individuals were screened (2246 men and 1604 women); 15% of men and women were in the predefined top quintile of the British family heart study risk score. Twenty four per cent of men and 22% of women smoked cigarettes and 62% of men and 44% of women were overweight (body mass index 25+). One third of men and one sixth of women with no known history of high blood pressure had a diastolic blood pressure of 90+ mmHg. Among the 491 individuals with previously reported high blood pressure 64% were not adequately controlled, having a diastolic blood pressure of 90+ mmHg, while 26% had diastolic blood pressure of 100+ mmHg. Eighteen per cent of men and women with no known history of a high cholesterol level had a random cholesterol level of 6.5+ mmol l-1. In the 173 people with a previously reported high cholesterol level and who had their level measured over half had a cholesterol level of 6.5+ mmol l-1 and in 7% this level was 8.0+ mmol l-1. One per cent of men and 0.3% of women were newly identified as diabetic (random glucose level of 10.0+ mmol l-1). In the 52 with previously diagnosed diabetes unsatisfactory control was found in 52% (random level of 10.0+ mmol l-1). A total of 3034 men and women overall (79%) qualified for follow up for one or more risk factor; 1909 men (85%) and 1125 women (70%). Among the 139 with pre-existing coronary heart disease 119 (86%) had modifiable risk factors: 27% were cigarette smokers, 68% had a body mass index of 25+, 40% had diastolic hypertension, 29% had hypercholesterolaemia and 19% had hyperglycaemia. Five per cent of men and women were taking antihypertensive drugs, 0.3% cholesterol lowering drugs and 0.7% drugs for diabetes. There is considerable scope for primary and secondary prevention among families registered with general practices, but whether nursing and medical intervention can reduce the risk factors related to cardiovascular disease in this setting remains unknown.


[INJECTION OF BOTULINUM TOXIN TYPE A IN THE BLADDER DETRUSOR AND SUBMUCOSA IN PATIENTS WITH OVERACTIVE BLADDER WITHOUT DETRUSOR OVERACTIVITY].
The objective of the study was to compare the efficacy and safety of injections of botulinum toxin type A in the submucosal layer of the bladder and in detrusor in patients who were refractory to anticholinergic therapy of overactive bladder without detrusor overactivity. 100 U botulinum toxin type A was diluted in 10 ml of 0.9% saline and injected with 0.5 ml (5 units) of this solution in 20 points of the bladder (the back and side walls except Letto triangle). In twenty-two patients (the first group) botulinum toxin was injected into the submucosal layer of the bladder, while in 34 patients (second group) - into the detrusor. In the first group after 1 and 3 months 3 (14%) patients and after 6 months 2 (9%) patients had positive treatment outcomes (improvement of symptoms in more than 50%). In 22 (65%) of the 34 patients of the second group positive results were observed at 1 and 3 months and in 17 (50%) - at 6 months. After 9 months, all patients had a relapse of urgent and frequent urination. Difficulties in emptying the bladder were observed in three (9%) of the second group patients who had to resort to periodic self-catheterization for 2-20 weeks. The obtained results allow us to state that the injections of 100 U of botulinum toxin type A in the submucosal layer of the bladder are ineffective in patients with overactive bladder without detrusor overactivity, whereas injections in the detrusor lead to a statistically significant improvement in symptoms of urgent and frequent urination for 6 months.