Physiologic activation of nuclear factor kappa-B in the endometrium during the menstrual cycle is altered in endometriosis patients.
To evaluate nuclear factor kappaB (NF-κB) activation and NF-κB-p65 subunit activation, immunolocalization, and expression in the endometrium of healthy women and endometriosis patients throughout the menstrual cycle. Prospective observational study. Affiliated hospital and university research laboratory. Twenty-four healthy women and 24 endometriosis patients. Menstrual, proliferative, and secretory endometrial biopsies. Assessment of NF-κB and p65 activation by protein-DNA binding assays and p65 localization and expression by immunohistochemistry. Total NF-κB-DNA binding was constitutive and variable in human endometrium accross the menstrual cycle. Healthy women (physiologic conditions) showed higher p65-DNA binding in proliferative than in menstrual and secretory endometrium. Conversely, in endometriosis patients, p65-DNA binding was higher in proliferative and secretory endometrium than in menstrual endometrium. Endometrial epithelial cells showed higher p65 expression level score than endometrial stromal cells. NF-κB activity is constitutive, physiologic, and variable in human endometrium. The physiologic cyclic p65 activation pattern was altered in endometriosis patients, showing no cyclic variation between the proliferative and secretory phase of the menstrual cycle. The absence of decreased p65 activity in secretory endometrium from endometriosis patients is concurrent with progesterone resistance and could participate in endometrial biologic alterations during the implantation window in endometriosis patients.


Characterisation of salmon and trout CD8alpha and CD8beta.
The genes and corresponding cDNAs of both alpha and beta chains of the Atlantic salmon (Salmo salar) CD8 molecule have been sequenced and characterized. In addition, the cDNAs for alpha and beta chains of brown trout (Salmo trutta) and for the beta chain in rainbow trout (Oncorhynchus mykiss) have been sequenced. The cDNAs code for signal sequences which are preceded by short 5' UTRs. These are followed by typical immunoglobulin superfamily variable sequences all of which contain two conserved cysteines for the intra-chain disulphide bond. The hinge regions display conserved cysteines for dimerisation and several O-glycosylation motifs for each predicted protein. The domain sharing the highest sequence identity with mammals is the single pass transmembrane domain for all sequences. In salmon, each domain is predominantly coded for by a single exon except the cytoplasmic/3' UTR domains, which are coded for by 3 and 2 exons for the alpha and beta genes, respectively. In the alpha gene, the second cytoplasmic exon may be spliced out to form an alternative shorter transcript which if expressed would exhibit a truncated cytoplasmic tail. A splice variant found for the salmon beta gene introduces a stop codon after only 40 amino acids. Overall amino acid identities between salmonid sequences were higher than 90%, whereas they shared only 15-20% identity with species such as, chicken and human. Analysis of the expression patterns of the two salmon genes using quantitative RT-PCR shows a very high expression in the thymus. This is mirrored by the expression of the TCRalpha gene, which is known to be co-expressed with CD8 on mammalian T cells. This is the first report of a sequence for CD8beta in a teleost and together with the CD8alpha sequence, it encodes the ortholog of the CD8 co-receptor molecule on mammalian T cells.


Effect of point of care blood testing on physical health check completion in mental health services: mixed-methods evaluation.
Physical health outcomes in severe mental illness are worse than in the general population. Routine physical health check completion in this group is poor. To quantitatively and qualitatively evaluate the impact of point of care (POC) blood testing on physical health check completion in community mental health services. In a prospective cohort design, we equipped an early intervention service (EIS) and a community mental health team (CMHT) with a POC blood testing device for 6 months. We compared rates of blood test and full physical health check completion in the intervention teams with a matched EIS and CMHT, historically and during the intervention. We explored attitudes to POC testing using thematic analysis of semi-structured interviews with patients and clinicians. Although the CMHT scarcely used the POC device and saw no change in outcomes, direct comparison of testing rates in the intervention period showed increased physical health check completion in the EIS with the device (rate ratio RR = 5.18; 95% CI 2.54-12.44; P < 0.001) compared with usual care. The rate was consistent with the EIS's increasing rate of testing over time (RR = 0.45; 95% 0.09-2.08; P = 0.32). Similar trends were seen in blood test completion. POC testing was acceptable to patients but clinicians reported usability, provision and impact on the therapeutic relationship as barriers to uptake. POC testing was beneficial and acceptable to patients and may increase physical health check uptake. Further research, accounting for clinician barriers, is needed to evaluate its clinical and cost-effectiveness.


One hundred pregnancies after treatment with pulsatile luteinising hormone releasing hormone to induce ovulation.
To review treatment with pulsatile luteinising hormone releasing hormone in infertile women who do not ovulate and are resistant to clomiphene after 100 pregnancies achieved with this treatment. Retrospective analysis of 146 courses of treatment over 434 cycles. Infertility clinic. 118 Women whose failure to ovulate was due to idiopathic hypogonadotrophic hypogonadism (n = 39), amenorrhoea related to low weight (n = 17), organic pituitary disease (n = 15), or polycystic ovaries (n = 47). Dose of 15 micrograms luteinising hormone releasing hormone/pulse subcutaneously every 90 minutes given with a miniaturised pump throughout cycle monitored by ultrasound. Women with hypogonadotrophic hypogonadism had 48 courses, women with amenorrhoea related to low weight 23, women with organic pituitary disease 18, and women with polycystic ovaries 57. Follow up of 100 pregnancies achieved in 77 women during six years after introducing treatment. MEASUREMENTS and main results--One hundred pregnancies (seven multiple, 28 miscarriages). Cumulative rates of pregnancy were 93-100% at six months in women with idiopathic hypogonadotrophic hypogonadism, amenorrhoea related to low weight, and organic pituitary disease. In women with polycystic ovaries (cumulative rate of pregnancy 74%) adverse prognostic factors were obesity, hyperandrogenism, and high luteinising hormone concentrations, which were also associated with a high rate of early pregnancy loss. Treatment with pulsatile luteinising hormone releasing hormone is safe, simple, and effective, and the preferred method of inducing ovulation in appropriately selected patients. Compared with exogenous gonadotrophin treatment there is little need for monitoring, no danger of hyperstimulation, and a low rate of multiple pregnancies.


COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study.
To date, few data on paediatric COVID-19 have been published, and most reports originate from China. This study aimed to capture key data on children and adolescents with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection across Europe to inform physicians and health-care service planning during the ongoing pandemic. This multicentre cohort study involved 82 participating health-care institutions across 25 European countries, using a well established research network-the Paediatric Tuberculosis Network European Trials Group (ptbnet)-that mainly comprises paediatric infectious diseases specialists and paediatric pulmonologists. We included all individuals aged 18 years or younger with confirmed SARS-CoV-2 infection, detected at any anatomical site by RT-PCR, between April 1 and April 24, 2020, during the initial peak of the European COVID-19 pandemic. We explored factors associated with need for intensive care unit (ICU) admission and initiation of drug treatment for COVID-19 using univariable analysis, and applied multivariable logistic regression with backwards stepwise analysis to further explore those factors significantly associated with ICU admission. 582 individuals with PCR-confirmed SARS-CoV-2 infection were included, with a median age of 5·0 years (IQR 0·5-12·0) and a sex ratio of 1·15 males per female. 145 (25%) had pre-existing medical conditions. 363 (62%) individuals were admitted to hospital. 48 (8%) individuals required ICU admission, 25 (4%) mechanical ventilation (median duration 7 days, IQR 2-11, range 1-34), 19 (3%) inotropic support, and one (<1%) extracorporeal membrane oxygenation. Significant risk factors for requiring ICU admission in multivariable analyses were being younger than 1 month (odds ratio 5·06, 95% CI 1·72-14·87; p=0·0035), male sex (2·12, 1·06-4·21; p=0·033), pre-existing medical conditions (3·27, 1·67-6·42; p=0·0015), and presence of lower respiratory tract infection signs or symptoms at presentation (10·46, 5·16-21·23; p<0·0001). The most frequently used drug with antiviral activity was hydroxychloroquine (40 [7%] patients), followed by remdesivir (17 [3%] patients), lopinavir-ritonavir (six [1%] patients), and oseltamivir (three [1%] patients). Immunomodulatory medication used included corticosteroids (22 [4%] patients), intravenous immunoglobulin (seven [1%] patients), tocilizumab (four [1%] patients), anakinra (three [1%] patients), and siltuximab (one [<1%] patient). Four children died (case-fatality rate 0·69%, 95% CI 0·20-1·82); at study end, the remaining 578 were alive and only 25 (4%) were still symptomatic or requiring respiratory support. COVID-19 is generally a mild disease in children, including infants. However, a small proportion develop severe disease requiring ICU admission and prolonged ventilation, although fatal outcome is overall rare. The data also reflect the current uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed. ptbnet is supported by Deutsche Gesellschaft für Internationale Zusammenarbeit.


A Decision Algorithm Is Not Superior to Clinician Judgment to Determine Need for Peripheral vs Central Venous Catheterization.
Venous access, via a midline peripheral catheter (midline) or a peripherally inserted central catheter, is used regularly in the neurointensive care unit as a means for prolonged infusion of drugs or medications. There is little research on how to choose the appropriate access device to use in this setting. The aim of this study is to trial an algorithm to assist clinicians in determining which device to use, as a way to reduce patient complications such as central line-associated bloodstream infection and deep vein thrombosis. This quality improvement initiative included both retrospective and prospective data. A retrospective chart review was performed, and data were analyzed for variables associated with decision making between the 2 access devices. An algorithm was developed to assist clinicians with deciding between midline access and peripherally inserted central catheter access. A total of 325 charts were reviewed (126 retrospective and 109 prospective). Results show no significant differences in the demographic characteristics of either group. Before intervention, clinicians chose the correct access device 86% of the time, whereas after the intervention, clinicians chose the correct device 78% of the time (P = .06). The results of this study indicate that the quality improvement intervention and algorithm decision-making tool did not improve accuracy of use of access devices.


Nickel requirement and factor F430 content of methanogenic bacteria.
Methanobacterium thermoautotrophicum has been reported to require nickel for growth and to contain high concentrations of a nickel tetrapyrrole designated factor F430. In this communication it is shown that all methanogenic bacteria investigated incorporated nickel during growth and also synthesized factor F430. This was also true for Methanobrevibacter smithii, which is dependent on acetate as a carbon source, and for Methanosarcina barkeri growing on acetate or methanol as energy sources. Other bacteria, including Acetobacterium woodii and Clostridium thermoaceticum, contained no factor F430. It is further shown that two yellow nickel-containing degradation products were formed from factor F430 when heated at pH 7. This finding explains why several forms of factor F430 were found in methanogenic bacteria when a heat step was employed in the purification procedure.


Ondansetron ameliorates depression associated with obesity in high-fat diet fed experimental mice: An investigation-based on the behavioral, biochemical, and molecular approach.
Obesity is an important risk factor for depression as more than half of the obese population is susceptible for depression at double rate. Our earlier studies reported the antidepressant potential of 5-HT3 receptor antagonist, ondansetron (OND) in depression associated obesity using behavioral tasks. The present research work is aimed to evaluate the effect of OND on depression associated with obesity with special emphasis on biochemical and molecular mechanisms such as hippocampal brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate (cAMP), 5-hydroxytryptamine (5-HT), hippocampal histological examination and immunohistochemical expression of p53 proteins. Mice were fed with high-fat diet (HFD) for 14 weeks, followed by treatment schedule for 28 days with vehicle/OND (0.5 and 1 mg/kg, p.o.)/reference antidepressant escitalopram (10 mg/kg, p.o.). Subsequently, animals were screened in the behavioral tests of depression such as forced swim test (FST) and sucrose preference test (SPT), biochemical estimations including hippocampal cAMP, BDNF and 5-HT, and molecular assays mainly histology and p53 expression of dentate gyrus (DG). HFD-fed mice showed increased immobility time in FST, reduced sucrose consumption in SPT, decreased level of signal transduction factor cAMP, neuronal growth factor BDNF and neurotransmitter 5-HT in the hippocampus, and raised and p53 expression neuronal damage in the DG region of mice fed with HFD in comparison to the mice fed with normal pellet diet. Chronic treatment with OND (0.5 and 1 mg/kg, p.o.) significantly inhibited the behavioral, biochemical and molecular modifications in HFD-fed mice. In the preliminary study, OND attenuated depression associated with obesity in mice fed with HFD using various assays procedures, at least in part by the modulation of serotonergic transmission.


25 years and still going strong: 2'-O-(pyren-1-yl)methylribonucleotides - versatile building blocks for applications in molecular biology, diagnostics and materials science.
Oligonucleotides (ONs) modified with 2'-O-(pyren-1-yl)methylribonucleotides have been explored for a range of applications in molecular biology, nucleic acid diagnostics, and materials science for more than 25 years. The first part of this review provides an overview of synthetic strategies toward 2'-O-(pyren-1-yl)methylribonucleotides and is followed by a summary of biophysical properties of nucleic acid duplexes modified with these building blocks. Insights from structural studies are then presented to rationalize the reported properties. In the second part, applications of ONs modified with 2'-O-(pyren-1-yl)methyl-RNA monomers are reviewed, which include detection of RNA targets, discrimination of single nucleotide polymorphisms, formation of self-assembled pyrene arrays on nucleic acid scaffolds, the study of charge transfer phenomena in nucleic acid duplexes, and sequence-unrestricted recognition of double-stranded DNA. The predictable binding mode of the pyrene moiety, coupled with the microenvironment-dependent properties and synthetic feasibility, render 2'-O-(pyren-1-yl)methyl-RNA monomers as a promising class of pyrene-functionalized nucleotide building blocks for new applications in molecular biology, nucleic acid diagnostics, and materials science.


Dispersal mode and spatial extent influence distance-decay patterns in pond metacommunities.
Assuming that dispersal modes or abilities can explain the different responses of organisms to geographic or environmental distances, the distance-decay relationship is a useful tool to evaluate the relative role of local environmental structuring versus regional control in community composition. Based on continuing the current theoretical framework on metacommunity dynamics and based on the predictive effect of distance on community similarity, we proposed a new framework that includes the effect of spatial extent. In addition, we tested the validity of our proposal by studying the community similarity among three biotic groups with different dispersal modes (macrofaunal active and passive dispersers and plants) from two pond networks, where one network had a small spatial extent, and the other network had an extent that was 4 times larger. Both pond networks have similar environmental variability. Overall, we found that environmental distance had larger effects than geographical distances in both pond networks. Moreover, our results suggested that species sorting is the main type of metacommunity dynamics shaping all biotic groups when the spatial extent is larger. In contrast, when the spatial extent is smaller, the observed distance-decay patterns suggested that different biotic groups were mainly governed by different metacommunity dynamics. While the distance-decay patterns of active dispersers better fit the trend that was expected when mass effects govern a metacommunity, passive dispersers showed a pattern that was expected when species sorting prevails. Finally, in the case of plants, it is difficult to associate their distance-decay patterns with one type of metacommunity dynamics.


The Invisible Carbon Footprint as a hidden impact of peatland degradation inducing marine carbonate dissolution in Sumatra, Indonesia.
In Indonesia, land use change (LUC) in the form of peatland degradation induces carbon loss through direct CO2 emissions, but also via soil leaching of which circa 50% is decomposed and emitted as CO2 from the rivers. However, the fate of the remaining exported leached carbon is uncertain. Here, we show that the majority of this carbon is respired in the estuaries and emitted to the atmosphere. However, a portion is adsorbed into the marine carbon pool where it favors CaCO3 dissolution and can therefore be seen as the invisible carbon footprint. We conclude that the effects of LUC stretch beyond the terrestrial realm and are not limited to CO2 emissions, but also affect marine ecosystems. Considering the ecological and economical importance of these ecosystems, it is important that this so far invisible carbon footprint, as well as the aquatic and marine CO2 emissions, are included in climate mitigation strategies.


Identification and profiling of conserved and novel microRNAs from Chinese Qinchuan bovine longissimus thoracis.
MicroRNAs (miRNAs) are a family of ~22 nucleotide small RNA molecules that regulate gene expression by fully or partially binding to their complementary sequences. Recently, a large number of miRNAs and their expression patterns have been identified in various species. However, to date no miRNAs have been reported to modulate muscle development in beef cattle. Total RNAs from the Chinese Qinchuan bovine longissimus thoracis at fetal and adult stages were used to construct small RNA libraries for Solexa SBS technology sequencing. A total of 15,454,182 clean reads were obtained from the fetal bovine library and 13,558,164 clean reads from the adult bovine library. In total, 521 miRNAs including 104 novel miRNA candidates were identified. Furthermore, the nucleotide bias, base edit and family of the known miRNAs were also analyzed. Based on stem-loop qPCR, 25 high-read miRNAs were detected, and the results showed that bta-miRNA-206, miRNA-1, miRNA-133, miRNAn12, and miRNAn17 were highly expressed in muscle-related tissue or organs, suggesting that these miRNAs may play a role in the development of bovine muscle tissues. This study confirmed the authenticity of 417 known miRNAs, discovered 104 novel miRNAs in bos taurus, and identified five muscle-specific miRNAs. The identification of novel miRNAs significantly expanded the repertoire of bovine miRNAs and could contribute to further studies on the muscle development of cattle.


How can referrals of patients who are obese to the local exercise referral scheme be increased? A UK based primary care quality improvement study.
Obesity is classified as a body mass index (BMI) >30kg/m2 and contributes to poor health outcomes in the UK. In 2017-18, obesity resulted in 711,000 hospital admissions. The National Institute for Health and Care Excellence (NICE) recommends GPs educate patients who are obese and refer them to exercise programmes. Our practice, Brierley Park Medical Centre, (NHS Mansfield and Ashfield CCG) is in a 4th decile most deprived region of North Nottinghamshire (UK) and serves a population of 9,288. The local exercise referral scheme (ERS) allows clinicians to refer patients to the local gym for a reduced fee at the point of access. To calculate and increase the number of adult patients who are obese in our practice who are referred to the local ERS. The number of adult obese patients who were referred to the local ERS scheme from October 2018 to September 2019 was calculated. An intervention comprising internal system alerts, GP education utilising Making Every Contact Count framework and targeted patient group text alerts was designed and delivered. Pre (cycle 1) and post (cycle 2) intervention data from November to February were generated and compared. In total, 2766 adult obese patients (29.8% of practice population) were identified: 16 (0.2%) patients were referred to ERS during cycle 1.96 (1%) patients were referred during cycle 2. The interventions that we have designed and implemented have increased the number of referrals to ERS and may be applied to similar primary care settings.


Effect of psychotropic drugs on the 21-hydroxylation of neurosteroids, progesterone and allopregnanolone, catalyzed by rat CYP2D4 and human CYP2D6 in the brain.
We determined the effects of psychotropic drugs on the cytochrome P450 2D (CYP2D)-mediated 21-hydroxylation of progesterone (PROG) and allopregnanolone (ALLO) with the goal of clarifying whether neurosteroid levels are affected by psychotropic drugs in the brain. PROG or ALLO was incubated with rat CYP2D4 or human CYP2D6 in the presence of typical psychotropic drugs, fluoxetine, imipramine, desipramine, mazindol, and GBR12909, and the 21-hydroxylated metabolites of PROG and ALLO were determined by high performance liquid chromatography and liquid chromatography-tandem mass spectrometry, respectively. Fluoxetine competitively inhibited CYP2D4-mediated PROG 21-hydroxylation and increased both Km and Vmax values of CYP2D6-mediated PROG 21-hydroxylation. In addition, fluoxetine competitively inhibited ALLO 21-hydroxylation mediated by CYP2D4 and CYP2D6. Imipramine, desipramine, mazindol, and GBR12909 competitively inhibited PROG 21-hydroxylation mediated by CYP2D4 and/or CYP2D6, and all psychotropic drugs inhibited ALLO 21-hydroxylation mediated by CYP2D4 and/or CYP2D6. The inhibition constants (Ki values) of imipramine, desipramine, and mazindol against the 21-hydroxylation of PROG and ALLO by CYP2D6 were lower than those by CYP2D4. These results indicate that psychotropic drugs including fluoxetine affected the metabolism of neurosteroids, such as PROG and ALLO in the brain, suggesting that the regulation of the neurosteroid levels is modified by central nervous system-active drugs that inhibit brain CYP2D isoforms.


Prediction of Prolonged Opioid Use After Surgery in Adolescents: Insights From Machine Learning.
Long-term opioid use has negative health care consequences. Patients who undergo surgery are at risk for prolonged opioid use after surgery (POUS). While risk factors have been previously identified, no methods currently exist to determine higher-risk patients. We assessed the ability of a variety of machine-learning algorithms to predict adolescents at risk of POUS and to identify factors associated with this risk. A retrospective cohort study was conducted using a national insurance claims database of adolescents aged 12-21 years who underwent 1 of 1297 surgeries, with general anesthesia, from January 1, 2011 to December 30, 2017. Logistic regression with an L2 penalty and with a logistic regression with an L1 lasso (Lasso) penalty, random forests, gradient boosting machines, and extreme gradient boosted models were trained using patient and provider characteristics to predict POUS (≥1 opioid prescription fill within 90-180 days after surgery) risk. Predictive capabilities were assessed using the area under the receiver-operating characteristic curve (AUC)/C-statistic, mean average precision (MAP); individual decision thresholds were compared using sensitivity, specificity, Youden Index, F1 score, and number needed to evaluate. The variables most strongly associated with POUS risk were identified using permutation importance. Of 186,493 eligible patient surgical visits, 8410 (4.51%) had POUS. The top-performing algorithm achieved an overall AUC of 0.711 (95% confidence interval [CI], 0.699-0.723) and significantly higher AUCs for certain surgeries (eg, 0.823 for spinal fusion surgery and 0.812 for dental surgery). The variables with the strongest association with POUS were the days' supply of opioids and oral morphine milligram equivalents of opioids in the year before surgery. Machine-learning models to predict POUS risk among adolescents show modest to strong results for different surgeries and reveal variables associated with higher risk. These results may inform health care system-specific identification of patients at higher risk for POUS and drive development of preventative measures.


Neurodevelopment and healthcare utilisation at age 5-6 years in bronchopulmonary dysplasia: an EPIPAGE-2 cohort study.
We aimed to study neurodevelopmental outcomes and healthcare utilisation at age 5-6 years in very preterm children with bronchopulmonary dysplasia (BPD). Prospective and national population-based study. All the neonatal units in 25 French regions (21 of the 22 metropolitan regions and 4 overseas regions). Children born before 32 weeks' gestation in 2011. Blind, comprehensive and standardised assessment by trained neuropsychologists and paediatricians at age 5-6 years. Overall neurodevelopmental disabilities, behavioural difficulties, developmental coordination disorders, full-scale IQ, cerebral palsy, social interaction disorders, rehospitalisation in the previous 12 months and detailed developmental support. Of the 3186 children included, 413 (11.7%) had BPD. The median gestational age of children with BPD was 27 weeks (IQR 26.0-28.0) and without BPD was 30 weeks (28.0-31.0). At age 5-6 years, 3150 children were alive; 1914 (60.8%) had a complete assessment. BPD was strongly associated with mild, moderate and severe overall neurodevelopmental disabilities (OR 1.49, 95% CI 1.05 to 2.20; 2.20, 1.41 to 3.42 and 2.71, 1.67 to 4.40). BPD was associated with developmental coordination disorders, behavioural difficulties, lower IQ score as well as rehospitalisation in the last 12 months and developmental support. The association between BPD and cerebral palsy was statistically significant before adjustment but not in adjusted analyses. BPD was strongly and independently associated with many neurodevelopmental disabilities. Improving medical and neurodevelopmental management of BPD in very preterm children should be a priority to reduce its long-term consequences.


Field-cage methodology for evaluating climatic suitability for introduced wood-borer parasitoids: preliminary results from the emerald ash borer system.
Field-cage methods were developed to evaluate the abilities of Tetrastichus planipennisi Yang (Hymenoptera: Eulophidae) and Spathius agrili Yang (Hymenoptera: Braconidae), biocontrol agents of Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), to parasitize, develop and overwinter following three late-season releases at both a northern (Michigan) and a southern (Maryland) location within the current North American range of A. planipennis. In August, September and October of 2009, five young green ash trees were selected at each location. Tetrastichus planipennisi and S. agrili were each randomly assigned to one of two cages attached to each tree, surrounding separate sections of trunk in which late-instar A. planipennis had been inserted. The following April, the caged trunk sections were dissected to determine the fate of each A. planipennis larva and the developmental stages of all recovered parasitoid progeny. At both locations, T. planipennisi and S. agrili were able to parasitize hosts and successfully overwinter (i.e., reach adulthood the following spring). For T. planipennisi, successful parasitism (i.e., parasitoid progeny reached adulthood) occurred for all caged releases in Maryland, but only for the August and September releases in Michigan. At both locations, percent parasitism by T. planipennisi was higher in August and September than in October. For S. agrili, successful parasitism occurred for all caged releases in Maryland, but only for the August release in Michigan. In Maryland, percent parasitism by S. agrili in August and September was higher than in October. The caging method described here should be useful in determining the climatic suitability of other regions before proceeding with large-scale releases of either species and may have utility in other wood-borer parasitoid systems as well.


Effects of immunosuppression on avian coccidiosis: cyclosporin A but not hormonal bursectomy abrogates host protective immunity.
The effects of cyclosporin A (CsA) treatment and hormonal bursectomy on Eimeria tenella infection of chickens were investigated to evaluate the role of humoral antibody and cell-mediated immunity (CMI) in the host protective immunity to an intestinal protozoan disease, coccidiosis. Hormonal bursectomy had no significant effect on the host response to E. tenella. CsA treatment had a differential effect on the course of disease depending on how CsA was given relative to infection. Daily administration of CsA for 7 days beginning 1 day before primary infection with E. tenella enhanced disease resistance, whereas a single dose of CsA given before primary infection enhanced disease susceptibility compared with that of untreated controls. Chickens treated with CsA during the primary infection were resistant to reinfection at 5 weeks post-primary infection. Treatment of chickens immune to E. tenella with CsA at the time of secondary infection abrogated their resistance to reinfection despite the presence of high levels of coccidia-specific secretory immunoglobulin A and serum immunoglobulin G. Splenic lymphocytes obtained after CsA treatment demonstrated a substantially depressed concanavalin A response, but not a depressed lipopolysaccharide response. Because CsA was not directly toxic to parasites in vivo when administered during the secondary infection, these results suggest that CsA interacts with the immune system to allow priming during the primary infection, while interfering with the effector function of CMI during the secondary infection. Taken together, present findings indicate that CMI plays a major role in host protective immunity to E. tenella.


[Exogenous surfactant therapy in pediatrics].
To review current knowledge about the use of exogenous surfactants in the treatment of different lung diseases causing acute respiratory failure in children. This review is based on the author's experience and on recent data retrieved from ONIA, Mdconsult, Medline and the Cochrane Database Library. In spite of the success of the use of exogenous surfactants in Respiratory Distress Syndrome (RDS) of the newborn, some questions remain unanswered, such as the optimal administration timing - either very early (prophylactic), based on gestational age or on quick tests of lung maturity, or later, when the clinical picture becomes unequivocal. In other severe diseases requiring ventilatory support, the use of surfactants is still controversial, and data in the literature are limited and conflicting. However, successful use in several other diseases has been reported. Recent studies have focused on surfactant inactivation by substances that can be found in the airways. New surfactants with the addition of substances to control inhibition, such as polyethyleneglycol, are being tested for diseases in which inactivation seems to be a significant factor. Therapy with exogenous surfactants, even as a treatment for RDS, has not been thoroughly investigated. Further studies should be conducted to improve surfactants - mainly their resistance to inhibition - and the treatment of diseases other than RDS.


Thermal unfolding and refolding of lysozyme in deep eutectic solvents and their aqueous dilutions.
The stability of hen's egg white lysozyme in different choline chloride-based pseudo-concentrated and neat deep eutectic solvents (DESs) has been studied by means of intrinsic fluorescence and CD spectroscopy. Thermal unfolding experiments carried out in non-diluted urea:choline chloride and glycerol:choline chloride eutectic solvents (UCCl-DES and GCCl-DES, respectively) showed the accumulation at certain temperatures of discrete, partially folded intermediates that displayed a high content of secondary structure and a disrupted tertiary structure. Reversibility of the unfolding process was incomplete in these circumstances, with the urea-based DES showing higher protein structure destabilization upon thermal treatment. On the other hand, aqueous dilution of the eutectic mixtures allowed the recovery of a reversible, two-state denaturation process. Lysozyme activity was also affected in neat and pseudo-concentrated GCCl-DES, with an increasing recovery of activity upon aqueous dilution, and full restoration after DES removal through extensive dialysis. These results suggest that protein interactions at room temperature are reversible and depend on the DES components and on the aqueous content of the original DES dilution.


Schizophrenia and the myth of intellectual decline.
The authors' goal was to investigate the issue of intellectual deterioration in schizophrenia. They examined the childhood IQs of adult patients with schizophrenia who had attended a child psychiatry service where measurement of intelligence was routine. Follow-up IQs of 34 of these patients were obtained an average of 19.4 years later. The mean child and adult IQs were greater than one standard deviation lower than those of the general population. There were no significant differences between the child and adult IQs, however, suggesting that the impairment in intelligence during childhood was stable over the follow-up period. The deficit in intellectual function observed in these patients, and reported in the literature, is lifelong and predates the onset of schizophrenia.


Astroglial pentose phosphate pathway rates in response to high-glucose environments.
ROS (reactive oxygen species) play an essential role in the pathophysiology of diabetes, stroke and neurodegenerative disorders. Hyperglycaemia associated with diabetes enhances ROS production and causes oxidative stress in vascular endothelial cells, but adverse effects of either acute or chronic high-glucose environments on brain parenchymal cells remain unclear. The PPP (pentose phosphate pathway) and GSH participate in a major defence mechanism against ROS in brain, and we explored the role and regulation of the astroglial PPP in response to acute and chronic high-glucose environments. PPP activity was measured in cultured neurons and astroglia by determining the difference in rate of (14)CO(2) production from [1-(14)C]glucose and [6-(14)C]glucose. ROS production, mainly H(2)O(2), and GSH were also assessed. Acutely elevated glucose concentrations in the culture media increased PPP activity and GSH level in astroglia, decreasing ROS production. Chronically elevated glucose environments also induced PPP activation. Immunohistochemical analyses revealed that chronic high-glucose environments induced ER (endoplasmic reticulum) stress (presumably through increased hexosamine biosynthetic pathway flux). Nuclear translocation of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), which regulates G6PDH (glyceraldehyde-6-phosphate dehydrogenase) by enhancing transcription, was also observed in association with BiP (immunoglobulin heavy-chain-binding protein) expression. Acute and chronic high-glucose environments activated the PPP in astroglia, preventing ROS elevation. Therefore a rapid decrease in glucose level seems to enhance ROS toxicity, perhaps contributing to neural damage when insulin levels given to diabetic patients are not properly calibrated and plasma glucose levels are not adequately maintained. These findings may also explain the lack of evidence for clinical benefits from strict glycaemic control during the acute phase of stroke.


Characterization and immunogenicity of a Shigella flexneri 2a O-antigen bioconjugate vaccine candidate.
Shigellosis remains a major cause of diarrheal disease in developing countries and causes substantial morbidity and mortality in children. Vaccination represents a promising preventive measure to fight the burden of the disease, but despite enormous efforts, an efficacious vaccine is not available to date. The use of an innovative biosynthetic Escherichia coli glycosylation system substantially simplifies the production of a multivalent conjugate vaccine to prevent shigellosis. This bioconjugation approach has been used to produce the Shigella dysenteriae type O1 conjugate that has been successfully tested in a phase I clinical study in humans. In this report, we describe a similar approach for the production of an additional serotype required for a broadly protective shigellosis vaccine candidate. The Shigella flexneri 2a O-polysaccharide is conjugated to introduced asparagine residues of the carrier protein exotoxin A (EPA) from Pseudomonas aeruginosa by co-expression with the PglB oligosaccharyltransferase. The bioconjugate was purified, characterized using physicochemical methods and subjected to preclinical evaluation in rats. The bioconjugate elicited functional antibodies as shown by a bactericidal assay for S. flexneri 2a. This study confirms the applicability of bioconjugation for the S. flexneri 2a O-antigen, which provides an intrinsic advantage over chemical conjugates due to the simplicity of a single production step and ease of characterization of the homogenous monomeric conjugate formed. In addition, it shows that bioconjugates are able to raise functional antibodies against the polysaccharide antigen.


Deformable grating optical modulator.
A new type of light modulator, the deformable grating modulator, based on electrically controlling the amplitude of a micromachined phase grating is described. Mechanical motion of one quarter of a wavelength is sufficient for switching in this device. The small mechanical motion allows the use of structures with high mechanical resonance frequencies. We have developed a deformable grating modulator with a bandwidth of 1.8 MHz and a switching voltage of 3.2 V and have demonstrated modulation with 16 dB of contrast. Smaller devices with bandwidths of as much as 6.1 MHz and predicted switching voltages of less than 10 V were also fabricated.


Renal protective effect of sacubitril/valsartan in patients with heart failure.
Sacubitril/valsartan is a combined neprilysin inhibitor/angiotensin II receptor blocker designed for treatment of heart failure (HF). Nonetheless, its renal protective effect remained an issue of debate. This retrospective cohort study investigated the renal protective effect of sacubitril/valsartan in HF patients. HF patients on sacubitril/valsartan or valsartan for > 30 days were matched for gender, age, estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LVEF) to be enrolled into analysis. The follow-up period was 18 months. The outcomes included end eGFR, renal function decline defined as 20% reduction of eGFR, mortality, and HF-related hospitalization. Each group had 137 patients after matching. The mean age was 72.7 years and 65.7% were male. Mean eGFR was 70.9 mL/min/1.73 m2 and LVEF was 54.0% at baseline. Overall, the eGFR of sacubitril/valsartan groups was significantly higher than valsartan group at the end (P < 0.01). Subgroup analysis showed that the difference in eGFR was significant in subgroups with LVEF ≥ 40% or eGFR ≥ 60 mL/min/1.73 m2. Multivariate Cox regression model showed that sacubitril/valsartan group had significantly reduced risk for renal function decline (hazard ratio: 0.5, 95% confidence interval: 0.3-0.9). Kaplan-Meier curve showed no difference in the risk for cardiovascular mortality, all-cause mortality or HF-related hospitalization. We showed renal protective effect of neprilysin inhibition in HF patients and specified that subgroups with LVEF ≥ 40% or eGFR ≥ 60 mL/min/1.73 m2 were sensitive to this effect, suggesting an optimal subgroup of this treatment.


D3-creatine dilution, computed tomography and dual-energy X-ray absorptiometry for assessing myopenia and physical function in colon cancer: A cross-sectional study.
Low skeletal muscle mass (myopenia) is common in cancer populations and is associated with functional decline and mortality, but prior oncology studies did not assess total body skeletal muscle mass. Instead, they measured surrogates such as cross-sectional area (CSA) of skeletal muscle at L3 from computed tomography (CT) or appendicular lean mass (ALM) from dual-energy X-ray absorptiometry (DXA). D3-creatine (D3Cr) dilution is a non-invasive method to assess total body skeletal muscle mass, which has been examined in a variety of populations but not in cancer. To compare the associations of D3Cr muscle mass, CT CSA, and DXA ALM with myopenia and physical function, we conducted a cross-sectional study among 119 patients with colon cancer (2018-2022). For each technique (D3Cr, CT and DXA), myopenia was defined as the lowest sex-specific quartile of its measurement. Physical function was measured by the short physical performance battery and grip strength. We calculated Pearson correlations (r) among three techniques, computed Cohen's kappa coefficients (κ) to assess the agreement of myopenia, and estimated Pearson correlations (r) of three techniques with physical function. All analyses were sex-specific. Sixty-one (51.3%) participants were male, the mean (standard deviation) age was 56.6 (12.9) years, and most (68.9%) had high physical function (short physical performance battery: ≥11 points). Correlations and myopenia agreement among three techniques were greater in men than women; for example, regarding D3Cr muscle mass versus CT CSA, r was 0.73 (P < 0.001) for men versus 0.45 (P < 0.001) for women, and κ was 0.82 (95% CI: 0.65, 0.99) for men versus 0.24 (95% CI: -0.08, 0.52) for women. Among men, higher D3Cr muscle mass was significantly correlated with faster gait speed (r = 0.43, P < 0.01) and stronger grip strength (r = 0.32, P < 0.05); similar correlations were observed for CT CSA and DXA ALM. However, among women, no measure of muscle or lean mass was significantly associated with physical function. This is the first study using D3-creatine dilution method to assess muscle mass in a cancer population. Regardless of the techniques used for muscle or lean mass assessment, we observed stronger correlations, greater myopenia agreement, and more significant associations with physical function in men with colon cancer than women. D3Cr, CT and DXA are not interchangeable methods for assessing myopenia and physical function, especially in women with colon cancer. Future studies should consider relative advantages of these techniques and examine the D3-creatine dilution method in other cancer types.


Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits.
Misfolded and hyperphosphorylated tau accumulates in several neurodegenerative disorders including Alzheimer's disease, frontotemporal dementia with Parkinsonism, corticobasal degeneration, progressive supranuclear palsy, Down syndrome, and Pick's disease. Tau is a microtubule-binding protein, and its role in microtubule stabilization is well defined. In contrast, while growing evidence suggests that tau is also involved in synaptic physiology, a complete assessment of tau function in the adult brain has been hampered by robust developmental compensation of other microtubule-binding proteins in tau knockout mice. To circumvent these developmental compensations and assess the role of tau in the adult brain, we generated an adeno-associated virus (AAV) expressing a doxycycline-inducible short-hairpin (Sh) RNA targeted to tau, herein referred to as AAV-ShRNATau. We performed bilateral stereotaxic injections in 7-month-old C57Bl6/SJL wild-type mice with either the AAV-ShRNATau or a control AAV. We found that acute knockdown of tau in the adult hippocampus significantly impaired motor coordination and spatial memory. Blocking the expression of the AAV-ShRNATau, thereby allowing tau levels to return to control levels, restored motor coordination and spatial memory. Mechanistically, the reduced tau levels were associated with lower BDNF levels, reduced levels of synaptic proteins associated with learning, and decreased spine density. We provide compelling evidence that tau is necessary for motor and cognitive function in the adult brain, thereby firmly supporting that tau loss-of-function may contribute to the clinical manifestations of many tauopathies. These findings have profound clinical implications given that anti-tau therapies are in clinical trials for Alzheimer's disease.


Factors associated with insulin resistance among children and adolescents perinatally infected with HIV-1 in the pediatric HIV/AIDS cohort study.
Because of prior inconsistent findings, we studied a large cohort of HIV-infected children to determine: (1) prevalence of insulin resistance (IR); (2) anthropometric and clinical correlates of IR, and (3) concomitant abnormalities of glucose tolerance. The study population consisted of 451 children from the Pediatric HIV/AIDS Cohort Study. The outcome of interest was HOMA-IR. Covariates included demographic, metabolic, growth, body composition, HIV laboratory tests, and treatment characteristics. Children meeting triggers for IR underwent oral glucose tolerance tests and hemoglobin A1c (HbA1c) measurements. Among 402 children with glucose and insulin measurements, 15.2% had IR of whom 79% were pubertal. IR was associated with higher alanine aminotransferase, body mass index, and nadir CD4%, Tanner stage 5, and ever having received amprenavir. Of those with IR, three had impaired fasting glucose (IFG), three impaired glucose tolerance (IGT), one IFG and IGT, none diabetic glucose tolerance, and three HbA1c between 6.1 and 6.5%. In our cohort of HIV-infected adolescents, we observed a 15.2% prevalence of IR more closely linked to obesity than any other variable. This finding mirrors the high prevalence of obesity-mediated IR in American youth. However, associations with CD4 count and use of protease inhibitors may indicate some effect of HIV and/or its treatment.


BRCA1/2 testing in hereditary breast and ovarian cancer families: effectiveness of problem-solving training as a counseling intervention.
It remains uncertain whether members of hereditary breast and ovarian cancer (HBOC) families experience psychological distress with genetic testing and whether pre-test counseling can have a moderating effect on client well-being. One purpose of this study was to assess change in psychological well-being from baseline to 6-9 months follow-up and the effect of a problem-solving training (PST) intervention on psychological well-being. Two hundred and twelve members of 13 HBOC families were offered BRCA1/2 testing for a previously identified family mutation. Participants received education and were randomized to one of two counseling interventions; PST or client-centered counseling. Psychological well-being was assessed at baseline and again at 6-9 months following the receipt of test results, or at the equivalent time for those participants who chose not to undergo testing. Well-being was assessed using measures of depressive symptoms (CESD), intrusive thoughts (IES), cancer worries, and self-esteem. Comparisons were made between those who chose testing and those who did not as well as between those who received positive and negative test results. One hundred eighty one participants elected to undergo genetic testing (85%) and 47 of these (26%) were identified as BRCA1/2 mutation carriers. Breast and ovarian cancer worries decreased significantly (p = 0.007 and 0.008, respectively) in those who tested negative while there was no appreciable change in psychological well-being from baseline to follow-up in either those who tested positive or in non-testers. Among all participants, particularly testers, those randomized to PST had a greater reduction in depressive symptoms than those randomized to client-centered counseling (p < 0.05 and p = 0.02, respectively). Regardless of the decision to test, individuals with a personal history of cancer (n = 22) were more likely to have an increase in breast cancer worries compared to those who had never been diagnosed with cancer (p < 0.001). Results suggest that a problem-solving counseling intervention may help to enhance psychological well-being following testing and that a personal history of cancer may increase psychological distress associated with genetic testing.


Compliance checking of cancer-screening Careflows: an approach based on Computational Logic.
Clinical guidelines and Careflow systems have been recently identified as a means to improve and standardize health care services. A number of ICT-based management solutions have been proposed, focussing on several aspects such as specification, process logs verification with respect to specification (compliance), enactment and administration of careflows. In this paper we introduce the GPROVE framework, based on Computational Logic, and focused on the (formal) specification of careflows and on the compliance verification of the process executions w.r.t. the specified models. In particular, we show its application to the Cancer Screening Guideline used by the sanitary organization of the Emilia Romagna region, discussing its formalization in GPROVE and the results of the compliance checking applied to logs of the screening process.


JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer.
Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P < 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P = 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease. SIGNIFICANCE: This study identifies JMJD6 as being critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention.


Effects of a skiing experience on adolescents with limb deficiencies: an occupational adaptation perspective.
Effects of a 6-day snow skiing trip on 14 adolescents with limb deficiencies were explored. The purpose was to determine whether components of mastery and self-esteem could be identified. Participant observation data collection methods included videotape, interviews, daily progress notes by ski instructors, and a 1-month posttrip questionnaire. Data were analyzed for evidence of efficiency, effectiveness, and satisfaction to self and others (properties of relative mastery described in occupational adaptation.) Skier reports of positive effects were analyzed for indications of an impact on self-esteem. Three occupational therapists who have extensive experience working with adolescents also reviewed videotapes and written information. The therapists acknowledged the presence of skill mastery as an important component of skiers' positive self-evaluation. They also commented that evidence of preexisting self-esteem and social aspects of the trip were as likely to produce positive effects as mastery of skiing. Research method considerations (use of participant observation for hypothesis testing) preclude definitive interpretation of a link between skill mastery and self-esteem. Short-term positive effects of the skiing experience reported by questionnaire were present 1 month after the trip. Long-term effects should be studied.


Sleep-dependent consolidation of statistical learning.
The importance of sleep for memory consolidation has been firmly established over the past decade. Recent work has extended this by suggesting that sleep is also critical for the integration of disparate fragments of information into a unified schema, and for the abstraction of underlying rules. The question of which aspects of sleep play a significant role in integration and abstraction is, however, currently unresolved. Here, we examined the role of sleep in abstraction of the implicit probabilistic structure in sequential stimuli using a statistical learning paradigm, and tested for its role in such abstraction by searching for a predictive relationship between the type of sleep obtained and subsequent performance improvements using polysomnography. In our experiments, participants were exposed to a series of tones in a probabilistically determined sequential structure, and subsequently tested for recognition of novel short sequences adhering to this same statistical pattern in both immediate- and delayed-recall sessions. Participants who consolidated over a night of sleep improved significantly more than those who consolidated over an equivalent period of daytime wakefulness. Similarly, participants who consolidated across a 4-h afternoon delay containing a nap improved significantly more than those who consolidated across an equivalent period without a nap. Importantly, polysomnography revealed a significant correlation between the level of improvement and the amount of slow-wave sleep obtained. We also found evidence of a time-based consolidation process which operates alongside sleep-specific consolidation. These results demonstrate that abstraction of statistical patterns benefits from sleep, and provide the first clear support for the role of slow-wave sleep in this consolidation.


Glial-derived adenosine modulates spinal motor networks in mice.
The activation of purinergic receptors modulates central pattern generators controlling rhythmic motor behaviors, including respiration in rodents and swimming in frog tadpoles. The present study aimed to determine whether purinergic signaling also modulates the mammalian locomotor central pattern generator. This was investigated by using isolated spinal cord preparations obtained from neonatal mice in which locomotor-related activity can be induced pharmacologically. The application of either ATP or adenosine led to a reduction in the frequency of locomotor activity recorded from ventral roots. ATP had no effect when applied in the presence of both the adenosine receptor antagonist theophylline and the ectonucleotidase inhibitor ARL67156, demonstrating that the effects of ATP application result from the breakdown of ATP to adenosine and subsequent activation of adenosine receptors. The application of theophylline or the A(1)-specific antagonist cyclopentyl dipropylxanthine, but not the A(2A)-receptor antagonist SCH58261, caused an increase in locomotor burst frequency, demonstrating that endogenously derived adenosine activates A(1) receptors during locomotor network activity. Furthermore, theophylline had no effect in the presence of the ectonucleotidase inhibitor ARL67156 or the glial toxins methionine sulfoximine or ethyl fluoracetate, suggesting that endogenous adenosine is derived from ATP, which is released from glia. Finally, adenosine had no effect on slow rhythmic activity recorded upon blockade of all inhibitory transmission, suggesting that adenosine may act via the modulation of inhibitory transmission. Together, these data highlight endogenous purinergic gliotransmission, involving activation of A(1) receptors, as an important intrinsic modulatory system controlling the frequency of activity generated by spinal locomotor circuitry in mammals.


Mercury bioaccumulation and trophic transfer in the terrestrial food web of a montane forest.
We investigated mercury (Hg) concentrations in a terrestrial food web in high elevation forests in Vermont. Hg concentrations increased from autotrophic organisms to herbivores < detritivores < omnivores < carnivores. Within the carnivores studied, raptors had higher blood Hg concentrations than their songbird prey. The Hg concentration in the blood of the focal study species, Bicknell's thrush (Catharus bicknelli), varied over the course of the summer in response to a diet shift related to changing availability of arthropod prey. The Bicknell's thrush food web is more detrital-based (with higher Hg concentrations) in early summer and more foliage-based (with lower Hg concentrations) during late summer. There were significant year effects in different ecosystem compartments indicating a possible connection between atmospheric Hg deposition, detrital-layer Hg concentrations, arthropod Hg concentrations, and passerine blood Hg concentrations.


Influence of Temperature on Void Collapse in Single Crystal Nickel under Hydrostatic Compression.
Employing atomistic simulations, we investigated the void collapse mechanisms in single crystal Ni during hydrostatic compression and explored how the atomistic mechanisms of void collapse are influenced by temperature. Our results suggest that the emission and associated mutual interactions of dislocation loops around the void is the primary mechanism of void collapse, irrespective of the temperature. The rate of void collapse is almost insensitive to the temperature, and the process is not thermally activated until a high temperature (∼1200-1500 K) is reached. Our simulations reveal that, at elevated temperatures, dislocation motion is assisted by vacancy diffusion and consequently the void is observed to collapse continuously without showing appreciable strain hardening around it. In contrast, at low and ambient temperatures (1 and 300 K), void collapse is delayed after an initial stage of closure due to significant strain hardening around the void. Furthermore, we observe that the dislocation network produced during void collapse remains the sample even after complete void collapse, as was observed in a recent experiment of nickel-base superalloy after hot isostatic pressing.


Building interpretable models for polypharmacy prediction in older chronic patients based on drug prescription records.
Multimorbidity presents an increasingly common problem in older population, and is tightly related to polypharmacy, i.e., concurrent use of multiple medications by one individual. Detecting polypharmacy from drug prescription records is not only related to multimorbidity, but can also point at incorrect use of medicines. In this work, we build models for predicting polypharmacy from drug prescription records for newly diagnosed chronic patients. We evaluate the models' performance with a strong focus on interpretability of the results. A centrally collected nationwide dataset of prescription records was used to perform electronic phenotyping of patients for the following two chronic conditions: type 2 diabetes mellitus (T2D) and cardiovascular disease (CVD). In addition, a hospital discharge dataset was linked to the prescription records. A regularized regression model was built for 11 different experimental scenarios on two datasets, and complexity of the model was controlled with a maximum number of dimensions (MND) parameter. Performance and interpretability of the model were evaluated with AUC, AUPRC, calibration plots, and interpretation by a medical doctor. For the CVD model, AUC and AUPRC values of 0.900 (95% [0.898-0.901]) and 0.640 (0.635-0.645) were reached, respectively, while for the T2D model the values were 0.808 (0.803-0.812) and 0.732 (0.725-0.739). Reducing complexity of the model by 65% and 48% for CVD and T2D, resulted in 3% and 4% lower AUC, and 4% and 5% lower AUPRC values, respectively. Calibration plots for our models showed that we can achieve moderate calibration with reducing the models' complexity without significant loss of predictive performance. In this study, we found that it is possible to use drug prescription data to build a model for polypharmacy prediction in older population. In addition, the study showed that it is possible to find a balance between good performance and interpretability of the model, and achieve acceptable calibration at the same time.


Consolidating new words from repetitive versus multiple stories: Prior knowledge matters.
Prior knowledge is proposed to support the consolidation of newly acquired material. The current study examined whether children with superior vocabulary knowledge show enhanced overnight consolidation, particularly when new words are encountered in varying stories. Children aged 10 and 11 years (N = 42) were exposed to two sets of eight spoken novel words (e.g., "crocodol"), with one set embedded in the same story presented twice and the other presented in two different stories. Children with superior vocabulary knowledge showed larger overnight gains in explicit phonological and semantic knowledge when novel words had been encountered in multiple stories. However, when novel words had been encountered in repetitive stories, existing knowledge exerted no influence on the consolidation of explicit phonological knowledge and had a negative impact on the consolidation of semantic knowledge. One full day (24 h) after story exposure, only very weak evidence of lexical integration (i.e., slower animacy decisions toward the basewords [e.g., "crocodile"] than toward the control words) was observed for novel words learned via repetitive (but not multiple) stories. These data suggest that although the consolidation of explicit new word knowledge learned through multiple contexts is supported by prior knowledge, lexical integration might benefit more from repetition.


Immune status and risk for infection in patients receiving chronic immunosuppressive therapy.
Chronic immunosuppressive therapy may be complicated by infections indicating a more or less profound immune defect. However, immune monitoring to estimate the risk for infection has so far not been performed routinely. The aim of this study was (1) to investigate the effects of commonly used immunosuppressive treatment regimens on lymphocyte subsets and cytokine release from stimulated whole blood cultures in patients with rheumatic or autoimmune diseases; and (2) to determine whether such measurements could be used as predictors of infection, and if so, to determine their predictive value for subsequent infectious complications. Patients with various chronic inflammatory diseases (n = 97) treated with different immunosuppressive regimens and healthy controls (n = 36) were evaluated for T lymphocyte subsets and for cytokine release in whole blood cultures after stimulation with lipopolysaccharide (LPS) or phorbol myristate acetate (PMA) and ionomycin. Therapy with corticosteroids induced dose-dependent lymphocyte depletion. Concomitant application of cytotoxic disease modifying drugs and corticosteroids caused an additive effect on lymphocytopenia, but did not change CD4/CD8 ratio. Corticosteroid therapy was also associated with impaired cytokine release from mononuclear cells in whole blood assays after in vitro stimulation with LPS or PMA/ionomycin. Infections requiring hospitalization developed in 19 of 95 evaluable patients during an average followup period of 2.3 years. On logistic regression analysis, lymphocytopenia < 600/microl, in particular < 250 CD4+ T cells/microl, and therapy with corticosteroids > 10 mg prednisolone equivalent per day were predictive of infections. Multiple logistic regression analysis showed that T-helper lymphocytopenia < 250/microl was the best predictor for future infections, with a positive predictive value of 0.53 and a negative predictive value of 0.97. Patients receiving chronic immunosuppressive therapy can develop severe lymphopenia that involves all subsets. Monitoring T-helper cell counts may be useful to estimate the risk for subsequent infections in such patients.


Trifluridine/tipiracil: A practical guide to its use in the management of refractory metastatic colorectal cancer in Australia.
Trifluridine/tipiracil is available on the Australian Pharmaceutical Benefits Scheme for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not considered candidates for, fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-vascular endothelial growth factor agents and anti-epidermal growth factor receptor agents. This article reviews trifluridine/tipiracil clinical data and presents practical information on its use in the management of refractory mCRC in Australia. Whereas the primary mechanism of action of fluoropyrimidines such as fluorouracil (5-FU) and capecitabine is enzyme inhibition of nucleotide synthesis, trifluridine/tipiracil primarily acts by incorporation into DNA, resulting in DNA dysfunction. Trifluridine/tipiracil has activity in patients with 5-FU-resistant tumors and can be considered in patients with prior intolerance or toxicity to 5-FU. In the pivotal phase III RECOURSE trial evaluating trifluridine/tipiracil in chemotherapy-refractory mCRC, efficacy benefits were observed across all a priori prognostic subgroups including those defined by age (≥65 and ≥75 years), geographical origin, primary tumor site or KRAS status. Trifluridine/tipiracil therapy benefits appropriately selected patients who have an ECOG performance status of 0 or 1, with no more than mild hepatic impairment or mild-to-moderate renal impairment, and who are capable of adhering to oral therapy safely. Appropriate dosing, monitoring for adverse events and effective management of side effects are essential.


Ketosis proportionately spares glucose utilization in brain.
The brain is dependent on glucose as a primary energy substrate, but is capable of utilizing ketones such as β-hydroxybutyrate and acetoacetate, as occurs with fasting, starvation, or chronic feeding of a ketogenic diet. The relationship between changes in cerebral metabolic rates of glucose (CMRglc) and degree or duration of ketosis remains uncertain. To investigate if CMRglc decreases with chronic ketosis, 2-[(18)F]fluoro-2-deoxy-D-glucose in combination with positron emission tomography, was applied in anesthetized young adult rats fed 3 weeks of either standard or ketogenic diets. Cerebral metabolic rates of glucose (μmol/min per 100 g) was determined in the cerebral cortex and cerebellum using Gjedde-Patlak analysis. The average CMRglc significantly decreased in the cerebral cortex (23.0±4.9 versus 32.9±4.7) and cerebellum (29.3±8.6 versus 41.2±6.4) with increased plasma ketone bodies in the ketotic rats compared with standard diet group. The reduction of CMRglc in both brain regions correlates linearly by ∼9% for each 1 mmol/L increase of total plasma ketone bodies (0.3 to 6.3 mmol/L). Together with our meta-analysis, these data revealed that the degree and duration of ketosis has a major role in determining the corresponding change in CMRglc with ketosis.


Open source platform for collaborative construction of wearable sensor datasets for human motion analysis and an application for gait analysis.
Nearly every practical improvement in modeling human motion is well founded in a properly designed collection of data or datasets. These datasets must be made publicly available for the community could validate and accept them. It is reasonable to concede that a collective, guided enterprise could serve to devise solid and substantial datasets, as a result of a collaborative effort, in the same sense as the open software community does. In this way datasets could be complemented, extended and expanded in size with, for example, more individuals, samples and human actions. For this to be possible some commitments must be made by the collaborators, being one of them sharing the same data acquisition platform. In this paper, we offer an affordable open source hardware and software platform based on inertial wearable sensors in a way that several groups could cooperate in the construction of datasets through common software suitable for collaboration. Some experimental results about the throughput of the overall system are reported showing the feasibility of acquiring data from up to 6 sensors with a sampling frequency no less than 118Hz. Also, a proof-of-concept dataset is provided comprising sampled data from 12 subjects suitable for gait analysis.


Tick-Borne Pathogens Shape the Native Microbiome Within Tick Vectors.
Ticks are blood-feeding arthropods and transmit a variety of medically important viral, bacterial, protozoan pathogens to animals and humans. Ticks also harbor a diverse community of microbes linked to their biological processes, such as hematophagy, and hence affect vector competence. The interactions between bacterial and/or protozoan pathogens and the tick microbiome is a black-box, and therefore we tested the hypothesis that the presence of a protozoan or bacterial pathogen will alter the microbial composition within a tick. Hence, this study was designed to define the microbial composition of two tick species, Hyalomma (H.) anatolicum and Rhipicephalus (R.) microplus. We used a combination of PCR based pathogen (Anaplasma marginale and Theileria species) and symbiont (Wolbachia species) identification followed by metagenomic sequencing and comparison of the microbial communities in PCR positive and negative ticks. A total of 1786 operational taxonomic units was identified representing 25 phyla, 50 classes, and 342 genera. The phylum Proteobacteria, Firmicutes, Actinobacteriota, and Bacteroidota were the most represented bacteria group. Alpha and beta diversity were not significantly affected in the presence or absence of Theileria sp. and A. marginale as see with H. anatolicum ticks. Interestingly, bacterial communities were significantly reduced in Theileria sp. infected R. microplus ticks, while also exhibiting a significant reduction in microbial richness and evenness. Putting these observations together, we referred to the effect the presence of Theileria sp. has on R. microplus a "pathogen-induced dysbiosis". We also identify the presence of Plasmodium falciparum, the causative agent of human malaria from the microbiome of both H. anatolicum and R. microplus ticks. These findings support the presence of a "pathogen-induced dysbiosis" within the tick and further validation experiments are required to investigate how they are important in the vector competence of ticks. Understanding the mechanism of "pathogen-induced dysbiosis" on tick microbial composition may aid the discovery of intervention strategies for the control of emerging tick-borne infections.


The mouse C2C12 myoblast cell surface N-linked glycoproteome: identification, glycosite occupancy, and membrane orientation.
Endogenous regeneration and repair mechanisms are responsible for replacing dead and damaged cells to maintain or enhance tissue and organ function, and one of the best examples of endogenous repair mechanisms involves skeletal muscle. Although the molecular mechanisms that regulate the differentiation of satellite cells and myoblasts toward myofibers are not fully understood, cell surface proteins that sense and respond to their environment play an important role. The cell surface capturing technology was used here to uncover the cell surface N-linked glycoprotein subproteome of myoblasts and to identify potential markers of myoblast differentiation. 128 bona fide cell surface-exposed N-linked glycoproteins, including 117 transmembrane, four glycosylphosphatidylinositol-anchored, five extracellular matrix, and two membrane-associated proteins were identified from mouse C2C12 myoblasts. The data set revealed 36 cluster of differentiation-annotated proteins and confirmed the occupancy for 235 N-linked glycosylation sites. The identification of the N-glycosylation sites on the extracellular domain of the proteins allowed for the determination of the orientation of the identified proteins within the plasma membrane. One glycoprotein transmembrane orientation was found to be inconsistent with Swiss-Prot annotations, whereas ambiguous annotations for 14 other proteins were resolved. Several of the identified N-linked glycoproteins, including aquaporin-1 and beta-sarcoglycan, were found in validation experiments to change in overall abundance as the myoblasts differentiate toward myotubes. Therefore, the strategy and data presented shed new light on the complexity of the myoblast cell surface subproteome and reveal new targets for the clinically important characterization of cell intermediates during myoblast differentiation into myotubes.


Human leukocyte antigen class I/II alleles and development of human papillomavirus-related cervical neoplasia: results from a case-control study conducted in the United States.
The host immune response to human papillomaviruses (HPVs) is believed to be an important determinant of progression of HPV-associated cervical neoplasia. Human leukocyte antigens (HLAs) are important in the presentation of foreign antigens to the immune system. Previous studies have suggested a possible association between HLA and cervical neoplasia, but the specific alleles found to be associated with disease have varied between studies. To further evaluate this issue, we conducted a nested case-control study within a 24,000-woman cohort study in the United States. A total of 711 women were selected for the study: 141 women diagnosed with high-grade squamous intraepithelial lesions (HSILs) of the cervix; 202 women diagnosed with low-grade SILs (LSILs); 166 women with no history of cervical neoplasia, but evidence of HPV-16 infection; and 202 women with no history of cervical abnormalities and who were HPV negative during follow-up as part of our cohort. Cervicovaginal lavage samples collected from participants were used for HPV testing by L1 consensus primer PCR and the Hybrid Capture tube test methods. DNA extracted from these same lavage samples were used for PCR-based HLA genotyping. Our results suggest a positive association between HLA B7 and HLA DQB1*0302 and disease. A negative association with disease was observed for HLA DRB1*1501-DQB1*0602 and DRB1*13. Associations were strongest when analyses were restricted to HPV-16-positive cases as follows. Compared with women who were cytologically normal and HPV negative, HLA B7 was associated with a 1.5-fold increased risk of HPV/LSIL [95% confidence interval (CI) = 0.95-2.5] and a 2.5-fold increased risk of HSIL (95% CI = 1.2-5.1). HLA DQB1*0302 was associated with a 1.5-fold increased risk of HPV/LSIL (95% CI = 0.94-2.4) and a 1.7-fold increased risk of HSIL (95% CI = 0.84-3.5). HLA DRB1*1501-DQB1*0602 was associated with a decreased risk of HSIL [relative risk (RR) = 0.21; 95% CI = 0.07-0.62]. HLA DRB1*13 was associated with a decreased risk of HPV/LSIL (RR = 0.78; 95% CI = 0.51-1.2) and HSIL (RR = 0.63; 95% CI = 0.30-1.3). Individuals who were either homozygous for DQB1*0302 or carriers of both B7 and DQB1*0302 were found to be at highest risk of disease (RR = 4.5, 95% CI = 1.5-14 for HPV/LSIL; and RR = 9.0, 95% CI = 2.4-34 for HSIL). No synergistic effect was observed for the alleles found to be associated with reduced risk of cervical neoplasia. Our findings support previous studies that have found HLA B7 and DQB1*0302 to be positively associated with cervical neoplasia and are consistent with those that have suggested that DRB1*13 is negatively associated with disease, but do not confirm previous assertions that DRB1*1501-DQB1*0602 increases the risk of cervical disease.


The Five-Minute Moment.
In today's hospital and clinic environment, the obstacles to bedside teaching for both faculty and trainees are considerable. As electronic health record systems become increasingly prevalent, trainees are spending more time performing patient care tasks from computer workstations, limiting opportunities to learn at the bedside. Physical examination skills rarely are emphasized, and low confidence levels, especially in junior faculty, pose additional barriers to teaching the bedside examination.


Genetic rescue of remnant tropical trees by an alien pollinator.
Habitat fragmentation is thought to lower the viability of tropical trees by disrupting their mutualisms with native pollinators. However, in this study, Dinizia excelsa (Fabaceae), a canopy-emergent tree, was found to thrive in Amazonian pastures and forest fragments even in the absence of native pollinators. Canopy observations indicated that African honeybees (Apis mellifera scutellata) were the predominant floral visitors in fragmented habitats and replaced native insects in isolated pasture trees. Trees in habitat fragments produced, on average, over three times as many seeds as trees in continuous forest, and microsatellite assays of seed arrays showed that genetic diversity was maintained across habitats. A paternity analysis further revealed gene flow over as much as 3.2 km of pasture, the most distant pollination precisely recorded for any plant species. Usually considered only as dangerous exotics, African honeybees have become important pollinators in degraded tropical forests, and may alter the genetic structure of remnant populations through frequent long-distance gene flow.


Inducing Acute Traumatic Coagulopathy In Vitro: The Effects of Activated Protein C on Healthy Human Whole Blood.
Acute traumatic coagulopathy has been associated with shock and tissue injury, and may be mediated via activation of the protein C pathway. Patients with acute traumatic coagulopathy have prolonged PT and PTT, and decreased activity of factors V and VIII; they are also hypocoagulable by thromboelastometry (ROTEM) and other viscoelastic assays. To test the etiology of this phenomenon, we hypothesized that such coagulopathy could be induced in vitro in healthy human blood with the addition of activated protein C (aPC). Whole blood was collected from 20 healthy human subjects, and was "spiked" with increasing concentrations of purified human aPC (control, 75, 300, 2000 ng/mL). PT/PTT, factor activity assays, and ROTEM were performed on each sample. Mixed effect regression modeling was performed to assess the association of aPC concentration with PT/PTT, factor activity, and ROTEM parameters. In all subjects, increasing concentrations of aPC produced ROTEM tracings consistent with traumatic coagulopathy. ROTEM EXTEM parameters differed significantly by aPC concentration, with stepwise prolongation of clotting time (CT) and clot formation time (CFT), decreased alpha angle (α), impaired early clot formation (a10 and a20), and reduced maximum clot firmness (MCF). PT and PTT were significantly prolonged at higher aPC concentrations, with corresponding significant decreases in factor V and VIII activity. A phenotype of acute traumatic coagulopathy can be induced in healthy blood by the in vitro addition of aPC alone, as evidenced by viscoelastic measures and confirmed by conventional coagulation assays and factor activity. This may lend further mechanistic insight to the etiology of coagulation abnormalities in trauma, supporting the central role of the protein C pathway. Our findings also represent a model for future investigations in the diagnosis and treatment of acute traumatic coagulopathy.


Quality assurance of metabolomics.
Metabolomics promises a holistic phenotypic characterization of biological responses to toxicants. This technology is based on advanced chemical analytical tools with reasonable throughput, including mass-spectroscopy and NMR. Quality assurance, however - from experimental design, sample preparation, metabolite identification, to bioinformatics data-mining - is urgently needed to assure both quality of metabolomics data and reproducibility of biological models. In contrast to microarray-based transcriptomics, where consensus on quality assurance and reporting standards has been fostered over the last two decades, quality assurance of metabolomics is only now emerging. Regulatory use in safety sciences, and even proper scientific use of these technologies, demand quality assurance. In an effort to promote this discussion, an expert workshop discussed the quality assurance needs of metabolomics. The goals for this workshop were 1) to consider the challenges associated with metabolomics as an emerging science, with an emphasis on its application in toxicology and 2) to identify the key issues to be addressed in order to establish and implement quality assurance procedures in metabolomics-based toxicology. Consensus has still to be achieved regarding best practices to make sure sound, useful, and relevant information is derived from these new tools.


Similar amino acid sequences: chance or common ancestry?
The systemic comparison of every newly determined amino acid sequence with all other known sequences may allow a complete reconstruction of the evolutionary events leading to contemporary proteins. But sometimes the surviving similarities are so vague that even computer-based sequence comparisons procedures are unable to validate relationships. In other cases similar sequences may appear in totally alien proteins as a result of mere chance or, occasionally, by the convergent evolution of sequences with special properties.


Materials learning from life: concepts for active, adaptive and autonomous molecular systems.
Bioinspired out-of-equilibrium systems will set the scene for the next generation of molecular materials with active, adaptive, autonomous, emergent and intelligent behavior. Indeed life provides the best demonstrations of complex and functional out-of-equilibrium systems: cells keep track of time, communicate, move, adapt, evolve and replicate continuously. Stirred by the understanding of biological principles, artificial out-of-equilibrium systems are emerging in many fields of soft matter science. Here we put in perspective the molecular mechanisms driving biological functions with the ones driving synthetic molecular systems. Focusing on principles that enable new levels of functionalities (temporal control, autonomous structures, motion and work generation, information processing) rather than on specific material classes, we outline key cross-disciplinary concepts that emerge in this challenging field. Ultimately, the goal is to inspire and support new generations of autonomous and adaptive molecular devices fueled by self-regulating chemistry.


Transvaginal sonography of cervical width and length during pregnancy.
Transvaginal ultrasonography has been proposed as a reliable method of assessing dimensions of the cervix. The purpose of the current investigation was to establish normative data for cervical width and length during pregnancy. This information may be helpful in predicting patients at risk for preterm birth. A transvaginal 5 or 7.5 MHz transducer was used on 132 consecutive low-risk pregnant women undergoing evaluation for gestational dating purposes. Even in cases of patient obesity or an empty bladder, high resolution was possible and permitted cervical measurement in all but one case. The external cervical width at the vaginal fornices was found to increase with advancing gestation (R = 0.512, P < 0.005). The cervical length from internal os to external os was found not to change with advancing gestation (R = 0.11, P = 0.30). Using these normative data, investigation is recommended to determine whether measuring cervical width and length is useful in predicting preterm labor and delivery.


Pilot-scale production of biodiesel from waste fats and oils using tetramethylammonium hydroxide.
Annually, a great amount of waste fats and oils not suitable for human consumption or which cannot be further treated are produced around the world. A potential way of utilizing this low-cost feedstock is its conversion into biodiesel. The majority of biodiesel production processes today are based on the utilization of inorganic alkali catalysts. However, it has been proved that an organic base - tetramethylammonium hydroxide - can be used as a very efficient transesterification catalyst. Furthermore, it can be employed for the esterification of free fatty acids - reducing even high free fatty acid contents to the required level in just one step. The work presented herein, is focused on biodiesel production from waste frying oils and animal fats using tetramethylammonium hydroxide at the pilot-plant level. The results showed that the process performance in the pilot unit - using methanol and TMAH as a catalyst, is comparable to the laboratory procedure, even when the biodiesel is produced from waste vegetable oils or animal fats with high free fatty acid content. The reaction conditions were set at: 1.5% w/w of TMAH, reaction temperature 65°C, the feedstock to methanol molar ratio to 1:6, and the reaction time to 120min. The conversion of triglycerides to FAME was approximately 98%. The cloud point of the biodiesel obtained from waste animal fat was also determined.


Carpal tunnel and transverse carpal ligament stiffness with changes in wrist posture and indenter size.
This study investigated the effects of loading and posture on mechanical properties of the transverse carpal ligament (TCL). Ten fresh-frozen cadaver arms were dissected to expose the TCL and positioned in the load frame of a servo-hydraulic testing machine, equipped with a load cell and custom made indenters. Four cylindrical indenters (5, 10, 20, and 35 mm) loaded the TCL in three wrist postures (30° extension, neutral and 30° flexion). Three loading cycles with a peak force of 50 N were applied at 5 N/s for each condition. The flexed wrist posture had significantly greater TCL stiffness (40.0 ± 3.3 N/mm) than the neutral (35.9 ± 3.5 N/mm, p = 0.045) and extended postures (34.9 ± 2.8 N/mm, p = 0.025). TCL stiffness using the 10 and 20 mm indenters was larger than the 5 mm indenter. Stiffness was greatest with the 20 mm indenter, which had the greatest indenter contact area on the TCL. The 35 mm indenter covered the carpal bones, compressed the carpal tunnel and produced the lowest stiffness. The complexity of the TCL makes it an important part of the carpal tunnel and the mechanical properties found are essential to understanding mechanisms of carpal tunnel syndrome.


The neural correlates of maternal and romantic love.
Romantic and maternal love are highly rewarding experiences. Both are linked to the perpetuation of the species and therefore have a closely linked biological function of crucial evolutionary importance. Yet almost nothing is known about their neural correlates in the human. We therefore used fMRI to measure brain activity in mothers while they viewed pictures of their own and of acquainted children, and of their best friend and of acquainted adults as additional controls. The activity specific to maternal attachment was compared to that associated to romantic love described in our earlier study and to the distribution of attachment-mediating neurohormones established by other studies. Both types of attachment activated regions specific to each, as well as overlapping regions in the brain's reward system that coincide with areas rich in oxytocin and vasopressin receptors. Both deactivated a common set of regions associated with negative emotions, social judgment and 'mentalizing', that is, the assessment of other people's intentions and emotions. We conclude that human attachment employs a push-pull mechanism that overcomes social distance by deactivating networks used for critical social assessment and negative emotions, while it bonds individuals through the involvement of the reward circuitry, explaining the power of love to motivate and exhilarate.


A time series study on the effects of cold temperature on road traffic injuries in Seoul, Korea.
Although traffic accidents are associated with weather, the influence of temperature on injuries from traffic accidents has not been evaluated sufficiently. The objective of this study was to evaluate the effect of temperature, especially cold temperatures, on injuries from traffic accidents in Seoul, Korea. We also explored the relationship of temperature with different types of traffic accident. The daily frequencies of injuries from traffic accidents in Seoul were summarized from the integrated database established by the Korea Road Traffic Authority. Weather data included temperature, barometric pressure, rainfall, snow, and fog from May 2007 to December 2011. The qualitative relationship between daily mean temperature and injuries from traffic accidents was evaluated using a generalized additive model with Poisson distribution. Further analysis was performed using piecewise linear regression if graph the showed non-linearity with threshold. The incidence of injuries was 216 per 100,000 person-months in Seoul. The effect of temperature on injuries from traffic accidents was minimal during spring and summer. However, injuries showed a more striking relationship with temperature in winter than in other seasons. In winter, the number of injuries increased as the temperature decreased to <0°C. The injuries increased by 2.1% per 1°C decrease under the threshold of the daily average temperature -5.7°C, which is 10-fold greater than the effect of temperature above the threshold. Some groups were more susceptible to injuries, such as young and male drivers, according to the types of traffic accident when the temperature decreased to below the freezing temperature. The incidence of injuries increased sharply when the temperature decreased below freezing temperature in winter. Temperature can be effectively used to inform high risk of road traffic injuries, thus helping to prevent road traffic injuries.


New p-tolylimido rhenium(V) complexes with carboxylate-based ligands: synthesis, structures and their catalytic potential in oxidations with peroxides.
Novel p-tolylimido rhenium(v) complexes trans-(Cl,Cl)-[Re(p-NC6H4CH3)Cl2(pyz-2-COO)(PPh3)]·MeCN (1), trans-(Cl,Cl)-[Re(p-NC6H4CH3)Cl2(pyz-2-COO)(PPh3)] (2), trans-(Br,Br)-[Re(p-NC6H4CH3)Br2(pyz-2-COO)(PPh3)] (3), cis-(Cl,Cl)-[Re(p-NC6H4CH3)Cl2(ind-3-COO)(PPh3)]·2MeOH (4), 2[Re(p-NC6H4CH3)Cl2(ind-3-COO)(PPh3)]·MeCN (5), 2[Re(p-NC6H4CH3)Br2(ind-3-COO)(PPh3)]·MeOH (6) and 2[Re(p-NC6H4CH3)Br2(ind-3-COO)(PPh3)]·MeCN (7) were obtained in the reactions of [Re(p-NC6H4CH3)X3(PPh3)2] (X = Cl, Br) with pyrazine-2-carboxylic (pyz-2-COOH or PCA) and indazole-3-carboxylic (ind-3-COOH) acids. The compounds were identified by elemental analysis, IR, (1)H, (13)C and (31)P NMR spectroscopy and X-ray crystallography. To get a deeper understanding of the structural and bonding properties of the imido rhenium(v) complexes, calculations at the DFT level were undertaken for trans-(Cl,Cl)-[Re(p-NC6H4CH3)Cl2(pyz-2-COO)(PPh3)] and cis-(Cl,Cl)-[Re(p-NC6H4CH3)Cl2(ind-3-COO)(PPh3)]. Complexes 1, 3, 4 and 6 exhibited high catalytic activity in oxidation of alkanes with H2O2 and tert-butyl hydroperoxide (TBHP) and of alcohols with TBHP. The selectivity parameters measured in the reactions with linear and branched alkanes indicated that the processes with H2O2 or TBHP proceed with the participation of hydroxyl or tert-butoxyl radicals, respectively. The composition of isomers from oxygenation of methylcyclohexane corresponds to the existence of some steric hindrance around the reaction centers.


A Tale of Two Water Supplies in China: Finding Practical Solutions to Urban and Rural Water Supply Problems.
Access to safe drinking water is among the 17 United Nations sustainable development goals. As the largest developing country, China has confronted large challenges to providing safe and sufficient drinking water to its population of 1.4 billion under the conditions of limited water sources and ubiquitous water contamination. This Account outlines these challenges as well as the practical solutions implemented by Chinese water professionals. We first provide a general introduction of the water supply in China. Next, we describe the main challenges of water source shortages and source water contamination. The practical solutions developed by Chinese water professionals are the core part of this Account, to which we have devoted ourselves to and contributed in some issues and cases. The water supply in China is a binary system that reflects the gap between urban and rural communities. Both urban and rural water supplies have been subject to water source shortages and contamination. Water shortages are mainly solved by long-distance water transportation projects. Urban water utilities generally pay attention to organic matter, ammonia, algae, and chemical spills in source water while also focusing on micro-organisms and disinfection byproducts in tap water. Micro-organisms are a widespread concern for rural water supplies, whereas arsenic, fluoride, and ammonia are an endemic concern in some rural communities. Investment in updating of treatment processes significantly benefits urban water supplies, and advanced treatment of ozonation and biologically activated carbon processes are now commonly used to ensure that strict drinking water quality standards are met. However, this is not the case for rural water supplies, where expensive advanced treatment is not affordable. Thus, improving rural water supplies requires approaches such as searching for sources with better water quality, using automated ultrafiltration instruments, or connecting to urban water supply distribution systems. For rural areas with high concentrations of arsenic or fluoride in source water, specific adsorbents are a practical way to help farmers. Similar challenges will be encountered elsewhere in the world; therefore, the practical solutions applied in China will be useful to other countries in different stages of development.


Chronic stress moderates the impact of social exclusion on pain tolerance: an experimental investigation.
Experiences of social pain due to social exclusion may be processed in similar neural systems that process experiences of physical pain. The present study aimed to extend the findings on social exclusion and pain by examining the impact of social exclusion on an affective (ie, heat pain tolerance) and a sensory component of pain (ie, heat pain intensity). Whether a potential effect may be moderated by chronic life stress, social status, or social sup-port was further examined. A community-based sample of 59 women was studied. Social exclusion and inclusion were experimentally manipulated by using a virtual ball-tossing game called Cyberball in which participants were randomly assigned to either being excluded or being included by two other virtual players. Heat pain tolerance and intensity were assessed before and after the game. Potential psychosocial moderators were assessed via a questionnaire. The main finding of this study is that chronic stress moderates the impact of social exclusion on pain tolerance (p<0.05). When chronic stress was high, socially excluded participants showed a lower heat pain tolerance than participants who were socially included. Contrary to the authors' hypothesis, pain sensitivity was increased in socially included participants compared with socially excluded participants after the game (p<0.05). Higher levels of chronic stress may enhance the vulnerability of affective pain processing to acute social exclusion.


Type I collagen and its daughter peptides for targeting mucosal healing in ulcerative colitis: A new treatment strategy.
Ulcerative colitis, particularly the chronic persistent form is characterized by the presence of active inflammation and extensive areas of ulceration in the colonic mucosa. The existing treatment protocol aims at only reducing intestinal inflammation, rather than targeting mucosal ulceration. In this study, type I collagen and its daughter peptides called collagen hydrolysate, highly popular reconstructive materials for tissue engineering applications, are hypothesized as healing matrices to target the recuperation of internal mucosal ulceration. The clinical assessments on day 10 of dextran sodium sulfate induced colitis in mice model revealed that both the collagen (1.56±0.29) and collagen hydrolysate treatments (1.33±0.33) showed a significant reduction in the rectal bleeding compared to the reference mesalamine treatment (2.50±0.33) and untreated negative control (2.40±0.40). VEGF, a potent angiogenic growth factor, over expressed during UC was down-regulated by collagen hydrolysate (1.06±0.25) and collagen (1.76±0.45) to a greater extent than by mesalamine (2.59±0.51) and untreated control (4.17±0.15). The down-regulation of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 also follows the same pattern. Histological observations were in accordance with the clinical indicators. Both collagen and collagen hydrolysate treatments showed significant reduction in mucosal damage score and facilitated faster regeneration of damaged mucosa.