Validation and comparative assessment of low anterior resection syndrome questionnaires in Greek rectal cancer patients.
Our study validated the low anterior resection syndrome (LARS) score questionnaire, the colorectal functional outcome (COREFO) questionnaire, and the Memorial Sloan-Kettering Cancer Center bowel function instrument (MSKCC-BFI) in Greek rectal cancer patients. Internal consistency, repeatability, construct and discriminant validity were evaluated for LARS, COREFO, and MSKCC-BFI questionnaires. The convergent validity was assessed by correlations with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-CR29 domains. The internal consistency of the questionnaire's subscales was satisfactory (Cronbach's a>0.6). The repeatability test showed extremely high reproducibility (intraclass correlation coefficient >0.9). High positive correlation was detected between the 3 questionnaires' total scores and each of their questions (rho>0.5), indicating their valid construction. All questionnaires demonstrated a good convergent validity through correlations with comparable domains of the EORTC QLQ-C30 and CR29. Statistically significant associations were detected between LARS, COREFO, MSKCC-BFI scores and tumor distance and temporary stoma (P<0.001 and P=0.009, P<0.001 and P=0.005, P<0.001 and P=0.002 respectively). In addition, COREFO and MSKCC-BFI scores were significantly associated with radiation therapy. LARS score was significantly correlated to all COREFO and MSKCC-BFI subscales. The Greek versions of the LARS score, COREFO and MSKCC-BFI questionnaires were proven to have good psychometric properties and can be used as specific and valid instruments for measuring LARS. Since the COREFO and MSKCC-BFI questionnaires, which are more extensive and possibly less applicable in routine clinical practice, showed no advantages in relation to the LARS score, the latter may be established as the simplest, fastest to complete and most targeted tool for assessing LARS.


Targeting SARS-CoV-2 RNA-dependent RNA polymerase: An in silico drug repurposing for COVID-19.
Background: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), took more lives than combined epidemics of SARS, MERS, H1N1, and Ebola. Currently, the prevention and control of spread are the goals in COVID-19 management as there are no specific drugs to cure or vaccines available for prevention. Hence, the drug repurposing was explored by many research groups, and many target proteins have been examined. The major protease (M pro), and RNA-dependent RNA polymerase (RdRp) are two target proteins in SARS-CoV-2 that have been validated and extensively studied for drug development in COVID-19. The RdRp shares a high degree of homology between those of two previously known coronaviruses, SARS-CoV and MERS-CoV. Methods: In this study, the FDA approved library of drugs were docked against the active site of RdRp using Schrodinger's computer-aided drug discovery tools for in silico drug-repurposing. Results: We have shortlisted 14 drugs from the Standard Precision docking and interaction-wise study of drug-binding with the active site on the enzyme. These drugs are antibiotics, NSAIDs, hypolipidemic, coagulant, thrombolytic, and anti-allergics. In molecular dynamics simulations, pitavastatin, ridogrel and rosoxacin displayed superior binding with the active site through ARG555 and divalent magnesium. Conclusion: Pitavastatin, ridogrel and rosoxacin can be further optimized in preclinical and clinical studies to determine their possible role in COVID-19 treatment.


Excitotoxic lesions of the pedunculopontine tegmental nucleus in rats impair performance on a test of sustained attention.
Recent research has suggested that the pontomesencephalic tegmentum might be an important part of a network underlying sustained attention. The largest structure of the pontomesencephalic tegmentum is the pedunculopontine tegmental nucleus, which has ascending connections to thalamus and with corticostriatal systems. In this experiment we examined the performance of rats following bilateral excitotoxic lesions of the pedunculopontine tegmental nucleus on a test of sustained attention previously used to examine frontal cortical function. After an initial period of darkness, the rats had to attend continuously to a dim stimulus light that would, at unpredictable intervals, become transiently brighter. During this period of increased stimulus brightness the rats could press a lever to obtain a food reward. Rats were trained to a criterion level of performance before lesions were made. After surgery, sham lesioned rats (n=7) resumed accurate responding, with an average successful detection rate of approximately 70%. Pedunculopontine lesioned rats (n=7), however, only achieved a successful detection rate of approximately 40%. When the duration of the bright target stimulus was increased from 1.5 to 4 s, the performance of the pedunculopontine lesioned rats significantly improved. The observation that an increase in brightness duration caused a marked improvement in lesioned rats' performance suggests strongly that the impairment was in attention rather than motor ability or simple sensory processing. These data are taken to be consistent with the hypothesis that the pedunculopontine tegmental nucleus is an important part of a network maintaining attention.


Is coronary computed tomography angiography a resource sparing strategy in the risk stratification and evaluation of acute chest pain? Results of a randomized controlled trial.
Annually, almost 6 million U.S. citizens are evaluated for acute chest pain syndromes (ACPSs), and billions of dollars in resources are utilized. A large part of the resource utilization results from precautionary hospitalizations that occur because care providers are unable to exclude the presence of coronary artery disease (CAD) as the underlying cause of ACPSs. The purpose of this study was to examine whether the addition of coronary computerized tomography angiography (CCTA) to the concurrent standard care (SC) during an index emergency department (ED) visit could lower resource utilization when evaluating for the presence of CAD. Sixty participants were assigned randomly to SC or SC + CCTA groups. Participants were interviewed at the index ED visit and at 90 days. Data collected included demographics, perceptions of the value of accessing health care, and clinical outcomes. Resource utilization included services received from both the primary in-network and the primary out-of-network providers. The prospectively defined primary endpoint was the total amount of resources utilized over a 90-day follow-up period when adding CCTA to the SC risk stratification in ACPSs. The mean (± standard deviation [SD]) for total resources utilized at 90 days for in-network plus out-of-network services was less for the participants in the SC + CCTA group ($10,134; SD ±$14,239) versus the SC-only group ($16,579; SD ±$19,148; p = 0.144), as was the median for the SC + CCTA ($4,288) versus SC only ($12,148; p = 0.652; median difference = -$1,291; 95% confidence interval [CI] = -$12,219 to $1,100; p = 0.652). Among the 60 total study patients, only 19 had an established diagnosis of CAD at 90 days. However, 18 (95%) of these diagnosed participants were in the SC + CCTA group. In addition, there were fewer hospital readmissions in the SC + CCTA group (6 of 30 [20%] vs. 16 of 30 [53%]; difference in proportions = -33%; 95% CI = -56% to -10%; p = 0.007). Adding CCTA to the current ED risk stratification of ACPSs resulted in no difference in the quantity of resources utilized, but an increased diagnosis of CAD, and significantly less recidivism and rehospitalization over a 90-day follow-up period.


Early cognitive skills of Mexican-origin children: The roles of parental nativity and legal status.
Although one-third of children of immigrants have undocumented parents, little is known about their early development. Using data from the Los Angeles Family and Neighborhood Survey and decennial census, we assessed how children's cognitive skills at ages 3 to 5 vary by ethnicity, maternal nativity, and maternal legal status. Specifically, Mexican children of undocumented mothers were contrasted with Mexican children of documented mothers and Mexican, white, and black children with U.S.-born mothers. Mexican children of undocumented mothers had lower emergent reading skills than all other groups and lower emergent mathematics skills than all groups with U.S.-born mothers. Multilevel regression models showed that differences in reading skills are explained by aspects of the home environment, but the neighborhood context also matters. Cross-level interactions suggest that immigrant concentration boosts emergent reading and mathematics skills for children with undocumented parents, but does not similarly benefit children whose parents are native born.


Ultra high performance liquid chromatography with mass spectrometry method for the simultaneous determination of phenolic constituents in honey from various floral sources using multiwalled carbon nanotubes as extraction sorbents.
An ultra high performance liquid chromatography with mass spectrometry method has been developed for the simultaneous separation, identification and determination of 22 phenolic constituents in honey from various floral sources from Yemen. Solid-phase extraction was used for extraction of the target phenolic constituents from honey samples, while multiwalled carbon nanotubes were used as solid-phase adsorbent. The chromatographic separation of all phenolic constituents was performed on a BEH C18 column using a linear gradient elution with a binary mobile phase mixture of aqueous 0.1% formic acid and methanol. The quantitation was carried out in selected ion reaction monitoring acquisition mode. The total amount of phenolic acids, flavonoids and other phenols in each analyzed honey was found in the range of 338-3312, 122-5482 and 2.4-1342 μg/100 g of honey, respectively. 4-Hydroxybenzoic acid was found to be the major phenolic acid. The main detected flavonoid was chrysin, while cinnamic acid was found to be the major other phenol compound. The regeneration of solid phase adsorbent to be reused and recovery results confirm that the proposed method could be potentially used for the routine analysis of phenolic constituents in honey extract.


Antibodies to a single, conserved epitope in Anopheles APN1 inhibit universal transmission of Plasmodium falciparum and Plasmodium vivax malaria.
Malaria transmission-blocking vaccines (TBVs) represent a promising approach for the elimination and eradication of this disease. AnAPN1 is a lead TBV candidate that targets a surface antigen on the midgut of the obligate vector of the Plasmodium parasite, the Anopheles mosquito. In this study, we demonstrated that antibodies targeting AnAPN1 block transmission of Plasmodium falciparum and Plasmodium vivax across distantly related anopheline species in countries to which malaria is endemic. Using a biochemical and immunological approach, we determined that the mechanism of action for this phenomenon stems from antibody recognition of a single protective epitope on AnAPN1, which we found to be immunogenic in murine and nonhuman primate models and highly conserved among anophelines. These data indicate that AnAPN1 meets the established target product profile for TBVs and suggest a potential key role for an AnAPN1-based panmalaria TBV in the effort to eradicate malaria.


Resolving plasmid structures in Enterobacteriaceae using the MinION nanopore sequencer: assessment of MinION and MinION/Illumina hybrid data assembly approaches.
This study aimed to assess the feasibility of using the Oxford Nanopore Technologies (ONT) MinION long-read sequencer in reconstructing fully closed plasmid sequences from eight Enterobacteriaceae isolates of six different species with plasmid populations of varying complexity. Species represented were Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens and Klebsiella oxytoca, with plasmid populations ranging from 1-11 plasmids with sizes of 2-330 kb. Isolates were sequenced using Illumina (short-read) and ONT's MinION (long-read) platforms, and compared with fully resolved PacBio (long-read) sequence assemblies for the same isolates. We compared the performance of different assembly approaches including SPAdes, plasmidSPAdes, hybridSPAdes, Canu, Canu+Pilon (canuPilon) and npScarf in recovering the plasmid structures of these isolates by comparing with the gold-standard PacBio reference sequences. Overall, canuPilon provided consistently good quality assemblies both in terms of assembly statistics (N50, number of contigs) and assembly accuracy [presence of single nucleotide polymorphisms (SNPs)/indels with respect to the reference sequence]. For plasmid reconstruction, Canu recovered 70 % of the plasmids in complete contigs, and combining three assembly approaches (Canu or canuPilon, hybridSPAdes and plasmidSPAdes) resulted in a total 78 % recovery rate for all the plasmids. The analysis demonstrated the potential of using MinION sequencing technology to resolve important plasmid structures in Enterobacteriaceae species independent of and in conjunction with Illumina sequencing data. A consensus assembly derived from several assembly approaches could present significant benefit in accurately resolving the greatest number of plasmid structures.


Tuberculosis knowledge and attitude in aspiring doctors and nurses - Is it time for our TB teaching methods to evolve?
India accounts for nearly 24% of all the new tuberculosis (TB) cases globally. A good core knowledge and a positive outlook towards TB patients among our aspiring doctors and nurses are necessities for India to meet the Sustainable Development Goals (SDG) proposed by the WHO as a part of its post-2015 global TB strategy and to successfully combat the newer challenges posed by this disease in the future. To evaluate knowledge related to transmission, prevention and treatment of tuberculosis amongst medical and nursing students. The study also aims to evaluate the attitude of students towards tuberculosis patients. A self-administered pre-tested questionnaire was completed by 200 final year undergraduate medical and nursing students at a teaching medical college hospital. We collected information pertaining to general aspects of TB, its prevention and treatment and also the attitude of these prospective doctors and nurses towards treating/nursing TB patients. Most respondents (98.5%) were aware of the person to person transmission of the disease. 20% thought it could spread by fomites, 6.5% by shaking hands and 17% believed kissing could spread the disease. 72% of those surveyed did not think that healthcare workers were at greater risk of contracting TB. Only 52% of students knew that non-DOTS treatment was associated with a greater probability of patient defaults, development of drug-resistance, chronic disease and deaths. 27% of the students chose a simple surgical mask believing that it could protect them against nosocomial TB. Only 50% of nursing students were aware that the sputum smear examination was the diagnostic test required to label the patient as an 'open' or infectious case. A reluctance to interact with TB patients for fear of personal safety was seen in 28% of both groups. 83% of nursing students and 53% of the medical students were willing to attend to TB patients in isolation wards. 98.5% of the participants believed that TB is a disease that can be prevented, treated and cured. There exists considerable scope for improving knowledge in areas relating to disease transmission and the preventive aspects of TB among our healthcare students. Since the present curriculum was deemed as adequate by the students, newer learning methods may be needed to disseminate any additional knowledge. Healthcare students did not display any prejudice towards TB patients which augurs well for TB control activities in the future.


Estimating drop-out probabilities in forensic DNA samples: a simulation approach to evaluate different models.
Allele drop-out is a well known phenomenon that is primarily caused by the stochastic effects associated with low quantity or low quality DNA samples. Recently, new interpretation models that employ the use of logistic regression have been utilised in order to estimate the probability of drop-out. The model parameters are estimated using profiles from samples of extracted DNA diluted to low template levels in order to induce drop-out. However, we propose that this approach is over-simplistic, because several sources of variability are not taken into account in this generalised model. For example, in real-life, small (discrete) crime-stains are analysed where cells are (or were) intact. The integrity of the paired chromosomes of the diploid cell is preserved. In extracted DNA that is diluted to low template levels, we argue that the paired-chromosome integrity is lost. This directly affects the outcome of the logistic model. To date, current experimentation procedures are more akin to haploid cells and thus, different logistic models are needed for haploid and diploid cells. In order to simplify the methodology to estimate the multiple logistic regressions, we propose the use of a simulation model of the entire process associated with the analysis of STR loci, as a supplement to the purely experimental approach to support the validation of new methods. We illustrate with an evaluation of some features of the logistic model proposed by Gill et al., 2009 [12] and discuss alternative models.


Hematologic abnormalities and acute myeloid leukemia in children and adolescents administered intensified chemotherapy for the Ewing sarcoma family of tumors.
Current treatment of the Ewing sarcoma family of tumors (ESFT) includes intensive multiagent chemotherapy with topoisomerase II inhibitors, alkylating agents, and granulocyte colony-stimulating factor (G-CSF). This treatment approach has been associated with myelodysplasia and acute myeloid leukemia. Because macrocytosis and thrombocytopenia are distinctive features of myelodysplasia, the authors evaluated a cohort of patients treated for ESFT to determine the degree and duration of macrocytosis and thrombocytopenia and their relation with the development of therapy-related hematologic malignancies. The study group consisted of 73 patients with ESFT treated on two consecutive protocols (EW92 and EW87). Both chemotherapy regimens incorporated the same agents but differed in cumulative drug dose, dose per course, and the use of G-CSF. Platelet counts and the mean corpuscular volume (MCV) of erythrocytes were determined at diagnosis and during follow-up visits after completion of treatment. Patients in the EW92 group had significantly greater MCVs after treatment than did the less intensively treated EW87 group. These changes persisted throughout the 40-month observation period. Patients in the EW92 group also had lesser mean platelet counts after treatment than those in the EW87 group. MCV differences (from baseline) were inversely related to platelet counts. The cumulative incidence of treatment-related acute myeloid leukemia was 7.8%+/-4.7% at 4 years in the EW92 group and zero in the EW87 group. Patients treated for ESFT with intensive chemotherapy that includes large doses of alkylators, topoisomerase II inhibitors, and G-CSF characteristically have persistently elevated MCVs and decreased platelet counts after completion of therapy. These hematologic abnormalities may represent stem cell damage, predisposing patients to myelodysplasia and acute myeloid leukemia, but further study is needed to establish this relation.


Endotoxin rapidly desensitizes the gonads to kisspeptin-induced luteinizing hormone release in male Siberian hamsters (Phodopus sungorus).
Activation of the immune system induces rapid reductions in hypothalamic-pituitary-gonadal (HPG) axis activity, which in turn decreases secretion of sex steroids. This response is likely adaptive for survival by temporarily inhibiting reproduction to conserve energy; however, the physiological mechanisms controlling this response remain unclear. The neuropeptide kisspeptin is a candidate to mediate the decrease in sex hormones seen during sickness through its key regulation of the HPG axis. In this study, the effects of acute immune activation on the response to kisspeptin were assessed in male Siberian hamsters (Phodopus sungorus). Specifically, an immune response was induced in animals by a single treatment of lipopolysaccharide (LPS), and reproductive hormone concentrations were determined in response to subsequent injections of exogenous kisspeptin. Saline-treated controls showed a robust increase in circulating testosterone in response to kisspeptin; however, this response was blocked in LPS-treated animals. Circulating luteinizing hormone (LH) levels were elevated in response to kisspeptin in both LPS- and saline-treated groups and, thus, were unaffected by LPS treatment, suggesting gonad-level inhibition of testosterone release despite central HPG activation. In addition, blockade of glucocorticoid receptors by mifepristone did not attenuate the LPS-induced inhibition of testosterone release, suggesting that circulating glucocorticoids do not mediate this phenomenon. Collectively, these findings reveal that acute endotoxin exposure rapidly renders the gonads less sensitive to HPG stimulation, thus effectively inhibiting sex hormone release. More broadly, these results shed light on the effects of immune activation on the HPG axis and help elucidate the mechanisms controlling energy allocation and reproduction.


HER2-specific aptide conjugated magneto-nanoclusters for potential breast cancer imaging and therapy.
Here, we report a nanotheranostic system that enables simultaneous imaging and therapy of HER2-overexpressing tumors. We first screened an aptide-based phage library for HER2-specific peptide ligands, identifying a HER2-specific aptide (APTHER2) phage clone. Chemically synthesized APTHER2 showed high affinity for its target protein (Kd≈ 89 nM) and specifically bound HER2-overexpressing cells (NIH3T6.7) and tumor tissue slices. Next, we prepared HER2-specific-aptide-conjugated magneto-nanoclusters (APTHER2-MNCs) by a rehydration method using oleic acid-stabilized superparamagnetic iron oxide nanoparticles (SPIONs) and amphiphilic phospholipids, yielding nanoparticles with a hydrodynamic diameter of 47 ± 10 nm. The APTHER2-MNCs showed higher transverse (r2) relaxivity (∼180 mM-1 s-1) and greater drug-loading capacity compared to the equivalent isolated SPIONs (∼120 mM-1 s-1). When intravenously injected into HER2-overexpressing NIH3T6.7 tumor-bearing mice, APTHER2-MNCs substantially accumulated in tumor tissue, enhancing the relative signal by ∼45% at 3 h post-injection. This allowed us to detect the tumor using magnetic resonance imaging. Furthermore, after docetaxel loading, the drug-loaded APTHER2-MNCs remarkably inhibited the growth of HER2-overexpressing tumors (∼50% relative to controls) with little apparent toxicity, measured as changes in body weight. Together, these results indicate that APTHER2-MNCs show promise as an efficient nanotheranostic system that enables specific cancer imaging as well as targeted therapy.


Studies of Pediatric Liver Transplantation (SPLIT): a summary of the 2003 Annual Report.
The SPLIT database is accumulating comprehensive data on both pre- and posttransplant outcomes after pediatric liver transplantation. The relatively small numbers of children receiving any solid organ transplant, even at the largest single centers makes it difficult to study outcomes and changing trends from any single center and necessitates the formation of a large multi-center database. SPLIT has designed its data collection specifically to address outcomes relevant to children after liver transplantation such as growth and school performance and which are not collected by any other exisiting database. From the outcome data generated to date, a subset of which is presented above, hypothesis-driven studies can be designed. The first example of such a study was the development of the Pediatric Endstage Liver Disease (PELD) score. This model, which predicts death on the liver transplant waiting list for children with chronic liver disease was developed using data from SPLIT, has been adopted, and subsequently verified within the national cadaveric organ allocation system.


Lung clearance index in adults with non-cystic fibrosis bronchiectasis.
Lung clearance index (LCI) is a measure of abnormal ventilation distribution derived from the multiple breath inert gas washout (MBW) technique. We aimed to determine the clinical utility of LCI in non-CF bronchiectasis, and to assess two novel MBW parameters that distinguish between increases in LCI due to specific ventilation inequality (LCIvent) and increased respiratory dead space (LCIds). Forty-three patients with non-CF bronchiectasis and 18 healthy control subjects underwent MBW using the sulphur hexafluoride wash-in technique, and data from 40 adults with CF were re-analysed. LCIvent and LCIds were calculated using a theoretical two-compartment lung model, and represent the proportional increase in LCI above its ideal value due to specific ventilation inequality and increased respiratory dead space, respectively. LCI was significantly raised in patients with non-CF bronchiectasis compared to healthy controls (9.99 versus 7.28, p < 0.01), and discriminated well between these two groups (area under receiver operating curve = 0.90, versus 0.83 for forced expiratory volume in one second [% predicted]). LCI, LCIvent and LCIds were repeatable (intraclass correlation coefficient > 0.75), and correlated significantly with measures of spirometric airflow obstruction. LCI is repeatable, discriminatory, and is associated with spirometric airflow obstruction in patients with non-CF bronchiectasis. LCIvent and LCIds are a practical and repeatable alternative to phase III slope analysis and may allow a further level of mechanistic information to be extracted from the MBW test in patients with severe ventilation heterogeneity.


CrossQuery: a web tool for easy associative querying of transcriptome data.
Enormous amounts of data are being generated by modern methods such as transcriptome or exome sequencing and microarray profiling. Primary analyses such as quality control, normalization, statistics and mapping are highly complex and need to be performed by specialists. Thereafter, results are handed back to biomedical researchers, who are then confronted with complicated data lists. For rather simple tasks like data filtering, sorting and cross-association there is a need for new tools which can be used by non-specialists. Here, we describe CrossQuery, a web tool that enables straight forward, simple syntax queries to be executed on transcriptome sequencing and microarray datasets. We provide deep-sequencing data sets of stem cell lines derived from the model fish Medaka and microarray data of human endothelial cells. In the example datasets provided, mRNA expression levels, gene, transcript and sample identification numbers, GO-terms and gene descriptions can be freely correlated, filtered and sorted. Queries can be saved for later reuse and results can be exported to standard formats that allow copy-and-paste to all widespread data visualization tools such as Microsoft Excel. CrossQuery enables researchers to quickly and freely work with transcriptome and microarray data sets requiring only minimal computer skills. Furthermore, CrossQuery allows growing association of multiple datasets as long as at least one common point of correlated information, such as transcript identification numbers or GO-terms, is shared between samples. For advanced users, the object-oriented plug-in and event-driven code design of both server-side and client-side scripts allow easy addition of new features, data sources and data types.


Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy.
Daily azithromycin decreases acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but long-term side effects are unknown. To identify the types of exacerbations most likely to be reduced and clinical subgroups most likely to benefit from azithromycin, 250 mg daily, added to usual care. Enrollment criteria included irreversible airflow limitation and AECOPD requiring corticosteroids, emergency department visit, or hospitalization in the prior year or use of supplemental oxygen. Recurrent events and cumulative incidence analyses compared treatment received for AECOPD by randomization group, stratified by subgroups of interest. Cox proportional hazards models estimated treatment effects in subgroups adjusted for age, sex, smoking status, FEV1% predicted, concomitant COPD medications, and oxygen use. Azithromycin was most effective in reducing AECOPD requiring both antibiotic and steroid treatment (n = 1,113; cumulative incidence analysis, P = 0.0002; recurrent events analysis, P = 0.002). No difference in treatment response by sex (P = 0.75), presence of chronic bronchitis (P = 0.19), concomitant inhaled therapy (P = 0.29), or supplemental oxygen use (P = 0.23) was observed. Older age and milder Global Initiative for Chronic Obstructive Lung Disease stage were associated with better treatment response (P = 0.02 and 0.04, respectively). A significant interaction between treatment and current smoking was seen (P = 0.03) and azithromycin did not reduce exacerbations in current smokers (hazard ratio, 0.99; 95% confidence interval, 0.71-1.38; P = 0.95). Azithromycin is most effective in preventing AECOPD requiring both antibiotic and steroid treatment. Adjusting for confounders, we saw no difference in efficacy by sex, history of chronic bronchitis, oxygen use, or concomitant COPD therapy. Greater efficacy was seen in older patients and milder Global Initiative for Chronic Obstructive Lung Disease stages. We found little evidence of treatment effect among current smokers. Clinical trial registered with www.clinicaltrials.gov (NCT0011986 and NCT00325897).


Sensitization of gamma-aminobutyric acid-induced depressions of cerebellar Purkinje neurons to the potentiative effects of ethanol by beta adrenergic mechanisms in rat brain.
We previously reported that both systemic administration and brief local application of ethanol potentiated gamma-aminobutyric acid (GABA)-induced depressions of cerebellar Purkinje neurons when the GABA responses were concomitantly facilitated (modulated) by catecholaminergic agonists. In the present study, we further investigated the effects of prolonged local applications of ethanol, which more closely mimic the systemic application of ethanol, and we characterized the pharmacological specificity of the catecholaminergic interaction with these ethanol effects. As has been previously observed, iontophoretic applications of isoproterenol (ISO), a beta adrenergic agonist, facilitated GABA-induced depressions of cerebellar Purkinje neurons. The prolonged local application of ethanol produced a long-lasting potentiation of the ISO-modulated GABA responses that was similar in duration to that caused by systemic ethanol administration. The ethanol-induced augmentation of the ISO-modulated GABA responses was diminished both by terminating the beta adrenergic agonist application as well as by administering the beta adrenergic antagonist timolol. The alpha adrenergic agonist phenylephrine, on the other hand, either attenuated or had no effects on the GABA-induced depressions of cerebellar Purkinje neurons, and a subsequent application of ethanol did not potentiate GABA responses in the presence of phenylephrine. We conclude that prolonged local application of ethanol mimics the interaction of systemic ethanol with GABA-induced depressions of cerebellar Purkinje neurons. Furthermore, the catecholaminergic sensitization of GABA responses to these potentiative effects of ethanol is mediated by a beta adrenergic mechanism.


Characterising cortical density in the mid-tibia: intra-individual variation in adolescent girls and boys.
Inter-individual differences in cortical bone volumetric density (CoD), such as those related to sex, are a product of differences in remodelling rates. While cortical bone is often treated as a uniform tissue, remodelling rates also vary within individual bones. This level of adaptation has largely been overlooked in analyses of peripheral quantitative computed tomography (pQCT) images. Further, such variation in CoD has never been assessed in growing bones. We hypothesised that CoD varied significantly within the same cross-section of the mid-tibia of adolescents. We further hypothesised that due to the profound impact of oestrogen on remodelling, this variation would be different between sexes. Subjects were 183 adolescents (99 girls and 84 boys) in grade 6 and 7 with a mean age of 12.1 years. We used age at peak height velocity to adjust for maturational differences between sexes. Image data from a mid-tibia pQCT scan of each subject were assessed regionally within eight sectors distributed about the cortex and aligned by the anterior tibial crest. We used a repeated measures general linear model to assess intra-individual variation in CoD while controlling for differences in ethnicity, maturity, height, weight, physical activity level and total cross-sectional bone area (ToA). Sector based variation in CoD was significant (p<0.001), with the anterior cortex having lower density than the posterior cortex. The largest percentage difference (anterior vs posteromedial sectors) was 12.2%. A significant sector*sex interaction (p = 0.018) was detected; however, its impact was relatively small with girls having 1.1-3.6% denser bones than boys depending on the sector (2.7% average difference). The magnitude of the variation in CoD across sectors within individuals of both sex was far greater than the mean differences between the sexes. This finding indicates that the microstructural variation within the mid-tibia is detectable by pQCT and its magnitude suggests an important level of adaptation to loading.


Increase of a calcium independent transglutaminase activity in the erythrocyte during the infection with Plasmodium falciparum.
We have studied the activity of a calcium dependent transglutaminase (EC 22.214.171.124) during the growth of the parasite Plasmodium falciparum inside the infected human erythrocyte. There is only one detectable transglutaminase in the two-cell-system, and its origin is erythrocytic. No activity was detected in preparations of the parasite devoid of erythrocyte cytoplasm. The Michaelis Menten constants (Km) of the enzyme for the substrates N'N' dimethylcaseine and putrescine were undistinguishable whether the cell extracts used in their determination were obtained from normal or from infected red cells. The total activity of transglutaminase in stringently synchronized cultures, measured at 0.5 mM Ca2+, decreased with the maturation of the parasite. However, a fraction which became irreversibly activated and independent of calcium concentration was detected. The proportion of this fraction grew with maturation; it represented only 20% of the activity in 20 hr-old-trophozoites while in 48-hr-schizonts it was more than 85% of the total activity. The activation of this fraction of transglutaminase did not depend on an increase in the erythrocyte cytoplasmic calcium, since most of the calcium was shown to be located in the parasite.


Age-related differences in plasma BDNF levels after prolonged bed rest.
Brain-derived neurotrophic factor (BDNF) is a member of the family of neurotrophins and has been implicated in brain resistance to insults. Murine studies have demonstrated increased hippocampal concentration after acute immobilization and decreased concentration after chronic immobilization. In humans, chronic stress and sedentary lifestyle result in decreased plasma BDNF levels, but there no data exist regarding acute immobilization. The aim of our study was to evaluate age-related responses [comparing 7 younger subjects (age 23 ± 3 yr) and 8 older subjects (age 60 ± 4 yr)] of plasma BDNF before (baseline data collection, BDC) and after 14 days (BR14) of horizontal bed rest (BR). At BDC, BDNF levels were not different between the two groups (P = 0.101), although at BR14, BDNF levels were higher in older subjects (62.02 ± 18.31) than in younger subjects (34.36 ± 15.24 pg/ml) (P = 0.002). A general linear model for repeated measures showed a significant effect of BR on BDNF (P = 0.002). The BDC BDNF levels correlated with fat-free mass in both populations (ALL) (R = 0.628, P = 0.012), (older, R = 0.753, P = 0.031; younger, R = 0.772, P = 0.042), and with total cholesterol in ALL (R = 0.647, P = 0.009) and older study subjects (R = 0.805, P = 0.016). At BR14, BDNF correlated with total cholesterol (R = 0.579, P = 0.024) and age (R = 0.647, P = 0.009) in ALL. With an increase in age, the brain could become naturally less resistant to acute stressors, including the detrimental effects of prolonged bed rest, and thus the increase in BDNF in the older study group might reflect a protective overshooting of the brain to counteract the negative effects in such conditions.


A genome-wide association study in multiple system atrophy.
To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10-6, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.


Comparison of Biopsychosocial Characteristics of Children with Juvenile Idiopathic Arthritis According to Common Disease Subtypes.
In this study, we assessed the functional and biopsychosocial characteristics of juvenile idiopathic arthritis (JIA) patients according to disease subtypes. Child Health Assessment Questionnaire (CHAQ), Juvenile Arthritis Disease Activity Score-71 (JADAS-71), and Juvenile Arthritis Biopsychosocial Questionnaire (JAB-Q) scales were administered to 304 JIA patients, and the subscale of JAB-Q was administered to their families. The median age of JIA patients at diagnosis was 7.9 (5.5-13) years (female/male = 1.3). Most patients were under treatment (68.7%) and had inactive disease (69.3%). While there was no significant difference between JADAS-71 scores according to the JIA subtypes, total CHAQ scores in polyarticular JIA patients were higher than in systemic JIA patients (P = .005). Enthesitis-related arthritis (ERA) patients had higher JAB-Q fatigue total scores compared to systemic JJIA patients (P = .001). Juvenile Arthritis Biopsychosocial Questionnaire-child psychosocial status scores were higher in polyarticular JIA patients than oligoarticular and systemic JIA patients (P = .004 and P = .003, respectively), and they had higher JAB-Q child form total scores than systemic JIA patients (P = .006). In addition, systemic JIA patients' parents had higher JAB-Q family total scores compared to oligoarticular JIA patients' parents (P = .03). Our results suggest that polyarticular JIA patients had higher CHAQ, JAB-Q psychosocial status, and child form total scores, and the JAB-Q fatigue score was higher in ERA patients. Also, JAB-Q-parent scores were higher in systemic JIA patients' parents. Biopsychosocial characteristics should be evaluated in both JIA patients and their parents.


Health status, quality of life, residential stability, substance use, and health care utilization among adults applying to a supportive housing program.
Supportive housing, defined as subsidized housing in conjunction with site-based social services, may help improve the health and residential stability of highly disadvantaged individuals. This study examined changes in health status, quality of life, substance use, health care utilization, and residential stability among 112 homeless and vulnerably housed individuals who applied to a supportive housing program in Toronto, Canada, from December 2005 to June 2007. Follow-up interviews were conducted every 6 months for 18 months. Comparisons were made between individuals who were accepted into the program (intervention) and those who were wait-listed (usual care) using repeated-measures analyses. Individuals who were accepted into the housing program experienced significantly greater improvements in satisfaction with living situation compared with individuals in the usual care group (time, F(3,3,261) = 47.68, p < 0.01; group × time, F(3,3,261) = 14.60, p < 0.01). There were no significant differences in other quality of life measures, health status, health care utilization, or substance use between the two groups over time. Significant improvement in residential stability occurred over time, independent of assigned housing group (time, F(3,3,261) = 9.96, p < 0.01; group × time, F(3,3,261) = 1.74, p = 0.17). The ability to examine the effects of supportive housing on homeless individuals was limited by the small number of participants who were literally homeless at baseline and by the large number of participants who gained stable housing during the study period regardless of their assigned housing status. Nonetheless, this study shows that highly disadvantaged individuals with a high prevalence of poor physical and mental health and substance use can achieve stable housing.


Predicting time to prostate cancer recurrence based on joint models for non-linear longitudinal biomarkers and event time outcomes.
Biological markers that are both sensitive and specific for tumour regrowth or metastasis are increasingly becoming available and routinely monitored during the regular follow-up of patients treated for cancer. Obtained by a simple blood test, these markers provide an inexpensive non-invasive means for the early detection of recurrence (or progression). Currently, the longitudinal behaviour of the marker is viewed as an indicator of early disease progression, and is applied by a physician in making clinical decisions. One marker that has been studied for use in both population screening for early disease and for detection of recurrence in prostate cancer patients is PSA. The elevation of PSA levels is known to precede clinically detectable recurrence by 2 to 5 years, and current clinical practice often relies partially on multiple recent rises in PSA to trigger a change in treatment. However, the longitudinal trajectory for individual markers is often non-linear; in many cases there is a decline immediately following radiation therapy or surgery, a plateau during remission, followed by an exponential rise following the recurrence of the cancer. The aim of this article is to determine the multiple aspects of the longitudinal PSA biomarker trajectory that can be most sensitive for predicting time to clinical recurrence. Joint Bayesian models for the longitudinal measures and event times are utilized based on non-linear hierarchical models, implied by unknown change-points, for the longitudinal trajectories, and a Cox proportional hazard model for progression times, with functionals of the longitudinal parameters as covariates in the Cox model. Using Markov chain Monte Carlo sampling schemes, the joint model is fit to longitudinal PSA measures from 676 patients treated at Massachusetts General Hospital between the years 1988 and 1995 with follow-up to 1999. Based on these data, predictive schemes for detecting cancer recurrence in new patients based on their longitudinal trajectory are derived.


Gender of infants conceived on different days of the menstrual cycle.
The baby's sex was studied in 3658 births to Jewish women who observed the orthodox ritual of sexual separation each month and who resumed intercourse within two days of ovulation. The day of resuming intercourse relative to ovulation was estimated from the characteristics of each woman's menstrual cycle and the number of days of sexual abstinence observed after the last menstruation. The proportion of male babies was significantly higher (65.5 +/- 3.9 per cent, mean +/- S.D.) in the offspring of women who resumed intercourse two days after ovulation. This proportion tended to be lower on or near the day of ovulation than on the previous one or two days. These results, which were consistent in different demographic subgroups, demonstrate that insemination on different days of the menstrual cycle does lead to variations in sex ratio. Couples should be cautioned against attempting to conceive a boy by delaying intercourse until after ovulation, until further research has established whether delayed fertilization causes birth defects.


Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides.
The current study explored the Na+/K+-ATPase (NKA) inhibition-independent proarrhythmic mechanisms of cardiac glycosides (CGs) which are well-known NKA inhibitors. With the cytosolic Ca2+ chelated by EGTA and BAPTA or extracellular Ca2+ replaced by Ba2+, effects of bufadienolides (bufalin (BF) and cinobufagin (CBG)) and cardenolides (ouabain (Oua) and pecilocerin A (PEA)) on the L-type calcium current (I Ca,L) were recorded in heterologous expression Cav1.2-CHO cells and human embryonic stem cell-derived cardiomyocytes (hESC-CMs). BF and CBG demonstrated a concentration-dependent (0.1 to100 µM) I Ca,L inhibition (maximal ≥50%) without and with the NKA activity blocked by 10 µM Oua. BF significantly shortened the action potential duration at 1.0 µM and shortened the extracellular field potential duration at 0.01~1.0 µM. On the other hand, BF and CBG at 100 µM demonstrated a strong inhibition (≥40%) of the rapidly activating component of the delayed rectifier K+ current (I Kr) in heterologous expression HEK293 cells and prolonged the APD of the heart of day-3 Zebrafish larva with disrupted rhythmic contractions. Moreover, hESC-CMs treated with BF (10 nM) for 24 hours showed moderate yet significant prolongation in APD90. In conclusion, our data indicate that CGs particularly bufadienolides possess cytosolic [Ca2+]i- and NKA inhibition- independent proarrhythmic potential through I Ca,L and I Kr inhibitions.


Allelic Variation and Distribution of the Major Maturity Genes in Different Soybean Collections.
Soybean time of flowering and maturity are genetically controlled by E genes. Different allelic combinations of these genes determine soybean adaptation to a specific latitude. The paper describes the first attempt to assess adaptation of soybean genotypes developed and realized at Institute of Field and Vegetable Crops, Novi Sad, Serbia [Novi Sad (NS) varieties and breeding lines] based on E gene variation, as well as to comparatively assess E gene variation in North-American (NA), Chinese, and European genotypes, as most of the studies published so far deal with North-American and Chinese cultivars and breeding material. Allelic variation and distribution of the major maturity genes (E1, E2, E3, and E4) has been determined in 445 genotypes from soybean collections of NA ancestral lines, Chinese germplasm, and European varieties, as well as NS varieties and breeding lines. The study showed that allelic combinations of E1-E4 genes significantly determined the adaptation of varieties to different geographical regions, although they have different impacts on maturity. In general, each collection had one major E genotype haplogroup, comprising over 50% of the lines. The exceptions were European varieties that had two predominant haplogroups and NA ancestral lines distributed almost evenly among several haplogroups. As e1-as/e2/E3/E4 was the most common genotype in NS population, present in the best-performing genotypes in terms of yield, this specific allele combination was proposed as the optimal combination for the environments of Central-Eastern Europe.


Activity-based proteomics reveals nine target proteases for the recombinant protein-stabilizing inhibitor SlCYS8 in Nicotiana benthamiana.
Co-expression of protease inhibitors like the tomato cystatin SlCYS8 is useful to increase recombinant protein production in plants, but key proteases involved in protein proteolysis are still unknown. Here, we performed activity-based protein profiling to identify proteases that are inhibited by SlCYS8 in agroinfiltrated Nicotiana benthamiana. We discovered that SlCYS8 selectively suppresses papain-like cysteine protease (PLCP) activity in both apoplastic fluids and total leaf extracts, while not affecting vacuolar-processing enzyme and serine hydrolase activity. A robust concentration-dependent inhibition of PLCPs occurred in vitro when purified SlCYS8 was added to leaf extracts, indicating direct cystatin-PLCP interactions. Activity-based proteomics revealed that nine different Cathepsin-L/-F-like PLCPs are strongly inhibited by SlCYS8 in leaves. By contrast, the activity of five other Cathepsin-B/-H-like PLCPs, as well as 87 Ser hydrolases, was unaffected by SlCYS8. SlCYS8 expression prevented protein degradation by inhibiting intermediate and mature isoforms of granulin-containing proteases from the Resistant-to-Desiccation-21 (RD21) PLCP subfamily. Our data underline the key role of endogenous PLCPs on recombinant protein degradation and reveal candidate proteases for depletion strategies.


Ascorbate recycling in human neutrophils: induction by bacteria.
Ascorbate (vitamin C) recycling occurs when extracellular ascorbate is oxidized, transported as dehydroascorbic acid, and reduced intracellularly to ascorbate. We investigated microorganism induction of ascorbate recycling in human neutrophils and in microorganisms themselves. Ascorbate recycling was determined by measuring intracellular ascorbate accumulation. Ascorbate recycling in neutrophils was induced by both Gram-positive and Gram-negative pathogenic bacteria, and the fungal pathogen Candida albicans. Induction of recycling resulted in as high as a 30-fold increase in intracellular ascorbate compared with neutrophils not exposed to microorganisms. Recycling occurred at physiologic concentrations of extracellular ascorbate within 20 min, occurred over a 100-fold range of effector/target ratios, and depended on oxidation of extracellular ascorbate to dehydroascorbic acid. Ascorbate recycling did not occur in bacteria nor in C. albicans. Ascorbate did not enter microorganisms, and dehydroascorbic acid entry was less than could be accounted for by diffusion. Because microorganism lysates reduced dehydroascorbic acid to ascorbate, ascorbate recycling was absent because of negligible entry of the substrate dehydroascorbic acid. Because ascorbate recycling occurs in human neutrophils but not in microorganisms, it may represent a eukaryotic defense mechanism against oxidants with possible clinical implications.


Glu300 of rat carboxypeptidase E is essential for enzymatic activity but not substrate binding or routing to the regulated secretory pathway.
Several recently discovered members of the carboxypeptidase E (CPE) gene family lack critical active site residues that are conserved in other family members. For example, three CPE-like proteins contain a Tyr in place of Glu300 (equivalent to Glu270 of carboxypeptidase A and B). To investigate the importance of this position, Glu300 of rat CPE was converted into Gln, Lys, or Tyr, and the proteins expressed in Sf9 cells using the baculovirus system. All three mutants were secreted from the cells, but the media showed no enzyme activity above background levels. Wild-type CPE and the Gln300 point mutant bound to a p-aminobenzoyl-Arg-Sepharose affinity resin, and this binding was competed by an active site-directed inhibitor, guanidinoethylmercaptosuccinic acid. The affinity purified mutant CPE protein showed no detectable enzyme activity (<0.004% of wild-type CPE) toward dansyl-Phe-Ala-Arg. Expression of the Gln300 and Lys300 mutant CPE proteins in the NIT3 mouse pancreatic beta-cell line showed that these mutants are routed into secretory vesicles and secreted via the regulated pathway. Taken together, these results indicate that Glu300 of CPE is essential for enzyme activity, but not required for substrate binding or for routing into the regulated secretory pathway.


Systematic review of the body of evidence for the use of biomarkers in the diagnosis of dementia.
Although recent diagnostic criteria for Alzheimer's disease propose the use of biomarkers, validation of these biomarkers by diagnostic test accuracy studies is a necessary first step, followed by the synthesis of the evidence from these studies in systematic reviews and meta-analyses. The quality of the resulting evidence depends on the number and size of the primary studies, their quality, and the adequacy of their reporting. This systematic review assesses the weight and quality of the evidence available from primary diagnostic test accuracy studies. A MEDLINE search was performed in August 2011 to identify all potentially relevant publications relating to the biomarkers β-amyloid, tau, positron emission tomography ((18)F-fluorodeoxyglucose or ligands for amyloid), or magnetic resonance imaging (MRI). The reporting and methodology were assessed using the Standards for Reporting of Diagnostic Accuracy and Quality Assessment of Diagnostic Accuracy Studies assessment tools, respectively. Because clinical progression to dementia is the most commonly used reference standard, this review focuses on participants with objective cognitive impairment but no dementia at baseline. Of the 19,104 published references identified by the search, 142 longitudinal studies relating to the biomarkers of interest were identified, which included subjects who had objective cognitive impairment but no dementia at baseline. The highest number of studies (n = 70) and of participants (n = 4722) related to structural MRI. MRI also yielded the highest number of studies with extractable data for meta-analysis (n = 32 [46% of all structural MRI studies]), followed by cerebrospinal fluid tau (n = 24 [73%]). There were few studies on positron emission tomography ligands for amyloid having suitable data for meta-analysis (n = 4). There was considerable variation across studies in reporting outcomes, methods of blinding and selection, means of accounting for indeterminate or missing values, the interval between the test and assessments, and the determination of test thresholds. The body of evidence for biomarkers is not large and is variable across the different types of biomarkers. Important information is missing from many study reports, highlighting the need for standardization of methodology and reporting to improve the rigor of biomarker validation.


Role of acinetobactin-mediated iron acquisition functions in the interaction of Acinetobacter baumannii strain ATCC 19606T with human lung epithelial cells, Galleria mellonella caterpillars, and mice.
Acinetobacter baumannii, which causes serious infections in immunocompromised patients, expresses high-affinity iron acquisition functions needed for growth under iron-limiting laboratory conditions. In this study, we determined that the initial interaction of the ATCC 19606(T) type strain with A549 human alveolar epithelial cells is independent of the production of BasD and BauA, proteins needed for acinetobactin biosynthesis and transport, respectively. In contrast, these proteins are required for this strain to persist within epithelial cells and cause their apoptotic death. Infection assays using Galleria mellonella larvae showed that impairment of acinetobactin biosynthesis and transport functions significantly reduces the ability of ATCC 19606(T) cells to persist and kill this host, a defect that was corrected by adding inorganic iron to the inocula. The results obtained with these ex vivo and in vivo approaches were validated using a mouse sepsis model, which showed that expression of the acinetobactin-mediated iron acquisition system is critical for ATCC 19606(T) to establish an infection and kill this vertebrate host. These observations demonstrate that the virulence of the ATCC 19606(T) strain depends on the expression of a fully active acinetobactin-mediated system. Interestingly, the three models also showed that impairment of BasD production results in an intermediate virulence phenotype compared to those of the parental strain and the BauA mutant. This observation suggests that acinetobactin intermediates or precursors play a virulence role, although their contribution to iron acquisition is less relevant than that of mature acinetobactin.


NIH Roundtable on Emergency Trauma Research.
The National Institutes of Health (NIH) formed an NIH Task Force on Research in Emergency Medicine to enhance NIH support for emergency care research. The NIH Trauma Research Roundtable was convened on June 22 to 23, 2009. The objectives of the roundtable are to identify key research questions essential to advancing the scientific underpinnings of emergency trauma care and to discuss the barriers and best means to advance research by exploring the role of trauma research networks and collaboration between NIH and the emergency trauma care community. Before the roundtable, the emergency care domains to be discussed were selected and experts in each of the fields were invited to participate in the roundtable. Domain experts were asked to identify research priorities and challenges and separate them into mechanistic, translational, and clinical categories. During and after the conference, the lists were circulated among the participants and revised to reach a consensus. Emergency trauma care research is characterized by focus on the timing, sequence, and time sensitivity of disease processes and treatment effects. Rapidly identifying the phenotype of patients on the time spectrum of acuity and severity after injury and the mechanistic reasons for heterogeneity in outcome are important challenges in emergency trauma research. Other research priorities include the need to elucidate the timing, sequence, and duration of causal molecular and cellular events involved in time-critical injuries, and the development of treatments capable of halting or reversing them; the need for novel experimental models of acute injury; the need to assess the effect of development and aging on the postinjury response; and the need to understand why there are regional differences in outcomes after injury. Important barriers to emergency care research include a limited number of trained investigators and experienced mentors, limited research infrastructure and support, and regulatory hurdles. The science of emergency trauma care may be advanced by facilitating the following: (1) development of an acute injury template for clinical research; (2) developing emergency trauma clinical research networks; (3) integrating emergency trauma research into Clinical and Translational Science Awards; (4) developing emergency care-specific initiatives within the existing structure of NIH institutes and centers; (5) involving acute trauma and emergency specialists in grant review and research advisory processes; (6) supporting learn-phase or small, clinical trials; (7) performing research to address ethical and regulatory issues; and (8) training emergency care investigators with research training programs.


Streptococcus infantarius sp. nov., Streptococcus infantarius subsp. infantarius subsp. nov. and Streptococcus infantarius subsp. coli subsp. nov., isolated from humans and food.
Eighteen strains isolated from human specimens or from food products were characterized as atypical variants of mannitol-negative Streptococcus bovis. They were tested for extended biochemical criteria, ribotyping and DNA-DNA hybridization in order to define their taxonomic status. These strains were demonstrated to constitute a DNA relatedness group that includes strains of DNA group 4 of Farrow et al. (1984). Comparative analysis of 16S rRNA sequences demonstrated that these strains represent a new species which belongs to the Streptococcus bovis/Streptococcus equinus complex and which has been provisionally named S. infantarius by Bouvet et al. (1997). Biotyping and ribotyping allowed differentiation of these strains from the aesculin-positive strains of S. bovis belonging to the previously described biotypes I, II.1 and II.2. The results of the ribotyping and hybridization assays demonstrated the presence of two different DNA subgroups within the 18 strains. On the basis of these data, the names S. infantarius subsp. infantarius (aesculin-negative for five strains out of seven, including the type strain HDP 90056T = NCDO 599T) and S. infantarius subsp. coli (aesculin-positive, reference strain HDP 90248 = NCDO 2620) are proposed as the names for these two subspecies within the S. infantarius species.


Inactivation of different strains of Escherichia coli O157:H7 in various apple ciders treated with dimethyl dicarbonate (DMDC) and sulfur dioxide (SO2) as an alternative method.
Escherichia coli has been identified as the causative agent in numerous foodborne illness outbreaks associated with the consumption of fresh apple cider. Apple cider has a pH which is normally below 4.0 and would not be considered a medium capable of supporting the growth of foodborne pathogens. The association of unpasteurized apple cider with foodborne illness due to E. coli O157:H7 has however, led to increased interest in potential alternative methods to produce pathogen free cider. Apple cider was prepared from eight different apple cultivars, inoculated with approximately 10(6)-10(7) CFU of three strains of E. coli O157:H7 per ml (933, ATCC 43889, and ATCC 43895) and tested to determine the effectiveness of sulfur dioxide (SO(2)) and dimethyl dicarbonate (DMDC). Bacterial populations for treated and untreated samples were then enumerated by using non-selective media. Eight different ciders were treated with DMDC (125 and 250 ppm) and SO(2) (25, 50, 75, 100 ppm). Greater than a 5-log reduction was achieved at room temperature with 250 ppm of DMDC and 50 ppm of SO(2) after the incubation time of 6h and 24h, respectively. Addition of DMDC and/or SO(2) may offer an inexpensive alternative to thermal pasteurization for the production of safe apple cider for small apple cider producers.


Activation of gamma delta T cells in the primary immune response to Mycobacterium tuberculosis.
Although the immunologic role of T cells bearing the conventional alpha beta T cell receptor (TCR) has been well characterized, little is known about the function of the population of T cells bearing the gamma delta TCR. Therefore, the role of gamma delta T cells in the immune response to Mycobacterium tuberculosis (MT) was investigated. The number of TCR gamma delta cells in the draining lymph nodes of mice immunized with MT was greatly increased in comparison with the number of TCR alpha beta cells. Three biochemically distinct gamma delta TCRs were detected. Analyses of cell cycle, of interleukin-2 receptor expression, and of interleukin-2 responsiveness showed that a large proportion of the gamma delta T cells were activated in vivo. TCR gamma delta cells responded to solubilized MT antigens in vitro but, in contrast to MT-specific alpha beta T cells, the response of gamma delta T cells to MT did not require major histocompatability complex class II recognition. These results provide an example of antigen-specific activation of gamma delta T cells in vivo and indicate that gamma delta T cells may have a distinct role in generating a primary immune response to certain microorganisms.


RXRs: collegial partners.
Retinoid X Receptors (RXR) were initially identified as nuclear receptors binding with stereo-selectivity the vitamin A derivative 9-cis retinoic acid, although the relevance of this molecule as endogenous activator of RXRs is still elusive. Importantly, within the nuclear receptor superfamily, RXRs occupy a peculiar place, as they are obligatory partners for a number of other nuclear receptors, thus integrating the corresponding signaling pathways. In this chapter, we describe the structural features allowing RXR to form homo- and heterodimers, and the functional consequences of this unique ability. Furthermore, we discuss the importance of studying RXR activity at a genome-wide level in order to comprehensively address the biological implications of their action that is fundamental to understand to what extent RXRs could be exploited as new therapeutic targets.


Effect of vascular endothelial growth factor rs35569394 in esophageal cancer and response to chemotherapy.
The objective of this study was to investigate the possible association between the single nucleotide polymorphism (SNP), rs35569394, of the vascular endothelial growth factor gene (VEGF) and the risk of esophageal cancer (EC) in the Han Chinese population. A total of 290 EC subjects and 322 ethnically matched unrelated healthy controls free from the esophageal disease were studied. Genomic DNA was isolated from peripheral blood by salting out. Genotyping of VEGF rs35569394 polymorphism was carried out via polymerase chain reaction followed by agarose gel electrophoresis. The results showed that the distribution of genotypes was significantly different across the gender groups (p=0.032) and clinical stages (p=0.034). VEGF rs35569394 was associated with EC risk (p= 0.012, OR=1.34). A gender analysis break-down showed that rs35569394-D allele frequency was significantly higher in females than in the controls (p=0.0004, OR=1.81). Moreover, significant associations were also found in females under the dominant model (II versus ID+DD: χ2=8.18, p=0.003, OR=2.12) and the recessive model (II+ID versus DD: χ2=8.25, p=0.004, OR=2.39). Additionally, we found that the genotype, rs35569394-DD, was associated with a complete response + partial response to chemotherapy when compared with rs35569394-II (χ2=4.67, p=0.030, OR=0.47). In conclusion, our case-control study showed that the VEGF rs35569394 was significantly associated with the clinical stages and the increased risk of EC in Han Chinese females. In addition, the genotype rs35569394-DD showed a better response to chemotherapy.


Linear systems approach to simulation of optical diffraction.
The diffractive processes within an optical system can be simulated by computer to compute the diffraction-altered electric-field distribution at the output of the system from the electric-field distribution at the input. In the paraxial approximation the system can be described by an ABCD ray matrix whose elements in turn can be used to simplify the computation such that only a single computational step is required. We describe two rearrangements of such computations that allow the simulation to be expressed in a linear systems formulation, in particular using the fast-Fourier-transform algorithm. We investigate the sampling requirements for the kernel-modifying function or chirp that arises. We also use the special properties of the chirp to determine the spreading imposed by the diffraction. This knowledge can be used to reduce the computation if only a limited region of either the input or the output is of interest.


DNA copy number evolution in Drosophila cell lines.
Structural rearrangements of the genome resulting in genic imbalance due to copy number change are often deleterious at the organismal level, but are common in immortalized cell lines and tumors, where they may be an advantage to cells. In order to explore the biological consequences of copy number changes in the Drosophila genome, we resequenced the genomes of 19 tissue-culture cell lines and generated RNA-Seq profiles. Our work revealed dramatic duplications and deletions in all cell lines. We found three lines of evidence indicating that copy number changes were due to selection during tissue culture. First, we found that copy numbers correlated to maintain stoichiometric balance in protein complexes and biochemical pathways, consistent with the gene balance hypothesis. Second, while most copy number changes were cell line-specific, we identified some copy number changes shared by many of the independent cell lines. These included dramatic recurrence of increased copy number of the PDGF/VEGF receptor, which is also over-expressed in many cancer cells, and of bantam, an anti-apoptosis miRNA. Third, even when copy number changes seemed distinct between lines, there was strong evidence that they supported a common phenotypic outcome. For example, we found that proto-oncogenes were over-represented in one cell line (S2-DRSC), whereas tumor suppressor genes were under-represented in another (Kc167). Our study illustrates how genome structure changes may contribute to selection of cell lines in vitro. This has implications for other cell-level natural selection progressions, including tumorigenesis.


Factors affecting the decline of ventilatory function in chronic bronchitis.
Ninety six middle aged male patients with chronic bronchitis with relatively well preserved ventilatory function who were resident in Queensland, New South Wales, or Victoria took part in a prospective study to determine the relationship of various factors to the rate of decline of the FEV1. Thirty of the subjects withdrew, leaving 66 to be followed for four to six years. The mean rate of decline of the FEV1 was 58.6 (SD 51.4) ml/year. The subjects' ventilatory responses to bronchodilator and to methacholine (measures of bronchial lability) were significantly related to each other and to sputum eosinophilia. With a linear model for the data on 57 patients who had methacholine and skin tests the rate of decline of the FEV1 was found, after adjustment had been made for other variables, to be significantly related to State of residence, current smoking, response to bronchodilator, age, and occupational exposure to dust. Response to bronchodilator was interchangeable with response to methacholine. With the five variables in the model none of the following factors was related to the rate of decline of the FEV1:FEV1 on entry, FEV1% predicted normal, FEV1/VC%, skin test reaction, occupation on entry, history of sinusitis and rhinitis, and height. When data from all 66 subjects were introduced into the model, in addition to the five significant individual variables (FEV1/VC% X response to bronchodilator) was significantly related to the rate of decline of the FEV1. Of these prognostic indices, response to bronchodilator was independent of the initial FEV1, FEV/VC%, and FEV1% predicted. The difference between States, which was not explained by differences due to sampling or withdrawal of subjects, was due to a low rate of decline in Queensland.


Infrared photodissociation spectroscopy of ion-radical networks in cationic dimethylamine complexes.
Infrared photodissociation spectroscopy was employed to establish the general trends in the stepwise growth motif of cationic dimethylamine (DMA)n+ (n = 4-13) complexes. Electronic structure calculations were performed to identify the structure of the low-lying isomers and to assign the observed spectral features. The results showed the preference of the formation of the proton-transferred (CH3)2NH2+ ion core. The (CH3)2NH2+-[(CH3)2N] ion-radical pair contact and the ion-radical separated pair could coexist at n = 4. The [(CH3)2N] radical is separated from the (CH3)2NH2+ ion core by one DMA molecule at n = 4-6 and by two or more DMA molecules in the larger clusters. This suggests that the (CH3)2NH2+-[(CH3)2N] ion-radical contact pair is not stable in the subsequent radiation-induced processes of DMA, and the [(CH3)2N] radical is released from the charged site in the cationic DMA networks.


Adaptive evolution of the symbiotic gene NORK is not correlated with shifts of rhizobial specificity in the genus Medicago.
The NODULATION RECEPTOR KINASE (NORK) gene encodes a Leucine-Rich Repeat (LRR)-containing receptor-like protein and controls the infection by symbiotic rhizobia and endomycorrhizal fungi in Legumes. The occurrence of numerous amino acid changes driven by directional selection has been reported in this gene, using a limited number of messenger RNA sequences, but the functional reason of these changes remains obscure. The Medicago genus, where changes in rhizobial associations have been previously examined, is a good model to test whether the evolution of NORK is influenced by rhizobial interactions. We sequenced a region of 3610 nucleotides (encoding a 392 amino acid-long region of the NORK protein) in 32 Medicago species. We confirm that positive selection in NORK has occurred within the Medicago genus and find that the amino acid positions targeted by selection occur in sites outside of solvent-exposed regions in LRRs, and other sites in the N-terminal region of the protein. We tested if branches of the Medicago phylogeny where changes of rhizobial symbionts occurred displayed accelerated rates of amino acid substitutions. Only one branch out of five tested, leading to M. noeana, displays such a pattern. Among other branches, the most likely for having undergone positive selection is not associated with documented shift of rhizobial specificity. Adaptive changes in the sequence of the NORK receptor have involved the LRRs, but targeted different sites than in most previous studies of LRR proteins evolution. The fact that positive selection in NORK tends not to be associated to changes in rhizobial specificity indicates that this gene was probably not involved in evolving rhizobial preferences. Other explanations (e.g. coevolutionary arms race) must be tested to explain the adaptive evolution of NORK.


Opportunities for cannabis in supportive care in cancer.
Cannabis has the potential to modulate some of the most common and debilitating symptoms of cancer and its treatments, including nausea and vomiting, loss of appetite, and pain. However, the dearth of scientific evidence for the effectiveness of cannabis in treating these symptoms in patients with cancer poses a challenge to clinicians in discussing this option with their patients. A review was performed using keywords related to cannabis and important symptoms of cancer and its treatments. Literature was qualitatively reviewed from preclinical models to clinical trials in the fields of cancer, human immunodeficiency virus (HIV), multiple sclerosis, inflammatory bowel disease, post-traumatic stress disorder (PTSD), and others, to prudently inform the use of cannabis in supportive and palliative care in cancer. There is a reasonable amount of evidence to consider cannabis for nausea and vomiting, loss of appetite, and pain as a supplement to first-line treatments. There is promising evidence to treat chemotherapy-induced peripheral neuropathy, gastrointestinal distress, and sleep disorders, but the literature is thus far too limited to recommend cannabis for these symptoms. Scant, yet more controversial, evidence exists in regard to cannabis for cancer- and treatment-related cognitive impairment, anxiety, depression, and fatigue. Adverse effects of cannabis are documented but tend to be mild. Cannabis has multifaceted potential bioactive benefits that appear to outweigh its risks in many situations. Further research is required to elucidate its mechanisms of action and efficacy and to optimize cannabis preparations and doses for specific populations affected by cancer.


Microalgae growth for nutrient recovery from sludge liquor and production of renewable bioenergy.
Proof-of-concept has been demonstrated for a process that will utilize nutrients from sludge liquor, natural light, and CO2 from biogas to grow microalgae at wastewater treatment plants. This process will reduce the impact of returning side-streams to the head of the plant. The produced algae will be fed to anaerobic digesters for increased biogas production. Dewatering of anaerobically digested sludge in centrifuges produces reject water with extremely low transmittance of light. A pretreatment procedure was developed that improved light transmittance for reject water from the FREVAR, Norway, wastewater treatment plant from 0.1% T to 77% T (670 nm, 1 cm path). Chlorella sp. microalgae were found to be suitable for growth in this pre-treated reject water. Typical nitrogen removal was 80-90 g N/kg TSS of produced microalgae. The microalgae were successfully harvested by chemically assisted flocculation followed by straining through a 33 microm sieve cloth, achieving up to 99% recovery. Harvested algae were anaerobically co-digested with wastewater sludge. The specific methane gas production (mL CH4/g VS fed) for the algae varied from less than 65% to 90% of the specific methane gas production for the wastewater sludge, depending on digester temperature, retention time and pre-treatment of the algae biomass.


Ethical and social implications of using predictive modeling for Alzheimer's disease prevention: a systematic literature review protocol.
The therapeutic paradigm in Alzheimer's disease (AD) has shifted towards secondary prevention, defined as an intervention aiming to prevent or delay disease onset in pre-symptomatic individuals at risk of developing dementia due to AD. The key feature of AD prevention is the need to treat years or even decades before the onset of cognitive, behavioural or functional decline. Prediction of AD risk and evaluation of long-term treatment outcomes in this setting requires predictive modelling and is associated with ethical concerns and social implications. The objective of this review is to identify and elucidate them, as presented in the literature. A systematic literature review was conducted in Medline, Embase, PsycInfo and Scopus, and was complemented with a grey literature search. All searches were conducted between March and July 2018. Two reviewers independently assessed each study for inclusion and disagreements were adjudicated by a third reviewer. Data are now being extracted using an extraction sheet developed within the group of reviewers, based on an initial sample of three manuscripts, but allowing for inclusion of newly identified data items (ethical arguments). Data will be analysed qualitatively using a thematic analysis technique. Potential biases in selection and interpretation of extracted data are mitigated by the fact that reviewers come from a range of different scientific backgrounds and represent different types of stakeholders in this ethical discussion (academia, industry, patient advocacy groups). The study does not require ethical approval. The findings of the review will be disseminated in a peer-reviewed journal and presented at conferences. They will also be reported through the Innovative Medicine Initiative project: Real World Outcomes Across the AD Spectrum for Better Care: Multi-modal Data Access Platform (IMI: ROADMAP). CRD42018092205.


Alterations in the proteome of the NHERF2 knockout mouse jejunal brush border membrane vesicles.
To identify additional potential functions for the multi-PDZ domain containing protein Na+/H+ exchanger regulatory factor 2 (NHERF2), which is present in the apical domain of intestinal epithelial cells, proteomic studies of mouse jejunal villus epithelial cell brush border membrane vesicles compared wild-type to homozygous NHERF2 knockout FVB mice by a two-dimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS)-iTRAQ approach. Jejunal architecture appeared normal in NHERF2 null in terms of villus length and crypt depth, Paneth cell number, and microvillus structure by electron microscopy. There was also no change in proliferative activity based on BrdU labeling. Four brush border membrane vesicles (BBMV) preparations from wild-type mouse jejunum were compared with four preparations from NHERF2 knockout mice. LC-MS/MS identified 450 proteins in both matched wild-type and NHERF2 null BBMV; 13 proteins were changed in two or more separate BBMV preparations (9 increased and 4 decreased in NHERF2 null mice), while an additional 92 proteins were changed in a single BBMV preparation (68 increased and 24 decreased in NHERF2 null mice). These proteins were categorized as 1) transport proteins (one increased and two decreased in NHERF2 null); 2) signaling molecules (2 increased in NHERF2 null); 3) cytoskeleton/junctional proteins (4 upregulated and 1 downregulated in NHERF2 null); and 4) metabolic proteins/intrinsic BB proteins) (2 upregulated and 1 downregulated in NHERF2 null). Immunoblotting of BBMV was used to validate or extend the findings, demonstrating increase in BBMV of NHERF2 null of MCT1, coronin 3, and ezrin. The proteome of the NHERF2 null mouse small intestinal BB demonstrates up- and downregulation of multiple transport proteins, signaling molecules, cytoskeletal proteins, tight junctional and adherens junction proteins, and proteins involved in metabolism, suggesting involvement of NHERF2 in multiple apical regulatory processes and interactions with luminal contents.


Effects of resistance training on regional and total bone mineral density in premenopausal women: a randomized prospective study.
This study was designed to assess the effects of 18 months of resistance exercise on regional and total bone mineral density (BMD) and soft tissue lean mass (STL) in premenopausal women aged 28-39 randomly assigned to an exercise or control group. Twenty-two exercise and 34 control subjects completed the 18-month training study. All subjects were previously inactive and untrained women. Initial, 5-, 12- and 18-month assessments were made of total and regional BMD and total and regional STL using dual energy X-ray absorptiometry. All subjects consumed a 500 mg/day elemental calcium supplement throughout the study. Initial Ca intake without supplement averaged 1,023 mg/day in total sample. Serum levels of bone osteocalcin and dietary assessments using 12 randomly assigned days of diet records were also completed. Muscular strength was assessed from both 1 repetition maximum (RM) testing of 10 weightlifting exercises and by peak torque for hip abduction/adduction and knee extension/flexion. Training increased strength by 58.1% based on 1 RM testing and by 33.8% based on isokinetic testing at 18 months versus baseline. BMD increased significantly above baseline at the lumbar spine for the exercise group at 5 months (2.8%), 12 months (2.3%), and 18 months (1.9%) as compared with controls. Femur trochanter BMD increased significantly (p < 0.05) in the exercise group at 12 months (1.8%) and 18 months (2.0%) but not at 5 months (0.7%) as compared with controls. No changes in total BMD, arm BMD, or leg BMD were found. There was a 20% increase in BGP in the exercise group as compared with controls at 5 months and this difference was maintained throughout the study. For STL, significant increases for total, arm, and leg were found at 5, 12, and 18 months for the exercise group versus control ranging from 1-6% over baseline. These results support the use of strength training for increasing STL and muscular strength with smaller but significant regional increases in BMD in the premenopausal population.


Preoperative urinary tract infection increases postoperative morbidity.
Preoperative urinary tract infection (UTI) may be associated with surgical site infections secondary to hematogenous spread of bacteria. The association between preoperative UTI and postoperative complications has not been evaluated in general surgery populations. Patients undergoing elective general surgery procedures from 2011 to 2013 were selected from the American College of Surgeons National Surgical Quality Improvement Program database. Patients with UTI present at the time of surgery (PATOS) were identified as cases. Patients without UTI PATOS were selected and matched 2:1 on age, American Society of Anesthesiologists class, and Current Procedural Terminology code with identified cases. Univariate and multivariate analyses compared postoperative outcomes between the two groups. A total of 434,802 patients were identified for inclusion in the study, with an overall preoperative UTI rate of 0.1% (n = 363). On univariate analysis, the UTI group had a significantly higher incidence of overall complications, infectious complications, and noninfectious complications. Multivariate analysis confirmed that patients with UTI had a higher risk of postoperative complications compared with those without preoperative UTI (odds ratio [OR] 1.551, 95% confidence interval [CI] 1.071-2.247). This relationship persisted for both infectious (OR 1.515, 95% CI 1.000-2.296) and noninfectious (OR 1.683, 95% CI 1.012-2.799) complications. We demonstrated an increased rate of 30-d complications in elective general surgery patients with UTI PATOS. These findings suggest that diligent efforts to diagnose and treat UTI before surgery may result in improved outcomes. Furthermore, surgeons should consider postponing elective procedures to allow for the complete resolution of preoperative UTI.


Reciprocal effects of reading and mathematics? Beyond the cross-lagged panel model.
Prior nonexperimental studies have been used to conclude that children's reading and mathematics achievement bidirectionally influence each other over time, with strong paths from (a) early reading to later mathematics and (b) early mathematics to later reading. In the most influential study on the topic, the early math-to-later-reading path was reported to be stronger than the early reading-to-later-math path (Duncan et al., 2007). Yet prior estimates may be confounded by stable environmental and personal factors influencing both reading and mathematics achievement. We reexamined the bidirectional relations between reading and mathematics achievement using both traditional models and extensions intended to account for unmeasured confounding. Results based on a large nationally representative sample of children from kindergarten to 3rd grade (N = 9,612) indicated that the estimated effects between reading and mathematics achievement differ substantially after accounting for the confounding effects of stable unmeasured factors. In these models, autoregressive and cross-lagged paths were substantially reduced. The finding that early mathematics predicts later reading more strongly than early reading predicts later math disappears and sometimes reverses, suggesting that larger paths from math to reading than from reading to math in previous related analyses are not causally informative. Stability in early mathematics and reading achievement resulted from substantially overlapping time invariant factors that correlate above .90. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus.
Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10(-8), odds ratio = 1.70) and Korean (P = 8.33 × 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-κB subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.


The Effects of Tai Chi Mind-Body Approach on the Mechanisms of Gulf War Illness: an Umbrella Review.
Gulf War illness (GWI) is a chronic and multisymptom disorder affecting military veterans deployed to the 1991 Persian Gulf War. It is characterized by a range of acute and chronic symptoms, including but not limited to, fatigue, sleep disturbances, psychological problems, cognitive deficits, widespread pain, and respiratory and gastrointestinal difficulties. The prevalence of many of these chronic symptoms affecting Gulf War veterans occur at markedly elevated rates compared to nondeployed contemporary veterans. To date, no effective treatments for GWI have been identified. The overarching goal of this umbrella review was to critically evaluate the evidence for the potential of Tai Chi mind-body exercise to benefit and alleviate GWI symptomology. Based on the most prevalent GWI chronic symptoms and case definitions established by the Centers for Disease Control and Prevention and the Kansas Gulf War Veterans Health Initiative Program, we reviewed and summarized the evidence from 7 published systematic reviews and meta-analyses. Our findings suggest that Tai Chi may have the potential for distinct therapeutic benefits on the major prevalent symptoms of GWI. Future clinical trials are warranted to examine the feasibility, efficacy, durability and potential mechanisms of Tai Chi for improving health outcomes and relieving symptomology in GWI.


Genetics of cognition: outline of a collaborative twin study.
A multidisciplinary collaborative study examining cognition in a large sample of twins is outlined. A common experimental protocol and design is used in The Netherlands, Australia and Japan to measure cognitive ability using traditional IQ measures (i.e., psychometric IQ), processing speed (e.g., reaction time [RT] and inspection time [IT]), and working memory (e.g., spatial span, delayed response [DR] performance). The main aim is to investigate the genetic covariation among these cognitive phenotypes in order to use the correlated biological markers in future linkage and association analyses to detect quantitative-trait loci (QTLs). We outline the study and methodology, and report results from our preliminary analyses that examines the heritability of processing speed and working memory indices, and their phenotypic correlation with IQ. Heritability of Full Scale IQ was 87% in the Netherlands, 83% in Australia, and 71% in Japan. Heritability estimates for processing speed and working memory indices ranged from 33-64%. Associations of IQ with RT and IT (-0.28 to -0.36) replicated previous findings with those of higher cognitive ability showing faster speed of processing. Similarly, significant correlations were indicated between IQ and the spatial span working memory task (storage [0.31], executive processing [0.37]) and the DR working memory task (0.25), with those of higher cognitive ability showing better memory performance. These analyses establish the heritability of the processing speed and working memory measures to be used in our collaborative twin study of cognition, and support the findings that individual differences in processing speed and working memory may underlie individual differences in psychometric IQ.


Empirically evaluating the impact of adjudicative tribunals in the health sector: context, challenges and opportunities.
Adjudicative tribunals are an integral part of health system governance, yet their real-world impact remains largely unknown. Most assessments focus on internal accountability and use anecdotal methodologies; few, studies if any, empirically evaluate their external impact and use these data to test effectiveness, track performance, inform service improvements and ultimately strengthen health systems. Given that such assessments would yield important benefits and have been conducted successfully in similar settings (e.g. specialist courts), their absence is likely attributable to complexity in the health system, methodological difficulties and the legal environment within which tribunals operate. We suggest practical steps for potential evaluators to conduct empirical impact evaluations along with an evaluation matrix template featuring possible target outcomes and corresponding surrogate endpoints, performance indicators and empirical methodologies. Several system-level strategies for supporting such assessments have also been suggested for academics, health system institutions, health planners and research funders. Action is necessary to ensure that policymakers do not continue operating without evidence but can rather pursue data-driven strategies that are more likely to achieve their health system goals in a cost-effective way.


Proceedings of the 3rd Expert Consultation and Planning Meeting on Infant and Young Child Nutrition--(Part 1).
During the 2nd ILSI SEA Region Expert Consultation and Planning Meeting in 2011, the following information gaps were identified: (i) Some Southeast Asian countries did not have data on infant and young child feeding (IYCF) indicators; (ii) There is a need to know the reasons for the disparities in duration of breastfeeding, age of giving complementary foods, and other breastfeeding and complementary feeding practices in Southeast Asian populations; (iii) Optimal complementary feeding practices that are most suitable in the context of Southeast Asia need to be identified. This report presents highlights from a literature review regarding the above topics. Findings from nationwide surveys and small scale studies were compiled to provide a snapshot of the state of infant and young child feeding practices in the region. Results for Cambodia, Indonesia, Philippines, and Vietnam are presented here.


BabyMEG: A whole-head pediatric magnetoencephalography system for human brain development research.
We developed a 375-channel, whole-head magnetoencephalography (MEG) system ("BabyMEG") for studying the electrophysiological development of human brain during the first years of life. The helmet accommodates heads up to 95% of 36-month old boys in the USA. The unique two-layer sensor array consists of: (1) 270 magnetometers (10 mm diameter, ∼15 mm coil-to-coil spacing) in the inner layer, (2) thirty-five three-axis magnetometers (20 mm × 20 mm) in the outer layer 4 cm away from the inner layer. Additionally, there are three three-axis reference magnetometers. With the help of a remotely operated position adjustment mechanism, the sensor array can be positioned to provide a uniform short spacing (mean 8.5 mm) between the sensor array and room temperature surface of the dewar. The sensors are connected to superconducting quantum interference devices (SQUIDs) operating at 4.2 K with median sensitivity levels of 7.5 fT/√Hz for the inner and 4 fT/√Hz for the outer layer sensors. SQUID outputs are digitized by a 24-bit acquisition system. A closed-cycle helium recycler provides maintenance-free continuous operation, eliminating the need for helium, with no interruption needed during MEG measurements. BabyMEG with the recycler has been fully operational from March, 2015. Ongoing spontaneous brain activity can be monitored in real time without interference from external magnetic noise sources including the recycler, using a combination of a lightly shielded two-layer magnetically shielded room, an external active shielding, a signal-space projection method, and a synthetic gradiometer approach. Evoked responses in the cortex can be clearly detected without averaging. These new design features and capabilities represent several advances in MEG, increasing the utility of this technique in basic neuroscience as well as in clinical research and patient studies.


X-ray Raman scattering provides evidence for interfacial acetonitrile-water dipole interactions in aqueous solutions.
Aqueous solutions of acetonitrile (MeCN) have been studied with oxygen K-edge x-ray Raman scattering (XRS) which is found to be sensitive to the interaction between water and MeCN. The changes in the XRS spectra can be attributed to water directly interacting with MeCN and are reproduced by density functional theory calculations on small clusters of water and MeCN. The dominant structural arrangement features dipole interaction instead of H-bonds between the two species as revealed by the XRS spectra combined with spectrum calculations. Small-angle x-ray scattering shows the largest heterogeneity for a MeCN to water ratio of 0.4 in agreement with earlier small-angle neutron scattering data.


Association of sleep duration with chronic diseases in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study.
In view of the reduced number of hours devoted to sleep in modern western societies the question arises what effects might result from sleep duration on occurrence of chronic diseases. Data from 23 620 middle-aged participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study, that were recruited between 1994-1998, were analyzed by using Cox proportional hazard regression to examine the association between self-reported sleep duration at baseline and incidence of chronic diseases, such as diabetes, myocardial infarction, stroke, and cancer. During a mean follow-up period of 7.8 years 841 incident cases of type 2 diabetes, 197 cases of myocardial infarction, 169 incident strokes, and 846 tumor cases were observed. Compared to persons sleeping 7-<8 h/day, participants with sleep duration of <6 h had a significantly increased risk of stroke (Hazard Ratio (HR) = 2.06, 95% confidence interval (CI): 1.18-3.59), cancer (HR = 1.43, 95% CI: 1.09-1.87), and overall chronic diseases (HR = 1.31, 95% CI: 1.10-1.55) in multivariable adjusted models. Self-reported daytime sleep at baseline was not associated with incident chronic diseases in the overall study sample. However, there had been an effect modification of daytime sleep by hypertension showing that daytime sleep was inversely related to chronic disease risk among non-hypertensive participants but directly related to chronic diseases among hypertensives. Sleep duration of less than 6 h is a risky behavior for the development of chronic diseases, particularly stroke and cancer, and should be therefore addressed in public health campaigns.