Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase.
Exposure to organophosphorus compounds (OPs) may be fatal if untreated, and a clear and present danger posed by nerve agent OPs has become palpable in recent years. OPs inactivate acetylcholinesterase (AChE) by covalently modifying its catalytic serine. Inhibited AChE cannot hydrolyze the neurotransmitter acetylcholine leading to its build-up at the cholinergic synapses and creating an acute cholinergic crisis. Current antidotes, including oxime reactivators that attack the OP-AChE conjugate to free the active enzyme, are inefficient. Better reactivators are sought, but their design is hampered by a conformationally rigid portrait of AChE extracted exclusively from 100K X-ray crystallography and scarcity of structural knowledge on human AChE (hAChE). Here, we present room temperature X-ray structures of native and VX-phosphonylated hAChE with an imidazole-based oxime reactivator, RS-170B. We discovered that inhibition with VX triggers substantial conformational changes in bound RS-170B from a "nonproductive" pose (the reactive aldoxime group points away from the VX-bound serine) in the reactivator-only complex to a "semi-productive" orientation in the VX-modified complex. This observation, supported by concurrent molecular simulations, suggested that the narrow active-site gorge of hAChE may be significantly more dynamic than previously thought, allowing RS-170B to reorient inside the gorge. Furthermore, we found that small molecules can bind in the choline-binding site hindering approach to the phosphorous of VX-bound serine. Our results provide structural and mechanistic perspectives on the reactivation of OP-inhibited hAChE and demonstrate that structural studies at physiologically relevant temperatures can deliver previously overlooked insights applicable for designing next-generation antidotes.


The Council of Psychological Advisers.
Findings in behavioral science, including psychology, have influenced policies and reforms in many nations. Choice architecture can affect outcomes even if material incentives are not involved. In some contexts, default rules, simplification, and social norms have had even larger effects than significant economic incentives. Psychological research is helping to inform initiatives in savings, finance, highway safety, consumer protection, energy, climate change, obesity, education, poverty, development, crime, corruption, health, and the environment. No nation has yet created a council of psychological advisers, but the role of behavioral research in policy domains is likely to grow in the coming years, especially in light of the mounting interest in promoting ease and simplification ("navigability"); in increasing effectiveness, economic growth, and competitiveness; and in providing low-cost, choice-preserving approaches.


Women-focused development intervention reduces delays in accessing emergency obstetric care in urban slums in Bangladesh: a cross-sectional study.
Recognizing the burden of maternal mortality in urban slums, in 2007 BRAC (formally known as Bangladesh Rural Advancement Committee) has established a woman-focused development intervention, Manoshi (the Bangla abbreviation of mother, neonate and child), in urban slums of Bangladesh. The intervention emphasizes strengthening the continuum of maternal, newborn and child care through community, delivery centre (DC) and timely referral of the obstetric complications to the emergency obstetric care (EmOC) facilities. This study aimed to assess whether Manoshi DCs reduces delays in accessing EmOC. This cross-sectional study was conducted during October 2008 to January 2009 in the slums of Dhaka city among 450 obstetric complicated cases referred either from DCs of Manoshi or from their home to the EmOC facilities. Trained female interviewers interviewed at their homestead with structured questionnaire. Pearson's chi-square test, t-test and Mann-Whitney test were performed. The median time for making the decision to seek care was significantly longer among women who were referred from home than referred from DCs (9.7 hours vs. 5.0 hours, p < 0.001). The median time to reach a facility and to receive treatment was found to be similar in both groups. Time taken to decide to seek care was significantly shorter in the case of life-threatening complications among those who were referred from DC than home (0.9 hours vs.2.3 hours, p = 0.002). Financial assistance from Manoshi significantly reduced the first delay in accessing EmOC services for life-threatening complications referred from DC (p = 0.006). Reasons for first delay include fear of medical intervention, inability to judge maternal condition, traditional beliefs and financial constraints. Role of gender was found to be an important issue in decision making. First delay was significantly higher among elderly women, multiparity, non life-threatening complications and who were not involved in income-generating activities. Manoshi program reduces the first delay for life-threatening conditions but not non-life-threatening complications even though providing financial assistance. Programme should give more emphasis on raising awareness through couple/family-based education about maternal complications and dispel fear of clinical care to accelerate seeking EmOC.


T-cell factor 4 (tcf7l2) is the main effector of Wnt signaling during zebrafish intestine organogenesis.
The Wnt pathway orchestrates cell fate decisions during embryonic development, organogenesis, and adult tissues homeostasis. T-cell factor (Tcf )/lymphoid enhancer-binding factor (Lef) transcription factors are the downstream effectors of canonical Wnt signaling. Upon Wnt signal activation, beta-catenin stabilizes and translocates to the nucleus, where it interacts with Tcfs activating the transcription of Wnt target genes. In the absence of Wnt, levels of stable beta-catenin are reduced by the action of adenomatous polyposis coli (Apc) and other cytoplasmic proteins. Mutations in Apc cause constitutive accumulation of beta-catenin and inappropriate activation of the Wnt pathway. apc(mcr/mcr) fish embryos show absence of expression of tissue-specific differentiation markers in the intestine, suggesting that inappropriate activation of Wnt signaling abrogates gut organogenesis. Which Tcf transcription factor mediates Wnt signaling during zebrafish gut organogenesis remains unclear. We studied the combined effect of loss of Tcf family members and Apc in the developing embryo. Tcf4 (tcf7l2) loss rescues the apc(mcr/mcr) phenotype in the intestine. Single depletion of Tcf1 (tcf7) and Tcf3 (tcf7l1a) function in an Apc mutant background had no effect on endoderm development. This study reveals that Tcf4 (tcf7l2) is the major effector of Wnt signaling in the intestine during zebrafish organogenesis.


Pulmonary mechanics during exercise in normal males.
A body plethysmograph adapted to contain the pedals of an electrically braked cycle ergometer was used to measure pulmonary mechanics during steady-state exercise in 12 normal male subjects aged 22-65 yr. During exercise there was a progressive increase in residual volume to 119% of the value at rest (P less than 0.01), but functional residual capacity and total lung capacity did not change. The maximum expiratory flow-volume (MEFV) curves did not change and flow rates during tidal breathing did not exceed the MEFV curve. Dynamic pulmonary compliance fell to 91.3% of the control value and static expiratory pulmonary compliance fell to 76.9% of the control value (P less than 0.05). Pulmonary resistance did not change during exercise. Transpulmonary pressure during tidal breathing was negative even at the highest power outputs. The fall in compliance may be due to an increase in pulmonary capillary blood volume. These results demonstrate the importance of measuring absolute thoracic gas volume and the elastic properties of the lung when comparing pulmonary mechanics at rest and during exercise.


ORFeome cloning and global analysis of protein localization in the fission yeast Schizosaccharomyces pombe.
Cloning of the entire set of an organism's protein-coding open reading frames (ORFs), or 'ORFeome', is a means of connecting the genome to downstream 'omics' applications. Here we report a proteome-scale study of the fission yeast Schizosaccharomyces pombe based on cloning of the ORFeome. Taking advantage of a recombination-based cloning system, we obtained 4,910 ORFs in a form that is readily usable in various analyses. First, we evaluated ORF prediction in the fission yeast genome project by expressing each ORF tagged at the 3' terminus. Next, we determined the localization of 4,431 proteins, corresponding to approximately 90% of the fission yeast proteome, by tagging each ORF with the yellow fluorescent protein. Furthermore, using leptomycin B, an inhibitor of the nuclear export protein Crm1, we identified 285 proteins whose localization is regulated by Crm1.


Regulation of yeast central metabolism by enzyme phosphorylation.
As a frequent post-translational modification, protein phosphorylation regulates many cellular processes. Although several hundred phosphorylation sites have been mapped to metabolic enzymes in Saccharomyces cerevisiae, functionality was demonstrated for few of them. Here, we describe a novel approach to identify in vivo functionality of enzyme phosphorylation by combining flux analysis with proteomics and phosphoproteomics. Focusing on the network of 204 enzymes that constitute the yeast central carbon and amino-acid metabolism, we combined protein and phosphoprotein levels to identify 35 enzymes that change their degree of phosphorylation during growth under five conditions. Correlations between previously determined intracellular fluxes and phosphoprotein abundances provided first functional evidence for five novel phosphoregulated enzymes in this network, adding to nine known phosphoenzymes. For the pyruvate dehydrogenase complex E1 α subunit Pda1 and the newly identified phosphoregulated glycerol-3-phosphate dehydrogenase Gpd1 and phosphofructose-1-kinase complex β subunit Pfk2, we then validated functionality of specific phosphosites through absolute peptide quantification by targeted mass spectrometry, metabolomics and physiological flux analysis in mutants with genetically removed phosphosites. These results demonstrate the role of phosphorylation in controlling the metabolic flux realised by these three enzymes.


Streptococcal group B integrative and mobilizable element IMESag-rpsI encodes a functional relaxase involved in its transfer.
Streptococcus agalactiae or Group B Streptococcus (GBS) are opportunistic bacteria that can cause lethal sepsis in children and immuno-compromised patients. Their genome is a reservoir of mobile genetic elements that can be horizontally transferred. Among them, integrative and conjugative elements (ICEs) and the smaller integrative and mobilizable elements (IMEs) primarily reside in the bacterial chromosome, yet have the ability to be transferred between cells by conjugation. ICEs and IMEs are therefore a source of genetic variability that participates in the spread of antibiotic resistance. Although IMEs seem to be the most prevalent class of elements transferable by conjugation, they are poorly known. Here, we have studied a GBS-IME, termed IMESag-rpsI, which is widely distributed in GBS despite not carrying any apparent virulence trait. Analyses of 240 whole genomes showed that IMESag-rpsI is present in approximately 47% of the genomes, has a roughly constant size (approx. 9 kb) and is always integrated at a single location, the 3'-end of the gene encoding the ribosomal protein S9 (rpsI). Based on their genetic variation, several IMESag-rpsI types were defined (A-J) and classified in clonal complexes (CCs). CC1 was the most populated by IMESag-rpsI (more than 95%), mostly of type-A (71%). One CC1 strain (S. agalactiae HRC) was deep-sequenced to understand the rationale underlying type-A IMESag-rpsI enrichment in GBS. Thirteen open reading frames were identified, one of them encoding a protein (MobSag) belonging to the broadly distributed family of relaxases MOBV1 Protein MobSag was purified and, by a newly developed method, shown to cleave DNA at a specific dinucleotide. The S. agalactiae HRC-IMESag-rpsI is able to excise from the chromosome, as shown by the presence of circular intermediates, and it harbours a fully functional mobilization module. Further, the mobSag gene encoded by this mobile element is able to promote plasmid transfer among pneumococcal strains, suggesting that MobSag facilitates the spread of IMESag-rpsI and that this spread would explain the presence of the same IMESag-rpsI type in GBS strains belonging to different CCs.


Acupuncture versus propranolol in migraine prophylaxis: an indirect treatment comparison meta-analysis.
Propranolol is recommended as first-line treatment for preventing migraine attacks; acupuncture has not been compared with propranolol in a head-to-head trial. To compare acupuncture with propranolol using indirect treatment comparison meta-analysis. We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). Randomized controlled trials comparing acupuncture or propranolol with sham acupuncture, placebo, waiting-list control or usual care were included. We extracted information from the included trials using a standardized extraction form. The primary outcome was migraine episodes. The secondary outcomes included migraine days, migraine frequency, and adverse events. We included 19 RCTs (n = 3656) after screening 1078 articles. The analysis showed that acupuncture had a significant advantage over propranolol in reducing migraine episodes over a 4-week period (SMD - 0.74, 95% CI - 1.04 to - 0.44). Acupuncture also had a significant advantage over waiting-list control in decreasing migraine frequency (SMD - 1.57, 95% CI - 2.08 to - 1.06). Acupuncture caused fewer adverse events than propranolol (RR 0.82, 95% CI 0.11-5.94). Acupuncture had a better effect than propranolol in reducing migraine episodes in indirect comparison. The result should be confirmed in subsequent head-to-head studies. Registration: PROSPERO CRD42018108585.


Host iron redistribution as a risk factor for incident tuberculosis in HIV infection: an 11-year retrospective cohort study.
Identifying people at higher risk of developing tuberculosis with human immunodeficiency virus (HIV) infection may improve clinical management of co-infections. Iron influences tuberculosis (TB) pathogenesis, but understanding the exact mechanisms of how and timing of when iron is involved remains challenging since biological samples are rarely available from the disease susceptibility period due to the difficulty in predicting in who and when, if ever, TB will develop. The objective of this research was to determine how host iron status measured at HIV diagnosis and genotypes related to host iron metabolism were associated with incident TB. Archived clinical data, plasma and DNA were analyzed from 1139 adult participants in a large HIV-1, HIV-2 and dual seroprevalent cohort based at the Medical Research Council Laboratories in The Gambia. Incident pulmonary and/or extrapulmonary TB diagnoses a minimum of 28 days after HIV diagnosis were independently re-confirmed using available evidence (n=152). Multiple host iron status biomarkers, Haptoglobin and solute carrier family 11, member 1 (SLC11A1) genotypes were modeled to characterize how indicators of host iron metabolism were associated with TB susceptibility. Hemoglobin (incidence rate ratio, IRR=0.88, 95% CI=0.79-0.98), plasma transferrin (IRR=0.53, 0.33-0.84) and ferritin (IRR=1.26, 1.05-1.51) were significantly associated with TB after adjusting for TB susceptibility factors. While genotype associations were not statistically significant, SLC11A1 associations replicated similar directions as reported in HIV-seronegative meta-analyses. Evidence of host iron redistribution at HIV diagnosis was associated with incident TB, and genetic influences on iron homeostasis may be involved. Low hemoglobin was associated with subsequent diagnosis of TB, but when considered in combination with additional iron status biomarkers, the collective findings point to a mechanism whereby anemia and iron redistribution are likely due to viral and/or bacteria-driven processes and the host immune response to infection. As a result, iron supplementation may not be efficacious or safe under these circumstances. Clinical and nutritional management of HIV and Mycobacterium tuberculosis co-infected individuals, especially in regions where food insecurity and malnutrition co-exist, may be further improved when the iron-related TB risk factors identified here are better understood and managed to favor host rather than pathogen outcomes.


How can we design better vaccines to prevent HIV infection in women?
The human immunodeficiency virus (HIV) burden in women continues to increase, and heterosexual contact is now the most common route of infection worldwide. Effective protection of women against HIV-1 infection may require a vaccine specifically targeting mucosal immune responses in the female genital tract (FGT). To achieve this goal, a much better understanding of the immunology of the FGT is needed. Here we review the architecture of the immune system of the FGT, recent studies of potential methods to achieve the goal of mucosal protection in women, including systemic-prime, mucosal-boost, FGT-tropic vectors and immune response altering adjuvants. Advances in other fields that enhance our understanding of female genital immune correlates and the interplay between hormonal and immunological systems may also help to achieve protection of women from HIV infection.


3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles.
We have used three dimensional (3D) extrusion printing to manufacture a multi-active solid dosage form or so called polypill. This contains five compartmentalised drugs with two independently controlled and well-defined release profiles. This polypill demonstrates that complex medication regimes can be combined in a single personalised tablet. This could potentially improve adherence for those patients currently taking many separate tablets and also allow ready tailoring of a particular drug combination/drug release for the needs of an individual. The polypill here represents a cardiovascular treatment regime with the incorporation of an immediate release compartment with aspirin and hydrochlorothiazide and three sustained release compartments containing pravastatin, atenolol, and ramipril. X-ray powder diffraction (XRPD) and Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) were used to assess drug-excipient interaction. The printed polypills were evaluated for drug release using USP dissolution testing. We found that the polypill showed the intended immediate and sustained release profiles based upon the active/excipient ratio used.


Measuring thermodynamic details of DNA hybridization using fluorescence.
Modern real-time PCR systems make it easy to monitor fluorescence while temperature is varied for hundreds of samples in parallel, permitting high-throughput studies. We employed such system to investigate melting transitions of ordered nucleic acid structures into disordered random coils. Fluorescent dye and quencher were attached to oligonucleotides in such a way that changes of fluorescence intensity with temperature indicated progression of denaturation. When fluorescence melting data were compared with traditional ultraviolet optical experiments, commonly used dye/quencher combinations, like fluorescein and tetramethylrhodamine, showed substantial discrepancies. We have therefore screened 22 commercially available fluorophores and quenchers for their ability to reliably report annealing and melting transitions. Dependence of fluorescence on temperature and pH was also investigated. The optimal performance was observed using Texas Red or ROX dyes with Iowa Black RQ or Black Hole quenchers. These labels did not alter two-state nature of duplex melting process and provided accurate melting temperatures, free energies, enthalpies, and entropies. We also suggest a new strategy for determination of DNA duplex thermodynamics where concentration of a dye-labeled strand is kept constant and its complementary strand modified with a quencher is added at increasing excess. These methodological improvements will help build predictive models of nucleic acid hybridization.


Cleansing and Imputation of Body Mass Index Data and Its Impact on a Machine Learning Based Prediction Model.
A challenge of using electronic health records for secondary analyses is data quality. Body mass index (BMI) is an important predictor for various diseases but often not documented properly. The aim of our study is to perform data cleansing on BMI values and to find the best method for an imputation of missing values in order to increase data quality. Further, we want to assess the effect of changes in data quality on the performance of a prediction model based on machine learning. After data cleansing on BMI data, we compared machine learning methods and statistical methods in their accuracy of imputed values using the root mean square error. In a second step, we used three variations of BMI data as a training set for a model predicting the occurrence of delirium. Neural network and linear regression models performed best for imputation. There were no changes in model performance for different BMI input data. Although data quality issues may lead to biases, it does not always affect performance of secondary analyses.


Identification and Validation of a Common Stem Rust Resistance Locus in Two Bi-parental Populations.
Races belonging to Ug99 lineage of stem rust fungus Puccinia graminis f. sp. tritici (Pgt) continue to pose a threat to wheat (Triticum aestivum L.) production in various African countries. Growing resistant varieties is the most economical and environmentally friendly control measure. Recombinant inbred line (RIL) populations from the crosses of susceptible parent 'Cacuke' with the resistant parents 'Huhwa' and 'Yaye' were phenotyped for resistance at the seedling stage to Pgt race TTKSK (Ug99) and in adult plants in field trials at Njoro, Kenya for two seasons in 2016. Using the Affymetrix Axiom breeders SNP array, two stem rust resistance genes, temporarily designated as SrH and SrY, were identified and mapped on chromosome arm 2BL through selective genotyping and bulked segregant analysis (BSA), respectively. Kompetitive allele specific polymorphism (KASP) markers and simple sequence repeat (SSR) markers were used to saturate chromosome arm 2BL in both RIL populations. SrH mapped between markers cim109 and cim114 at a distance of 0.9 cM proximal, and cim117 at 2.9 cM distal. SrY was flanked by markers cim109 and cim116 at 0.8 cM proximal, and IWB45932 at 1.9 cM distal. Two Ug99-effective stem rust resistance genes derived from bread wheat, Sr9h and Sr28, have been reported on chromosome arm 2BL. Infection types and map position in Huhwa and Yaye indicated that Sr28 was absent in both the parents. However, susceptible reactions produced by resistant lines from both populations against Sr9h-virulent race TTKSF+ confirmed the presence of a common resistance locus Sr9h in both lines. Test of allelism is required to establish genetic relationships between genes identified in present study and Sr9h. Marker cim117 linked to SrH was genotyped on set of wheat lines with Huhwa in the pedigree and is advised to be used for marker assisted selection for this gene, however, a combination of phenotypic and genotypic assays is desirable for both genes especially for selection of Sr9h in breeding programs.


Investigating accuracy of 3D printed liver models with computed tomography.
The aim of this study was to evaluate the accuracy of three-dimensional (3D) printed liver models developed by a cost-effective approach for establishing validity of using these models in a clinical setting. Fifteen patients undergoing laparoscopic liver resection in a single surgical department were included. Patient-specific, 1-1 scale 3D printed liver models including the liver, tumor, and vasculature were created from contrast-enhanced computed tomography (CT) images using a cost-effective approach. The 3D models were subsequently CT scanned, 3D image post-processing was performed, and these 3D computer models (MCT) were compared to the original 3D models created from the original patient images (PCT). 3D computer models of each type were co-registered using a point set registration method. 3D volume measurements of the liver and lesions were calculated and compared for each set. In addition, Hausdorff distances were calculated and surface quality was compared by generated heatmaps. The median liver volume in MCT was 1,281.84 [interquartile range (IQR) =296.86] cm3, and 1,448.03 (IQR =413.23) cm3 in PCT. Analysis of differences between surfaces showed that the median value of mean Hausdorff distances for liver parenchyma was 1.92 mm. Bland-Altman plots revealed no significant bias in liver volume and diameters of hepatic veins and tumor location. Median errors of all measured vessel diameters were smaller than CT slice height. There was a slight trend towards undersizing anatomical structures, although those errors are most likely due to source imaging. We have confirmed the accuracy of 3D printed liver models created by using the low-cost method. 3D models are useful tools for pre-operative planning and intra-operative guidance. Future research in this field should continue to move towards clinical trials for assessment of the impact of these models on pre-surgical planning decisions and perioperative outcomes.


Correlation of tape location and tension with surgical outcome after transobturator suburethral tape procedures.
To explore, using 4D ultrasound, the importance of location and tension of transobturator sub- urethral tape (TOT) with respect to surgical outcome. Enrolled into the study were 56 women who had undergone TOT placement in the treatment of urodynamic stress incontinence. Tape location and tension were assessed by 4D ultrasound with the women at rest, during straining and during coughing. Ultrasound parameters representing tape location included the sagittal tape-symphysis pubis distance (sTSD), sagittal tape-symphysis pubis angle (sTSA) and tape percentile (an indication of tape position along the urethra with respect to urethral length), while those representing tape tension included urethral encroachment, sagittal tape-urethra distances at the upper end (sTUDu), center (sTUDc) and lower end (sTUDl) of the tape and axial urethral central echolucent area at the tape center (aUCEAc). In women in whom the tape procedure had been successful, during increased intra-abdominal pressure sTSA and the incidence of urethral encroachment increased, while sTUDu, sTUDc, sTUDl and aUCEAc decreased. Compared with those reporting no stress urinary incontinence (SUI) symptoms, women who reported SUI postoperatively had lower tape percentile. Women with SUI postoperatively demonstrated no manifestation on ultrasound of urethral encroachment at rest or during increased intra-abdominal pressure. Women with postoperative overactive bladder (OAB) symptoms had shorter resting sTSD and larger resting sTSA than did women without OAB symptoms. Women reporting postoperative de novo or worsening voiding difficulty had larger resting sTSA and higher incidence of urethral encroachment at rest than did women without this difficulty. Both tape location and tape tension are associated with surgical outcome of TOT procedures. Assessment of tape location and tension can be achieved using 4D ultrasound.


No Evidence of Mosquito Involvement in the Transmission of Equine Hepacivirus (Flaviviridae) in an Epidemiological Survey of Austrian Horses.
Prevalence studies have demonstrated a global distribution of equine hepacivirus (EqHV), a member of the family Flaviviridae. However, apart from a single case of vertical transmission, natural routes of EqHV transmission remain elusive. Many known flaviviruses are horizontally transmitted between hematophagous arthropods and vertebrate hosts. This study represents the first investigation of potential EqHV transmission by mosquitoes. More than 5000 mosquitoes were collected across Austria and analyzed for EqHV ribonucleic acid (RNA) by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Concurrently, 386 serum samples from horses in eastern Austria were analyzed for EqHV-specific antibodies by luciferase immunoprecipitation system (LIPS) and for EqHV RNA by RT-qPCR. Additionally, liver-specific biochemistry parameters were compared between EqHV RNA-positive horses and EqHV RNA-negative horses. Phylogenetic analysis was conducted in comparison to previously published sequences from various origins. No EqHV RNA was detected in mosquito pools. Serum samples yielded an EqHV antibody prevalence of 45.9% (177/386) and RNA prevalence of 4.15% (16/386). EqHV RNA-positive horses had significantly higher glutamate dehydrogenase (GLDH) levels (p = 0.013) than control horses. Phylogenetic analysis showed high similarity between nucleotide sequences of EqHV in Austrian horses and EqHV circulating in other regions. Despite frequently detected evidence of EqHV infection in Austrian horses, no viral RNA was found in mosquitoes. It is therefore unlikely that mosquitoes are vectors of this flavivirus.


Cannabinoids and schizophrenia: therapeutic prospects.
Approximately one third of patients diagnosed with schizophrenia do not achieve adequate symptom control with standard antipsychotic drugs (APs). Some of these may prove responsive to clozapine, but non-response to APs remains an important clinical problem and cause of increased health care costs. In a significant proportion of patients, schizophrenia is associated with natural and iatrogenic metabolic abnormalities (obesity, dyslipidaemia, impaired glucose tolerance or type 2 diabetes mellitus), hyperadrenalism and an exaggerated HPA response to stress, and chronic systemic inflammation. The endocannabinoid system (ECS) in the brain plays an important role in maintaining normal mental health. ECS modulates emotion, reward processing, sleep regulation, aversive memory extinction and HPA axis regulation. ECS overactivity contributes to visceral fat accumulation, insulin resistance and impaired energy expenditure. The cannabis plant synthesises a large number of pharmacologically active compounds unique to it known as phytocannabinoids. In contrast to the euphoric and pro-psychotic effects of delta-9-tetrahydrocannabinol (THC), certain non-intoxicating phytocannabinoids have emerged in pre-clinical and clinical models as potential APs. Since the likely mechanism of action does not rely upon dopamine D2 receptor antagonism, synergistic combinations with existing APs are plausible. The anti-inflammatory and immunomodulatory effects of the non-intoxicating phytocannabinoid cannabidiol (CBD) are well established and are summarised below. Preliminary data reviewed in this paper suggest that CBD in combination with a CB1 receptor neutral antagonist could not only augment the effects of standard APs but also target the metabolic, inflammatory and stress-related components of the schizophrenia phenotype.


Behavioural Difficulties That Co-occur With Specific Word Reading Difficulties: A UK Population-Based Cohort Study.
This study aimed to examine the association between specific word reading difficulties (SWRD) identified at age 7 years using a discrepancy approach and subsequent dimensional measures of behavioural difficulties reported by teachers and parents at age 11 years. Behavioural problems were assessed using the Strengths and Difficulties Questionnaire. Secondary analysis of a UK representative population-based sample of children (n = 12,631) was conducted using linear regression models. There were 284 children (2.2%) identified with SWRD at age 7 years. Children with SWRD had significantly higher scores on all measures of behavioural difficulties in unadjusted analysis. SWRD was associated with elevated behavioural difficulties at age 11 years according to parent report, and with greater emotional problems, hyperactivity and conduct issues according to teachers, even after having controlled for baseline difficulties. These results were replicated for children with low reading attainment, but no cognitive ability discrepancy. Categories of special educational need into which children with SWRD were classed at school were varied. Given high rates of co-occurring behavioural difficulties, assessment that identifies each individual child's specific functional, rather than categorical, difficulties is likely to be the most effective way of providing classroom support.


Valproic acid causes dose- and time-dependent changes in nuclear structure in prostate cancer cells in vitro and in vivo.
Histone deacetylase inhibitors such as valproic acid (VPA) are promising anticancer agents that change the acetylation status of histones and loosen the chromatin structure. We assessed nuclear structure changes induced by VPA in prostate cancer LNCaP, CWR22R, DU145, and PC3 cell lines and xenografts and their potential use as a biomarker of treatment. In vitro tissue microarrays consisted of prostate cancer cell lines treated for 3, 7, or 14 days with 0, 0.6, or 1.2 mmol/L VPA. In vivo tissue microarrays consisted of cores from prostate cancer xenografts from nude mice treated for 30 days with 0.2% or 0.4% VPA in drinking water. Digital images of at least 200 Feulgen DNA-stained nuclei were captured using the Nikon CoolScope and nuclear alterations were measured. With a set of seven most frequently significant nuclear alterations (determined by univariate logistic regression analysis), control and VPA treatment nuclei were compared in vitro and in vivo. Depending on the cell line, area under the curve-receiver operating characteristics ranged between 0.6 and 0.9 and were dose- and time-dependent both in vitro and in vivo. Also, VPA treatment caused significant nuclear alterations in normal drug-filtering organs (liver and kidney tissue). In vitro and in vivo VPA treatment of prostate cancer cell lines results in significant dose- and time-dependent changes in nuclear structure. Further, VPA induces nuclear structural changes in normal liver and kidney tissue, which likely reflects a natural physiologic response. Therefore, nuclear structural alterations may serve as a biomarker for histone deacetylase inhibitor treatment.


Prevalence of migraine and tension-type headache in primary-school children in Shiraz.
From January to June 2003 we determined the prevalence of the various types of headache in 2226 schoolchildren in Shiraz (age 6-13 years) selected by multistage random sampling. Data were collected by questionnaire and clinical examination. International Headache Society criteria were used for diagnosis. The overall prevalence of headache was 31%. Prevalence rates of migraine and tension-type headache were 1.7% and 5.5% respectively. The prevalence of headache increased with age and girls were significantly more likely to report tensions-type headache. Positive family history of headache and abnormal sleep pattern were significantly associated with migraine.


Lectin-induced agglutination method of urinary exosomes isolation followed by mi-RNA analysis: Application for prostate cancer diagnostic.
Prostate cancer is the most common cancer in men. Prostate-specific antigen has, however, insufficient diagnostic specificity. Novel complementary diagnostic approaches are greatly needed. MiRNAs are small regulatory RNAs which play an important role in tumorogenesis and are being investigated as a cancer biomarker. In addition to their intracellular regulatory functions, miRNAs are secreted into the extracellular space and can be found in various body fluids, including urine. The stability of extracellular miRNAs is defined by association with proteins, lipoprotein particles, and membrane vesicles. Among the known forms of miRNA packaging, tumour-derived exosome-enclosed miRNAs is thought to reflect the vital activity of cancer cells. The assessment of the exosomal fraction of urinary miRNA may present a new and highly specific method for prostate cancer diagnostics; however, this is challenged by the absence of reliable and inexpensive methods for isolation of exosomes. Prostate cancer (PC) cell lines and urine samples collected from 35 PC patients and 35 healthy donors were used in the study. Lectins, phytohemagglutinin, and concanavalin A were used to induce agglutination of exosomes. The efficiency of isolation process was evaluated by AFM and DLS assays. The protein content of isolated exosomes was analysed by western blotting. Exosomal RNA was assayed by automated electrophoresis and expression level of selected miRNAs was evaluated by RT-qPCR. The diagnostic potency of the urinary exosomal miRNA assessment was estimated by the ROC method. The formation of multi-vesicular agglutinates in urine can be induced by incubation with lectin at a final concentration of 2 mg/ml. These agglutinates contain urinary exosomes and may be pelleted by centrifugation with a relatively low G-force. The analysis of PC-related miRNA in urinary exosomes revealed significant up-regulation of miR-574-3p, miR-141-5p, and miR-21-5p associated with PC. Lectin-induced aggregation is a low-cost and easily performed method for isolation of exosomes from urine. Isolated exosomes can be further analysed in terms of miRNA content. The miRNA profile of urinary exosomes reflects development of prostate cancer and may present a promising diagnostic tool.


Listeriolysin is processed efficiently into an MHC class I-associated epitope in Listeria monocytogenes-infected cells.
Listeria monocytogenes is an intracellular pathogen that enters the cytoplasm of infected cells by secreting listeriolysin (LLO), a protein that destroys the phagosomal membrane. In infected mice, LLO is a major Ag detected by protective, MHC class I-restricted CTLs. Although the role of LLO in pathogenesis and host immunity is well established, its rate of intracellular synthesis has yet to be determined. Herein we show that cytosolic L. monocytogenes secrete LLO at a relatively low rate of approximately one molecule per bacterium per minute. Under extracellular labeling conditions, the rate of LLO secretion is approximately 50-fold higher. Intracellular LLO synthesis suffices, however, for the accumulation of 600 to 1000 H-2Kd-associated LLO 91-99 epitopes per cell. We calculate that between four and 11 LLO molecules are degraded for each LLO 91-99 epitope bound by H-2Kd. Our findings indicate that the antigenicity of LLO, with respect to MHC class I-restricted CTLs, cannot be attributed to high levels of intracellular secretion. Rather, LLO is a dominant Ag because it is rapidly degraded and very efficiently processed into an MHC class I-associated epitope.


Heralded preparation and readout of entangled phonons in a photonic crystal cavity.
We propose a realistic protocol for the preparation and readout of mechanical Bell states in an optomechanical system. The proposal relies on parameters characterizing a photonic crystal cavity mode, coupled to two localized flexural modes of the structure, but equally applies to other optomechanical systems in the same parameter range. The nonclassical states are heralded via optical postselection and revealed in specific interference patterns characterizing the emission at the cavity frequency.


Evolution of Joint-Level Control for Quadrupedal Locomotion.
We investigate a hierarchical approach to robot control inspired by joint-level control in animals. The method combines a high-level controller, consisting of an artificial neural network (ANN), with joint-level controllers based on digital muscles. In the digital muscle model (DMM), morphological and control aspects of joints evolve concurrently, emulating the musculoskeletal system of natural organisms. We introduce and compare different approaches for connecting outputs of the ANN to DMM-based joints. We also compare the performance of evolved animats with ANN-DMM controllers with those governed by only high-level (ANN-only) and low-level (DMM-only) controllers. These results show that DMM-based systems outperform their ANN-only counterparts while also exhibiting less complex ANNs in terms of the number of connections and neurons. The main contribution of this work is to explore the evolution of artificial systems where, as in natural organisms, some aspects of control are realized at the joint level.


Student exchange for nursing students: does it raise cultural awareness'? A descriptive, qualitative study.
With free movement for citizens within the European Union and with distant parts of our globe becoming more accessible, cultural awareness and cultural competence are becoming important skills for nurses. Internationalisation and raising awareness of other cultural contexts are essential elements in Swedish higher education, thus explaining the variety of student exchange programmes that are available. The aim of this study was to explore Swedish nursing students' perceptions of student exchange and their experiences. Data were collected through group interviews and then analysed following the principles of content analysis. Our analysis resulted in three categories: Preparing to go abroad, Reasons for going abroad and From expectation to experience. Cultural aspects and cultural awareness were emphasised as strong motivational factors, both personal and professional, behind participation in student exchange programmes. Information was also highlighted as a crucial means of reaching potential students as well as the power of knowledge through personal experience. This study highlights the importance of student exchange in expanding the individual student's personal and professional horizons. It also stresses the importance of including a transcultural nursing element in nursing curricula.


InterPro in 2011: new developments in the family and domain prediction database.
InterPro (http://www.ebi.ac.uk/interpro/) is a database that integrates diverse information about protein families, domains and functional sites, and makes it freely available to the public via Web-based interfaces and services. Central to the database are diagnostic models, known as signatures, against which protein sequences can be searched to determine their potential function. InterPro has utility in the large-scale analysis of whole genomes and meta-genomes, as well as in characterizing individual protein sequences. Herein we give an overview of new developments in the database and its associated software since 2009, including updates to database content, curation processes and Web and programmatic interfaces.


The Effect of Pain Relief on Daily Physical Activity: In-Home Objective Physical Activity Assessment in Chronic Low Back Pain Patients after Paravertebral Spinal Block.
This study evaluates the effect of paravertebral spinal injection (PSI), utilizing both subjective and objective assessments in chronic low back pain (LBP) associated with facet joint arthrosis over a one-month duration. Subjective questionnaires included the visual analogue scale (VAS) for pain, the Oswestry Disability Index, the Health Survey SF-12, and the short Falls Efficacy Scale International (FES-I). Objective assessments included in-clinic gait and Timed Up and Go (TUG) tests using wearable sensors, as well as 48 h daily physical activity (DPA) monitored using a chest-worn triaxial accelerometer. Subjective and objective measures were performed prior to treatment, immediately after the treatment, and one month after the treatment. Eight LBP patients were recruited for this study (mean age = 54 ± 13 years, body mass index = 31.41 ± 6.52 kg/m², 50% males). Results show significant decrease in pain (~55%, p < 0.05) and disability (Oswestry scores, ~21%, p < 0.05). In-clinic gait and TUG were also significantly improved (~16% and ~18% faster walking and shorter TUG, p < 0.05); however, DPA, including the percentage of physical activities (walking and standing) and the number of steps, showed no significant change after PSI (p > 0.25; effect size ≤ 0.44). We hypothesize that DPA may continue to be truncated to an extent by conditioned fear-avoidance, a psychological state that may prevent increase in daily physical activity to avoid pain.


Ancient fossil specimens of extinct species are genetically more distant to an outgroup than extant sister species are.
There exists a remarkable correlation between genetic distance as measured by protein or DNA dissimilarity and time of species divergence as inferred from fossil records. This observation has provoked the molecular clock hypothesis. However, data inconsistent with the hypothesis have steadily accumulated in recent years from studies of extant organisms. Here the published DNA and protein sequences from ancient fossil specimens were examined to see if they would support the molecular clock hypothesis. The hypothesis predicts that ancient specimens cannot be genetically more distant to an outgroup than extant sister species are. Also, two distinct ancient specimens cannot be genetically more distant than their extant sister species are. The findings here do not conform to these predictions. Neanderthals are more distant to chimpanzees and gorillas than modern humans are. Dinosaurs are more distant to frogs than extant birds are. Mastodons are more distant to opossums than other placental mammals are. The genetic distance between dinosaurs and mastodons is greater than that between extant birds and mammals. Therefore, while the molecular clock hypothesis is consistent with some data from extant organisms, it has yet to find support from ancient fossils. Far more damaging to the hypothesis than data from extant organisms, which merely question the constancy of mutation rate, the study of ancient fossil organisms here challenges for the first time the fundamental premise of modern evolution theory that genetic distances had always increased with time in the past history of life on Earth.


Epidemiology of necrotizing meningoencephalitis in Pug dogs.
Although the histopathologic features of necrotizing meningoencephalitis (NME) have been described previously, little information is available concerning the signalment, geographic distribution, seasonal onset, treatment, and survival of affected dogs. Sixty Pugs with NME and 14 contemporaneous control Pugs with other intracranial diseases (non-NME group). Pugs that were euthanized or died because of intracranial disease were prospectively obtained. All dogs had necropsy, histopathology, and testing for various infectious diseases and were subsequently divided into NME and non-NME groups. Signalment, geographic distribution, seasonal onset, treatment, and survival were compared between groups. In Pugs with NME, median age at onset of clinical signs was 18 months (range, 4-113 months). A greater proportion of female dogs were present in the NME group (40/60) compared with the control group (6/14). Pugs with NME had a significantly lower mean weight (7.81 kg) than control Pugs (9.79 kg) (P= .012). Mean survival in Pugs with NME was 93 days (range, 1-680 days), with dogs receiving any form of treatment living significantly longer than those that were not treated (P= .003). Anticonvulsive drugs were the only treatment significantly associated with longer survival (P= .003). NME appears to be a common cause of intracranial signs in Pugs, based on the high proportion of NME dogs reported in this population. Pugs with NME are most commonly young adult female dogs. Although further investigation is needed to determine the optimal treatment of NME, anticonvulsive drugs appear to beneficially affect duration of survival.


Cellular telephones and cancer--a nationwide cohort study in Denmark.
Use of cellular telephones is increasing exponentially and has become part of everyday life. Concerns about possible carcinogenic effects of radiofrequency signals have been raised, although they are based on limited scientific evidence. A retrospective cohort study of cancer incidence was conducted in Denmark of all users of cellular telephones during the period from 1982 through 1995. Subscriber lists from the two Danish operating companies identified 420 095 cellular telephone users. Cancer incidence was determined by linkage with the Danish Cancer Registry. All statistical tests are two-sided. Overall, 3391 cancers were observed with 3825 expected, yielding a significantly decreased standardized incidence ratio (SIR) of 0.89 (95% confidence interval [CI] = 0.86 to 0.92). A substantial proportion of this decreased risk was attributed to deficits of lung cancer and other smoking-related cancers. No excesses were observed for cancers of the brain or nervous system (SIR = 0.95; 95% CI = 0.81 to 1.12) or of the salivary gland (SIR = 0.72; 95% CI = 0.29 to 1.49) or for leukemia (SIR = 0.97; 95% CI = 0.78-1.21), cancers of a priori interest. Risk for these cancers also did not vary by duration of cellular telephone use, time since first subscription, age at first subscription, or type of cellular telephone (analogue or digital). Analysis of brain and nervous system tumors showed no statistically significant SIRs for any subtype or anatomic location. The results of this investigation, the first nationwide cancer incidence study of cellular phone users, do not support the hypothesis of an association between use of these telephones and tumors of the brain or salivary gland, leukemia, or other cancers.


Maternal depression from pregnancy to 4 years postpartum and emotional/behavioural difficulties in children: results from a prospective pregnancy cohort study.
Considerable attention has been focused on women's mental health in the perinatal period and the subsequent impacts on children. Comparatively, we know much less about maternal depression at later time points and the potential implications for child mental health. The objective of this paper was to explore the association between maternal depression and child emotional/behavioural difficulties at 4 years postpartum, taking into account earlier episodes of perinatal depression. The Maternal Health Study is a prospective cohort study of 1,507 nulliparous women. Maternal depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS) in early pregnancy and at 3, 6 and 12 months postpartum and again at 4 years postpartum. Maternal depressive symptoms at 4 years postpartum were associated with significantly increased odds of child emotional/behavioural difficulties (odds ratio (OR) = 3.46, 95 % confidence interval (CI) = 2.21-5.43). This remained significant after adjusting for earlier episodes of perinatal depression and socio-demographic characteristics (OR = 2.07, 95 % CI = 1.18-3.63). We also observed a robust association between child difficulties at age 4 and measures of socio-economic disadvantage. Our findings suggest a pressing need to rethink current paradigms of maternal health surveillance and extend mental health surveillance and support to at least 4 years postpartum.


The role of resistance training in patients with cardiac disease.
During the past decade, research has demonstrated that resistance training is a safe and effective mode of exercise for cardiac patients who are suitable candidates for conventional exercise rehabilitation. Fears of an excessive pressor response seem unwarranted and the incidence of ischaemia is less than that during dynamic exercise such as walking and cycling. Major benefits from resistance training include improved muscular strength, increased peak exercise capacity and submaximal endurance, reduced ratings of perceived exertion during exercise and improved self-efficacy in strength-related tasks. The effects of resistance training on blood pressure and blood lipids levels are equivocal, but there may be positive effects on glucose metabolism. This form of training is likely to assume greater importance in cardiac rehabilitation in the future.


Abnormal functional activation during a simple word repetition task: A PET study of adult dyslexics.
Eight dyslexic subjects, impaired on a range of tasks requiring phonological processing, were matched for age and general ability with six control subjects. Participants were scanned using positron emission tomography (PET) during three conditions: repeating real words, repeating pseudowords, and rest. In both groups, speech repetition relative to rest elicited widespread bilateral activation in areas associated with auditory processing of speech; there were no significant differences between words and pseudowords. However, irrespective of word type, the dyslexic group showed less activation than the control group in the right superior temporal and right post-central gyri and also in the left cerebellum. Notably, the right anterior superior temporal cortex (Brodmann's area 22 [BA 22]) was less activated in each of the eight dyslexic subjects, compared to each of the six control subjects. This deficit appears to be specific to auditory repetition as it was not detected in a previous study of reading which used the same sets of stimuli (Brunswick, N., McCrory, E., Price, C., Frith, C.D., & Frith, U. [1999]. Explicit and implicit processing of words and pseudowords by adult developmental dyslexics: A search for Wernicke's Wortschatz? Brain, 122, 1901-1917). This implies that the observed neural manifestation of developmental dyslexia is task-specific (i.e., functional rather than structural). Other studies of normal subjects indicate that attending to the phonetic structure of speech leads to a decrease in right-hemisphere processing. Lower right hemisphere activation in the dyslexic group may therefore indicate less processing of non-phonetic aspects of speech, allowing greater salience to be accorded to phonological aspects of attended speech.


Nitrogen and Potassium Effect on the Color of Red Roses.
Variable coloration was displayed by Rosa hybrida, var. Better Times, grown in solutions of various concentrations of nitrogen and potassium. As revealed by measuring the color in Hunter values, growth in high potassium and low nitrogen concentrations resulted in less reddish and more bluish roses, while cultivation in a low nitrogen concentration, irrespective of the N/ K ratio, resulted in roses which were more lightly colored than those grown in high concentrations of nitrogen and potassium. The results were statistically significant at the 1 percent probability level.


Alteration of copper-zinc superoxide dismutase 1 expression by influenza A virus is correlated with virus replication.
Viruses have evolved mechanisms designated to potentiate virus replication by modulating the physiological condition of host cells. The generation of reactive oxygen species (ROS) during infection with influenza virus A (IAV) is a well-established mechanism in animals, but little is known about the generation of ROS in in vitro cell culture models and about its role in virus replication. We show here that IAV H1N1 infected human alveolar cells increased superoxide anion level mainly by suppressing the copper-zinc superoxide dismutase 1 (SOD1) gene, and that the SOD1-controlled generation of ROS was tightly correlated with virus replication. The transcription factor Sp1, which is a major element of the proximal region of the sod1 promoter, was slightly downregulated at the transcriptional level during IAV infection, and subsequently modulated by post-translational control. A gradual reduction of whole Sp1 was largely responsible for the repression of sod1 transcription with increasing time post-infection, and their rescue by the proteasome inhibitor, MG132, proved the involvement of proteasomal degradation in Sp1 regulation during IAV infection. Furthermore, we observed that expression of viral polymerase PB1 was inversely proportional to SOD1 level. The antioxidant N-acetyl-cysteine (NAC) neutralized IAV-mediated oxidative stress, and either NAC treatment or sod1 transfection considerably diminished viral polymerase activity. These data indicate that IAV-induced SOD1 repression, which may cause impaired redox balance in host cells, can be attributed, at least in part, to enhance viral replication.


Primary Breast Cancer Tumor and Patient Characteristics as Predictors of Adjuvant Radiation Therapy.
Adjuvant radiation therapy reduces the risk of local recurrence of breast cancer. Our study identifies patient and tumor characteristics that guide the use of adjuvant radiation therapy and evaluates our adherence to recommended guidelines. A retrospective review was undertaken of 1,667 stage I-III breast cancer patients treated at a regional cancer center from 2004 to 2007. Univariate analysis was used to select factors for entry into a multivariate stepwise logistic regression model. Descriptive statistics was used to compare use of radiation therapy of 382 stage I-III breast cancer patients diagnosed in 2013 to those from 2004 to 2007. The primary indicators for any radiation therapy (n = 935) were breast conserving surgery (OR 79.5, 95% CI [47.6-132.9]), four to nine positive lymph nodes (71.9, [17.0-304.7]), and greater than nine positive lymph nodes (60.5, [7.9-460.8]). In post-mastectomy patients (n = 408), the indicators for radiation therapy were four to nine positive lymph nodes (29.4, [12.9-67.4]) and greater than nine positive lymph nodes (108.3, [14.5-807.5]). In breast conserving surgery patients (n = 1,081) 96.1% were offered radiation therapy. Patients offered local-regional radiation therapy were more likely to have any positive nodes (ORs 4.3-91.0), have had a mastectomy (4.3, [2.2-8.4]), and had larger tumors (1.6, [1.3-2.0]). Local-regional radiation therapy was recommended less frequently in node positive patients in 2004-2007 (35.0%) compared to in 2013 (70.5%) [p < 0.001]. Patients who had a breast conserving surgery or had four or more positive lymph nodes were more likely to receive radiation therapy. Patients with any positive lymph nodes, larger tumors, or who had a mastectomy were more likely to receive local-regional radiation therapy. Our institution was more likely to offer local-regional radiation therapy in node positive breast cancer in 2013 compare to 2004-2007.


Visualization, Selection, and Analysis of Traffic Flows.
Visualization of the trajectories of moving objects leads to dense and cluttered images, which hinders exploration and understanding. It also hinders adding additional visual information, such as direction, and makes it difficult to interactively extract traffic flows, i.e., subsets of trajectories. In this paper we present our approach to visualize traffic flows and provide interaction tools to support their exploration. We show an overview of the traffic using a density map. The directions of traffic flows are visualized using a particle system on top of the density map. The user can extract traffic flows using a novel selection widget that allows for the intuitive selection of an area, and filtering on a range of directions and any additional attributes. Using simple, visual set expressions, the user can construct more complicated selections. The dynamic behaviors of selected flows may then be shown in annotation windows in which they can be interactively explored and compared. We validate our approach through use cases where we explore and analyze the temporal behavior of aircraft and vessel trajectories, e.g., landing and takeoff sequences, or the evolution of flight route density. The aircraft use cases have been developed and validated in collaboration with domain experts.


Long-term care in Spain: Difficulties in professionalizing services.
The aim of this article is to analyze the difficulties in professionalizing the long-term care system in Spain. Since 2006, the new Spanish law has recognized care as a subjective right, and regulations are being designed to create a framework for its professionalization. Nowadays, family remains the most important group of providers who care for their elders, and women remain the main informal caregivers. Why do families resist using public long-term care services and professional carers included in the new law? The hypothesis highlights sociocultural factors as an obstacle to professionalization of long-term care services in addition to political and economic factors. The results show qualitative data about expectations, preferences, and discourses that women caregivers have in relation to their responsibility. The empirical material includes 25 interviews with different profiles of caregivers and six focus groups with family caregivers. The article suggests that the Spanish ideal of care is a problem for the professionalization of services because the family remains as the main provider of care-without specific skills, knowledge, and abilities.


Mortality of patients with respiratory insufficiency and adult respiratory distress syndrome after surgery: the obesity paradox.
Obesity has long been considered a risk factor for the development of various pathologies, yet evidence supporting increased risk of perioperative mortality in obese individuals developing postoperative complications is limited. Therefore, we sought to characterize the demographics of obese and nonobese individuals developing postoperative respiratory insufficiency (RI)/adult respiratory distress syndrome (ARDS) and to quantify the impact of obesity on in-hospital mortality among this patient population utilizing data collected for the Nationwide Inpatient Sample (NIS). Nationwide Inpatient Sample data for each year between 1998 and 2007 were accessed. Entries were included if they underwent a surgical procedure and had a diagnosis of RI/ARDS following surgery. Patients fulfilling entry criteria were divided into those with and without obesity. In-hospital mortality was the primary outcome. A logistic regression model was fitted to elucidate if obesity was associated with increased odds for the outcome while controlling for age, gender, admission and procedure type, and comorbidity burden. We identified 9 149 030 admissions that underwent the included surgical procedures between 1998 and 2007. Of those, 5.48% had a diagnosis of obesity. The incidence of RI/ARDS was 1.82% among obese and 2.01% among nonobese patients. Obese patients whose postoperative course was complicated by RI/ARDS had a significantly lower incidence of the need for mechanical ventilation (50% vs 55%). In-hospital mortality was significantly lower compared to nonobese patients (5.45% vs 18.72%). For those patients with RI/ARDS requiring intubation, the in-hospital mortality rate was 11% for obese and 25% for nonobese patients. In the multivariate regression analysis, obesity was associated with a 69% reduction in the odds of in-hospital mortality in postoperative patients with RI/ARDS. In our analysis, obesity was associated with a decreased incidence and adjusted odds for in-hospital mortality after surgery. Our results support the emerging concept of the "obesity paradox."


Premature guinea pigs: a new paradigm to investigate the late-effects of preterm birth.
Preterm birth is common and the associated short-term morbidity well described. The adult-onset consequences of preterm birth are less clear, but cardiovascular and metabolic health may be adversely affected. Although large animal models of preterm birth addressing important short-term issues exist, long-term studies are hampered by significant logistical constraints. Current small animal models of prematurity require terminal caesarean section of the mother; both caesarean birth and early maternal care modify offspring adult cardio-metabolic function. We describe a novel method for inducing preterm labour in guinea pigs. With support comparable to that received by moderately preterm human infants, preterm pups are viable. Growth trajectories between preterm and term-born pups differ significantly; between term equivalent age and weaning ex-preterm animals demonstrate increased weight and ponderal index. We believe this novel paradigm will significantly improve our ability to investigate the cardio-metabolic sequelae of preterm birth throughout the life course and into the second generation.


Lung cancer risk score for ever and never smokers in China.
Most lung cancer risk prediction models were developed in European and North-American cohorts of smokers aged ≥ 55 years, while less is known about risk profiles in Asia, especially for never smokers or individuals aged < 50 years. Hence, we aimed to develop and validate a lung cancer risk estimate tool for ever and never smokers across a wide age range. Based on the China Kadoorie Biobank cohort, we first systematically selected the predictors and explored the nonlinear association of predictors with lung cancer risk using restricted cubic splines. Then, we separately developed risk prediction models to construct a lung cancer risk score (LCRS) in 159,715 ever smokers and 336,526 never smokers. The LCRS was further validated in an independent cohort over a median follow-up of 13.6 years, consisting of 14,153 never smokers and 5,890 ever smokers. A total of 13 and 9 routinely available predictors were identified for ever and never smokers, respectively. Of these predictors, cigarettes per day and quit years showed nonlinear associations with lung cancer risk (Pnon-linear < 0.001). The curve of lung cancer incidence increased rapidly above 20 cigarettes per day and then was relatively flat until approximately 30 cigarettes per day. We also observed that lung cancer risk declined sharply within the first 5 years of quitting, and then continued to decrease but at a slower rate in the subsequent years. The 6-year area under the receiver operating curve for the ever and never smokers' models were respectively 0.778 and 0.733 in the derivation cohort, and 0.774 and 0.759 in the validation cohort. In the validation cohort, the 10-year cumulative incidence of lung cancer was 0.39% and 2.57% for ever smokers with low (< 166.2) and intermediate-high LCRS (≥ 166.2), respectively. Never smokers with a high LCRS (≥ 21.2) had a higher 10-year cumulative incidence rate than those with a low LCRS (< 21.2; 1.05% vs. 0.22%). An online risk evaluation tool (LCKEY; http://ccra.njmu.edu.cn/lckey/web) was developed to facilitate the use of LCRS. The LCRS can be an effective risk assessment tool designed for ever and never smokers aged 30 to 80 years.


Repetition suppression in auditory-motor regions to pitch and temporal structure in music.
Music performance requires control of two sequential structures: the ordering of pitches and the temporal intervals between successive pitches. Whether pitch and temporal structures are processed as separate or integrated features remains unclear. A repetition suppression paradigm compared neural and behavioral correlates of mapping pitch sequences and temporal sequences to motor movements in music performance. Fourteen pianists listened to and performed novel melodies on an MR-compatible piano keyboard during fMRI scanning. The pitch or temporal patterns in the melodies either changed or repeated (remained the same) across consecutive trials. We expected decreased neural response to the patterns (pitch or temporal) that repeated across trials relative to patterns that changed. Pitch and temporal accuracy were high, and pitch accuracy improved when either pitch or temporal sequences repeated over trials. Repetition of either pitch or temporal sequences was associated with linear BOLD decrease in frontal-parietal brain regions including dorsal and ventral premotor cortex, pre-SMA, and superior parietal cortex. Pitch sequence repetition (in contrast to temporal sequence repetition) was associated with linear BOLD decrease in the intraparietal sulcus (IPS) while pianists listened to melodies they were about to perform. Decreased BOLD response in IPS also predicted increase in pitch accuracy only when pitch sequences repeated. Thus, behavioral performance and neural response in sensorimotor mapping networks were sensitive to both pitch and temporal structure, suggesting that pitch and temporal structure are largely integrated in auditory-motor transformations. IPS may be involved in transforming pitch sequences into spatial coordinates for accurate piano performance.


A multi-responsive biomimetic nano-complex platform for enhanced gene delivery.
RNA interference (RNAi) is widely regarded as a promising technology for disease treatment, yet one major obstacle for its clinical application is the lack of enhanced siRNA delivery vehicles to circumvent complex extra- and intracellular barriers. By integrating unique peculiarities of thioglycolic acid conjugated chitosan nanoparticles (TCS NPs), biomimetic transfersomes (T) and amphiphilic hyaluronic acid (HA-GMS), a novel nano-complex was prepared, where vascular endothelial growth factor (VEGF) siRNA loaded TCS NPs were cloaked by transfersomes with HA-GMS assembled on the surface (HT-TCS-siRNA NPs). The nano-complex provided superior siRNA protection and desirable stability at pH 7.4 and 6.5 (mimicking tumor tissue) and exerted proton sponge effects at acidic pH 5.0 (mimicking endo/lysosomes). The TCS NPs were stable at pH 5.0 but disintegrated in the presence of 10 mM glutathione (GSH) at pH 7.4 (mimicking tumor cytosol), which was favorable to release siRNA to the cytoplasm. In vitro cell uptake and gene silencing assays exhibited enhanced intracellular siRNA accumulation and VEGF silencing efficacy of HT-TCS-siRNA NPs in HeLa cells. The enhanced gene delivery capacity of the multi-responsive biomimetic nano-complex gives them potential for application in cancer therapy.


Quality control of Pulsatilla koreana based on the simultaneous determination of triterpenoidal saponins by HPLC-ELSD and principal component analysis.
Pulsatilla koreana Nakai, with triterpenoidal saponins as its main pharmacological effective compounds, is known to have several biological activities, including hypoglycaemic, antitumour, cognition-enhancing, neuroprotective, cytotoxic and antiangiogenic activities. However, few analytical methods have been reported on the quality assessment of P. koreana roots. To establish a high-performance liquid chromatography coupled with evaporative light scattering detection for the simultaneous determination of five triterpenoidal saponins, including pulsatilloside E (1), pulsatilla saponin H (2), anemoside B4 (3), hederacolchiside E (4) and cussosaponin C (5) in P. koreana. The chromatographic separation was performed on a Shiseido CapCell PAK C18 analytical column efficiently using gradient elution with acetonitrile and water. All calibration curves showed excellent linear regressions (R(2) > 0.9996) within the range of tested concentrations. The intra- and inter-day variations were below 4.78% in terms of RSD. The recoveries were 94.82-102.97% with RSD of 0.27-3.92% for spiked P. koreana samples. The validated method was successfully used for the analysis of five saponins in P. koreana from different locations. Moreover, the different samples were clustered in accordance with contents of triterpenoidal saponins based on aglycon type by a principal component analysis.


Labor augmentation in an Egyptian teaching hospital.
The study documented facility-based obstetric practices for normal labor in Egypt for the first time, to determine their relationship to evidence-based medicine. This paper describes the labor augmentation pattern observed. 176 cases of normal labor were observed by medically-trained observers using a checklist. Ward activities were also documented. Observed women were interviewed postpartum and all findings were shared with the providers for their feedback. Labor was augmented in 91% (165) of the labors observed; this was inappropriate for 93% or 154 women. Reasons for inappropriateness were: oxytocin ordered at the first vaginal exam (41%); in spite of intact membranes (36%), at the time of membrane rupture (42%), in spite of good progress (24%), or a combination of these. The monitoring of oxytocin-receiving women and their babies was inadequate. Labor augmentation and monitoring deviated from evidence-based guidelines. Obstacles to implementing protocols need to be explored.


Breakfast consumption and physical activity in British adolescents.
Studies show an inverse relationship between breakfast frequency and weight gain. This may reflect poor eating habits generally and associated low physical activity (PA) or direct impacts of breakfast on mechanisms leading to lethargy and reduced PA. The relationship between breakfast frequency and PA is inconclusive. We aimed to determine whether breakfast frequency is associated with PA levels in British adolescents independent of body composition and socio-economic status (SES). Habitual breakfast frequency (self-report questionnaire) was assessed in 877 adolescents (43% male, age 14·5 (SD 0·5) years old). PA was measured over 5 d (accelerometry, average counts/ min; cpm). Associations between daily PA and breakfast frequency were assessed using linear regression adjusted for body fat percentage and SES. Effect modification by sex and associations with PA during the morning (06.00-12.00 hours) were explored. For boys, there were no significant associations between breakfast frequency and PA. For girls, less frequent breakfast consumption was significantly associated with lower PA (cpm) during the morning (occasional v. frequent b - 6·1 (95% CI - 11·1, -1·1), P = 0·017) when adjusted for body fat percentage and SES. There were no associations between PA and breakfast consumption over the whole day; however, for girls, less frequent breakfast consumption may be associated with lower PA levels during the morning, suggesting that breakfast consumption should perhaps be taken into consideration when aiming to promote PA in adolescent girls.


Quantification of intramyocellular lipids in obese subjects using spectroscopic imaging with high spatial resolution.
Quantification of intramyocellular lipids (IMCL) in obese subjects by single-voxel spectroscopy (SVS) or conventional spectroscopic imaging (SI) often fails due to overlap of IMCL spectral lines by extramyocellular lipids (EMCL), and signal contamination from subcutaneous fat and bone marrow. This study demonstrates that these problems can be solved by high-resolution SI with 128 phase-encoding steps and a read gradient during acquisition. The small voxels obtained in this way facilitated differentiation between EMCL and IMCL. This method offers the possibility of studying different muscle groups and the variation of lipids within one muscle.


Video Snapshots: Creating High-Quality Images from Video Clips.
We describe a unified framework for generating a single high-quality still image ("snapshot") from a short video clip. Our system allows the user to specify the desired operations for creating the output image, such as super resolution, noise and blur reduction, and selection of best focus. It also provides a visual summary of activity in the video by incorporating saliency-based objectives in the snapshot formation process. We show examples on a number of different video clips to illustrate the utility and flexibility of our system.


Reducing cardiovascular risk in diabetes: beyond glycemic and blood pressure control.
Patients with diabetes mellitus have a much higher rate of cardiovascular disease (CVD) than the general population, and, in addition to glycaemia and hypertension, dyslipidemia has emerged as an important modifiable cardiovascular risk factor in these patients. In most patients with type 2 diabetes, the major features of dyslipidemia are increased triglyceride levels, decreased high-density lipoprotein cholesterol (HDL-C) levels, and changes in the composition and level of low-density lipoprotein cholesterol (LDL-C). Clinical trials evaluating both primary and secondary prevention of CVD demonstrate that lipid-lowering therapy results in a substantial reduction of cardiovascular risk in patients with type 2 diabetes. Low-density lipoprotein cholesterol is the first priority for treatment, with a statin in adequate dosage as the first choice for pharmacological therapy. The first statin trial conducted solely in patients with type 2 diabetes and no prior CVD demonstrated a 37% reduction in cardiovascular events in patients randomized to atorvastatin 10 mg compared with placebo. Additional trials that further address the benefits of lipid-lowering therapy in patients with diabetes are near completion, or are underway, and should provide important information about further attenuating risk in patients with diabetes.


Pharmacological and surgical treatment of nonreproductive outcomes in polycystic ovary syndrome: An overview of systematic reviews.
Polycystic ovary syndrome (PCOS) affects up to 13% women and is associated with significant complications. The quality of evidence supporting the recommendations on treatment of nonreproductive outcomes in PCOS is unknown. To summarize and appraise the methodological quality of systematic reviews and meta-analyses evaluating pharmacological and surgical treatments for nonreproductive outcomes in PCOS. A literature search from MEDLINE, EMBASE, CINAHL PLUS and PROSPERO was performed from inception until 15th of September 2017. Article selection, data extraction and quality appraisal of included reviews were performed in duplicate. A narrative synthesis of the findings was conducted. This overview included 31 reviews. The quality was low for 7 (23%), moderate for sixteen (52%) and high for 8 reviews (26%). Two reviews assessed psychological outcomes. Metformin improved anthropometric (7 of 10 reviews), metabolic (4 of 14 reviews) and endocrine outcomes (3 of twelve reviews). Thiazolidinediones improved metabolic (2 of 5 reviews) and endocrine outcomes (one of 5 reviews) but worsened weight gain (5 of 5 reviews). Combined oral contraceptive pill (COCP) improved clinical hyperandrogenism (2 of 2 reviews). Statins improved lipid profile (3 of 3 reviews) and testosterone level (2 of 3 reviews). There was no conclusive evidence from included systematic reviews regarding the use of other interventions. There is reliable evidence regarding the use of metformin for anthropometric outcomes and COCPs for hyperandrogenism in women with PCOS but not for other interventions. There is significant gap in knowledge regarding the management of psychological outcomes in women with PCOS which needs further evaluation.


The effects of monoclonal anti-CD47 on RBCs, compatibility testing, and transfusion requirements in refractory acute myeloid leukemia.
CD47 is a novel therapeutic target in the treatment of solid-organ and hematologic malignancies. CD47 is also expressed on RBCs. Here, we report our experience of the RBC effects and the impact on blood bank testing and transfusion management in a Phase 1 trial of the humanized anti-CD47 monoclonal antibody Hu5F9-G4 in relapsed or primary refractory acute myeloid leukemia (AML) (NCT02678338). Nineteen patients with relapsed or primary refractory AML treated across five UK centers were included for analysis. Patients received escalating doses of Hu5F9-G4. Serial laboratory data were collected to evaluate impact on hemoglobin (Hb), markers of hemolysis (bilirubin, lactate dehydrogenase, reticulocyte count), transfusion requirements, and blood compatibility testing. A decline in Hb was observed with drug administration (median Hb change, -1.0 g/dL; range, 0.4-1.6) with associated increase in transfusion requirements. Patients responded to transfusion with a median Hb increment per unit of 1.0 g/dL. RBC agglutination was seen in all cases without associated change in Hb, lactate dehydrogenase, bilirubin, or reticulocyte count. Nine of 19 (47%) patients developed a newly positive antibody screen with a pan-agglutinin identified in plasma. Invalid ABO blood grouping occurred in 4 of 12 (33%) non-group O patients due to anomalous reactivity in the reverse ABO-type results. Treatment with Hu5F9-G4 in patients with AML resulted in an Hb decline and increased transfusion requirements. Problems with ABO blood typing and compatibility testing were widely observed and should be expected by centers treating recipients of Hu5F9-G4.


Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells.
Mesenchymal stem cells (MSC) are adult multipotent cells found in bone marrow, adipose tissue, and other adult tissues. MSC have been shown to improve regeneration of injured tissues in vivo, but the mechanisms remain unclear. Typically, MSC are cultured under ambient, or normoxic, conditions (21% oxygen). However, the physiological niches for MSC in the bone marrow and other sites have much lower oxygen tension. When used as a therapeutic tool to repair tissue injuries, MSC cultured in standard conditions must adapt from 21% oxygen in culture to less than 1% oxygen in the ischemic tissue. We therefore examined the effects of preculturing human bone marrow-derived MSC in hypoxic conditions (1%-3% oxygen) to elucidate the best conditions that enhance their tissue regenerative potential. We demonstrated that MSC cultured in hypoxia activate the Akt signaling pathway while maintaining their viability and cell cycle rates. We also showed that MSC cultured in hypoxia induced expression of cMet, the major receptor for hepatocyte growth factor (HGF), and enhanced cMet signaling. MSC cultured in hypoxic conditions increased their migration rates. Since migration and HGF responsiveness are thought to be key mediators of MSC recruitment and/or activation in vivo, we next examined the tissue regenerative potential of MSC cultured under hypoxic conditions, using a murine hind limb ischemia model. We showed that local expression of HGF is increased in ischemic muscle in this model. Intra-arterial injection of MSC cultured in either normoxic or hypoxic conditions 24 hours after surgical induction of hind limb ischemia enhanced revascularization compared with saline controls. However, restoration of blood flow was observed significantly earlier in mice that had been injected with hypoxic preconditioned MSC. Collectively, these data suggest that preculturing MSC under hypoxic conditions prior to transplantation improves their tissue regenerative potential. Disclosure of potential conflicts of interest is found at the end of this article.


Role of twenty-four-hour ambulatory blood pressure monitoring in children on dialysis.
Pre- or postdialysis BP recordings are imprecise, can be biased, and have poor test-retest reliability in children on dialysis. We aimed to examine the possible differences between pre- and postdialysis BP levels and 24-hour ambulatory BP monitoring (ABPM) in diagnosis of hypertension (HTN). Twenty-four children on dialysis had 24-hour ABPM in the interdialytic period, and values were compared with average pre- and postdialysis systolic BP (SBP) and diastolic BP (DBP) recordings that week. Each patient had an echocardiogram to determine presence of left ventricular hypertrophy (LVH). By ABPM, 8% of patients had white coat HTN and 12% had masked HTN. There was no significant difference in diagnosis of systolic HTN based on ABPM daytime SBP mean or load and postdialysis SBP. However, only 15% of patients had diastolic HTN based on postdialysis measures, whereas 46% of patients had significantly elevated daytime DBP loads and 71% had high nighttime DBP loads on ABPM. Forty-eight percent of patients were SBP nondippers. Children with LVH had higher daytime and nighttime SBP loads, significantly higher daytime and nighttime DBP loads, and lesser degree of nocturnal dipping of SBP compared with those who did not. ABPM is more informative than pre- and postdialysis BPs and improves the predictability of BP as a risk factor for target organ damage. Diagnosis and treatment monitoring of HTN among pediatric dialysis patients is enhanced with addition of ABPM.


KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel.
Mutations in HERG and KCNQ1 (or KVLQT1) genes cause the life-threatening Long QT syndrome. These genes encode K(+) channel pore-forming subunits that associate with ancillary subunits from the KCNE family to underlie the two components, I(Kr) and I(Ks), of the human cardiac delayed rectifier current I(K). The KCNE family comprises at least three members. KCNE1 (IsK or MinK) recapitulates I(Ks) when associated with KCNQ1, whereas it augments the amplitude of an I(Kr)-like current when co-expressed with HERG. KCNE3 markedly changes KCNQ1 as well as HERG current properties. So far, KCNE2 (MirP1) has only been shown to modulate HERG current. Here we demonstrate the interaction of KCNE2 with the KCNQ1 subunit, which results in a drastic change of KCNQ1 current amplitude and gating properties. Furthermore, KCNE2 mutations also reveal their specific functional consequences on KCNQ1 currents. KCNQ1 and HERG appear to share unique interactions with KCNE1, 2 and 3 subunits. With the exception of KCNE3, mutations in all these partner subunits have been found to lead to an increased propensity for cardiac arrhythmias.


Bilateral simultaneous non-arteritic anterior ischemic optic neuropathy with occlusion of unilateral cilioretinal artery: A case report.
A 45-year-old female patient consulted our hospital for bilateral visual loss. She was receiving hemodialysis for 15 years. At presentation ophthalmologic examination, her visual acuity was hand movements in the right eye and light perception negative in the left eye. The direct light response was weak in the right eye and absent in the left eye. A total afferent pupillary defect was detected in the left eye. Fundoscopy revealed bilateral sectorial pale, sectorial hyperaemia and swollen optic discs. On the left papilla, there were splinter haemorrhages. At the right eye, there was pale edema at superior maculo-papillary bunch that coherent with occlusion of the cilioretinal artery. She was diagnosed as non-arteritic ischemic optic neuropathy based on the clinical and funduscopic examination. Methylprednisolone intravenous 1000mg/day for three days, then, oral methylprednisolone 1 mg/kg/day were administered for one week. Simultaneous acetylsalicylic acid 325 mg/day and hydration with 0.9% 1000cc isotonic solution treatment started. After two months, visual acuities did not change in both eyes, and both optic disks were pale.


Weight at birth and infancy in relation to adult leukocyte count: a population-based study of 5619 men and women followed from the fetal period to adulthood.
Impaired fetal growth is associated with increased risk for coronary heart disease and diabetes in adulthood, but the underlying mechanism is unclear. The objective of the study was to examine the relation between early growth (weight at birth and first year) and adult total leukocyte count, the primary cell effectors of inflammation. This was a birth cohort study (Northern Finland Birth Cohort 1966) with participants prospectively and longitudinally followed up from birth to age 31 yr. This was a general population-based cohort in Finland. A total of 5619 offspring of expectant mothers who attended a clinical examination and blood draw at 31-yr follow-up (4486 with complete data on weight at 1 yr) participated in the study. MAIN EXPOSURE VARIABLES: Weight at birth and at 1 year. Absolute leukocyte count was measured. Total leukocyte count was lower at higher birth weight categories with or without adjustments for adult systolic blood pressure, total cholesterol, fasting insulin, body mass index, cigarette smoking, sex, gestational age, and other life course factors. The covariate-adjusted regression coefficient for log-transformed total leukocyte count (x 10(9) cells/liter) per 1 SD (525 g) increase in birth weight was -0.012 (95% confidence interval -0.021 to -0.004). The association persisted, even when limiting our analyses among healthy and nonsmoking individuals, and the inversely linear relation was steepest among those with lower weight attained at 1 yr (P for interaction = 0.027). Poorer growth in early life was associated with systemic low-grade inflammation in adulthood. This relation suggests a plausible inflammatory mechanism linking early growth impairment with risk of coronary heart disease and diabetes later in life.


Community-level consumption of antibiotics according to the AWaRe (Access, Watch, Reserve) classification in rural Vietnam.
To review community-level consumption of antibiotics in rural Vietnam, according to the WHO Access, Watch, Reserve (AWaRe) classification of 2019, and identify factors associated with the choice of these antibiotics. In this cross-sectional study, data on antibiotic purchases were collected through a customer exit survey of 20 community antibiotic suppliers in Ba Vi District, Hanoi, between September 2017 and July 2018. Antibiotic consumption was estimated through the number of antibiotic encounters, the number of DDDs supplied and the number of treatment days (DOTs) with antibiotics, and analysed according to the AWaRe classification. The factors associated with watch-group antibiotic supply were identified through multivariable logistic regression analysis. In total, there were 1342 antibiotic encounters, with access-group antibiotics supplied in 792 encounters (59.0%), watch-group antibiotics supplied in 527 encounters (39.3%) and not-recommended antibiotics supplied in 23 encounters (1.7%). No reserve-group antibiotics were supplied. In children, the consumption of watch-group antibiotics dominated in all three measures (54.8% of encounters, 53.0% of DOTs and 53.6% of DDDs). Factors associated with a higher likelihood of watch-group antibiotic supply were: private pharmacy (OR, 4.23; 95% CI, 2.8-6.38; P < 0.001), non-prescription antibiotic sale (OR, 2.62; 95% CI, 1.78-3.87; P < 0.001) and children (OR, 2.56; 95% CI, 1.84-3.55; P < 0.001). High consumption of watch-group antibiotics was observed, especially for use in children. The frequent supply of watch-group antibiotics at private pharmacies reconfirms the need for implementing pharmacy-targeted interventions in Vietnam.


Subcortical surface morphometry in substance dependence: An ENIGMA addiction working group study.
While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.


Identification of a novel tRNA wobble uridine modifying activity in the biosynthesis of 5-methoxyuridine.
Derivatives of 5-hydroxyuridine (ho5U), such as 5-methoxyuridine (mo5U) and 5-oxyacetyluridine (cmo5U), are ubiquitous modifications of the wobble position of bacterial tRNA that are believed to enhance translational fidelity by the ribosome. In gram-negative bacteria, the last step in the biosynthesis of cmo5U from ho5U involves the unique metabolite carboxy S-adenosylmethionine (Cx-SAM) and the carboxymethyl transferase CmoB. However, the equivalent position in the tRNA of Gram-positive bacteria is instead mo5U, where the methyl group is derived from SAM and installed by an unknown methyltransferase. By utilizing a cmoB-deficient strain of Escherichia coli as a host and assaying for the formation of mo5U in total RNA isolates with methyltransferases of unknown function from Bacillus subtilis, we found that this modification is installed by the enzyme TrmR (formerly known as YrrM). Furthermore, X-ray crystal structures of TrmR with and without the anticodon stemloop of tRNAAla have been determined, which provide insight into both sequence and structure specificity in the interactions of TrmR with tRNA.


Poly(2-ethyl-2-oxazoline)-PLA-g-PEI amphiphilic triblock micelles for co-delivery of minicircle DNA and chemotherapeutics.
The design of nanocarriers for the delivery of drugs and nucleic-acids remains a very challenging goal due to their physicochemical differences. In addition, the reported accelerated clearance and immune response of pegylated nanomedicines highlight the necessity to develop carriers using new materials. Herein, we describe the synthesis of amphiphilic triblock poly(2-ethyl-2-oxazoline)-PLA-g-PEI (PEOz-PLA-g-PEI) micelles for the delivery of minicircle DNA (mcDNA) vectors. In this copolymer the generally used PEG moieties are replaced by the biocompatible PEOz polymer backbone that assembles the hydrophilic shell. The obtained results show that amphiphilic micelles have low critical micellar concentration, are hemocompatible and exhibit stability upon incubation in serum. The uptake in MCF-7 cells was efficient and the nanocarriers achieved 2.7 fold higher expression than control particles. Moreover, mcDNA-loaded micelleplexes penetrated into 3D multicellular spheroids and promoted widespread gene expression. Additionally, to prove the concept of co-delivery, mcDNA and doxorubicin (Dox) were simultaneously encapsulated in PEOz-PLA-g-PEI carriers, with high efficiency. Dox-mcDNA micelleplexes exhibited extensive cellular uptake and demonstrated anti-tumoral activity. These findings led us to conclude that this system has a potential not only for the delivery of novel mcDNA vectors, but also for the co-delivery of drug-mcDNA combinations without PEG functionalization.


Reform in public health: where does it take nursing?
The Australian healthcare system is undergoing changes that are impacting tangibly on professional nursing practice. While the evidence is clear that the changes pose a challenge to maintaining standards amidst resource cuts and restructuring, the processes through which these changes occur and the decisions which drive the reforms remain complex and largely obscure. This paper intends to stimulate further thinking and debate among nurses about the effects of these reforms on the conduct of practice, both in terms of our emerging discipline and our ability to conduct clinical nursing practice. It offers a way of understanding the policy 'reform' process through an application of policy analysis grounded in critical social theory. The discussion sets out to apply these analytical propositions to specific events that constitute examples of change in the nursing workplace, and to focus on the implications for nurses and health service clientele.


Conformational preferences of 1-amino-2-phenylcyclohexanecarboxylic acid, a phenylalanine cyclohexane analogue.
The intrinsic conformational preferences of the restricted phenylalanine analogue generated by including the alpha and beta carbon atoms into a cyclohexane ring (1-amino-2-phenylcyclohexanecarboxylic acid, c(6)Phe) have been determined using quantum mechanical calculations. Specifically, the conformational profile of the N-acetyl-N'-methylamide derivative of the c(6)Phe stereoisomers exhibiting either a cis or a trans relative orientation between the amino and phenyl substituents has been analyzed in different environments (gas phase, chloroform, and aqueous solutions). Calculations were performed using B3LYP, MP2, and HF methods combined with the 6-31+G(d,p) and 6-311++G(d,p) basis sets, and a self-consistent reaction-field (SCRF) method was applied to analyze the influence of the solvent. The amino acids investigated can be viewed as constrained phenylalanine analogues with a rigidly oriented aromatic side chain that may interact with the peptide backbone not only sterically but also electronically through the aromatic pi orbitals. Their conformational propensities have been found to be strongly influenced by the specific orientation of the aromatic substituent in each stereoisomer and the conformation adopted by the cyclohexane ring, as well as by the environment.