Protistan grazing impacts microbial communities and carbon cycling at deep-sea hydrothermal vents.
Microbial eukaryotes (or protists) in marine ecosystems are a link between primary producers and all higher trophic levels, and the rate at which heterotrophic protistan grazers consume microbial prey is a key mechanism for carbon transport and recycling in microbial food webs. At deep-sea hydrothermal vents, chemosynthetic bacteria and archaea form the base of a food web that functions in the absence of sunlight, but the role of protistan grazers in these highly productive ecosystems is largely unexplored. Here, we pair grazing experiments with a molecular survey to quantify protistan grazing and to characterize the composition of vent-associated protists in low-temperature diffuse venting fluids from Gorda Ridge in the northeast Pacific Ocean. Results reveal protists exert higher predation pressure at vents compared to the surrounding deep seawater environment and may account for consuming 28 to 62% of the daily stock of prokaryotic biomass within discharging hydrothermal vent fluids. The vent-associated protistan community was more species rich relative to the background deep sea, and patterns in the distribution and co-occurrence of vent microbes provide additional insights into potential predator-prey interactions. Ciliates, followed by dinoflagellates, Syndiniales, rhizaria, and stramenopiles, dominated the vent protistan community and included bacterivorous species, species known to host symbionts, and parasites. Our findings provide an estimate of protistan grazing pressure within hydrothermal vent food webs, highlighting the important role that diverse protistan communities play in deep-sea carbon cycling.


Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies.
Atypical hemolytic uremic syndrome (aHUS) is a rare, possibly life-threatening disease characterized by platelet activation, hemolysis and thrombotic microangiopathy (TMA) leading to renal and other end-organ damage. We originally conducted two phase 2 studies (26 weeks and 1 year) evaluating eculizumab, a terminal complement inhibitor, in patients with progressing TMA (trial 1) and those with long duration of aHUS and chronic kidney disease (trial 2). The current analysis assessed outcomes after 2 years (median eculizumab exposure 100 and 114 weeks, respectively). At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 patients, the platelet count was significantly improved from baseline, and hematologic normalization was achieved in 13 patients at week 26, and in 15 patients at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2 with 20 patients, TMA event-free status was achieved by 16 patients at week 26, 17 patients at year 1, and 19 patients at year 2. Criteria for hematologic normalization were met by 18 patients at each time point. Improvement of 15 ml/min per 1.73 m(2) or more in eGFR was achieved by 1 patient at week 26, 3 patients at 1 year, and 8 patients at 2 years. The mean change in eGFR was not significant compared with baseline, week 26, or year 1. Eculizumab was well tolerated, with no new safety concerns or meningococcal infections. Thus, a 2-year analysis found that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up.


What is the role of nursing students and schools of nursing during disaster? a discussion paper.
During times of disaster, the front-line nursing workforce and the health services in which they work may be overwhelmed by a surge in patient demand. As a result, assistance will be required to bolster the nursing workforce. Commonly, discussions regarding workforce supply and sustainability during disasters are isolated within particular health service institutions. The aims of this discussion paper are to; firstly, consider the potential contribution of nursing students and schools of nursing within Australian universities to increase the health workforce during a disaster, and secondly, to present a number of recommendations that universities and schools of nursing could consider in developing their own emergency and disaster plans.


In vitro enhancement effect of humic acid on the progression of lung cancer cells.
Humic acid, a group of polymer, resulting from the decomposition of organic matter has been implicated as a possible etiological factor for Black foot disease and cancer. However, the role of humic acid in carcinogenesis is not well clarified. In this study, we evaluated the enhancement effect of humic acid on the progression of A549 human lung cancer cells. Our findings showed that humic acid increased the migration, adhesion and invasion of A549 cells significantly after treatment at the concentration of 50 and 100 microg/ml for 24 and 48 h as compared with the untreated group. Results of zymography assay indicated that humic acid enhanced the activity of matrix metalloproteinase 9 (MMP-9). By western blotting analysis, humic acid increased the expression of phosphorylated focal adhesion kinase (FAK) and integrin alpha2 that may mediate cell motility and adhesion. Since the activation of signal pathways such as phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinases (MAPKs) may play a role in the cell invasion, we detected the expression of phosphorylated Akt and phosphorylated MAPKs including extracellular signal-regulated kinase (ERK), Jun N-terminus kinase (JNK), and p38. The result indicated that all kinases stated above were activated by humic acid in A549 cells. However, by adding an inhibitor respectively in the invasion assay, only Akt, ERK, and JNK pathways were found to be involved in the enhancing the invasion of A549 cells by humic acid. In addition, results of electrophoretic mobility shift assay (EMSA) demonstrated that humic acid increased nuclear extract binding to the DNA probe of activator protein 1 (AP-1) and nuclear factor kappaB (NFkappaB) respectively, implying that humic acid enhanced the progression of A549 lung cancer cells through activating multiple signaling pathways including ERK, JNK, and PI3K/Akt and increasing the transcription activation of AP-1 and NFkappaB.


High-performance liquid chromatography-based determination of nicarbazin excretion in waterfowl.
A method for the high-performance liquid chromatography (HPLC) determination of nicarbazin uptake and excretion in ducks is presented. The method uses few clean-up steps and provides a rapid assessment of nicarbazin excretion by measuring the analyte 4,4'-dinitrocarbanalide (DNC). During method development the effect of extraction volume, number of extractions, mobile phase composition, column temperature, and injection volume were varied to optimize sensitivity and achieve as short a run time as possible. For our purposes, a 2 x 5.0 ml 1:1 dimethyl formamide (DMF):acetonitrile (ACN) extraction injected (40 ml) into an HPLC system equipped with a Keystone octadecylsilyl (ODS) C18 column and a UV variable wavelength detector (lambda=347 nm) with a mobile phase of 60:40 (v/v) ACN-H2O, at a flow-rate of 1.0 ml/min at a column temperature of 35 degrees C provided adequate resolution and an acceptable total run time. Studies conducted during method development for inter-day recovery efficiencies for 0.46, 1.8 and 88.5 microg fortified samples (n=3) had mean recoveries of 91, 94 and 97% and intra-day (n=3) recoveries at the same fortification levels of 103, 94, and 92%. The method has been used successfully in excretion studies of nicarbazin in ducks.


Piper Species: A Comprehensive Review on Their Phytochemistry, Biological Activities and Applications.
Piper species are aromatic plants used as spices in the kitchen, but their secondary metabolites have also shown biological effects on human health. These plants are rich in essential oils, which can be found in their fruits, seeds, leaves, branches, roots and stems. Some Piper species have simple chemical profiles, while others, such as Piper nigrum, Piper betle, and Piper auritum, contain very diverse suites of secondary metabolites. In traditional medicine, Piper species have been used worldwide to treat several diseases such as urological problems, skin, liver and stomach ailments, for wound healing, and as antipyretic and anti-inflammatory agents. In addition, Piper species could be used as natural antioxidants and antimicrobial agents in food preservation. The phytochemicals and essential oils of Piper species have shown strong antioxidant activity, in comparison with synthetic antioxidants, and demonstrated antibacterial and antifungal activities against human pathogens. Moreover, Piper species possess therapeutic and preventive potential against several chronic disorders. Among the functional properties of Piper plants/extracts/active components the antiproliferative, anti-inflammatory, and neuropharmacological activities of the extracts and extract-derived bioactive constituents are thought to be key effects for the protection against chronic conditions, based on preclinical in vitro and in vivo studies, besides clinical studies. Habitats and cultivation of Piper species are also covered in this review. In this current work, available literature of chemical constituents of the essential oils Piper plants, their use in traditional medicine, their applications as a food preservative, their antiparasitic activities and other important biological activities are reviewed.


Planned home compared with planned hospital births in the Netherlands: intrapartum and early neonatal death in low-risk pregnancies.
The purpose of our study was to compare the intrapartum and early neonatal mortality rate of planned home birth with planned hospital birth in community midwife-led deliveries after case mix adjustment. The perinatal outcome of 679,952 low-risk women was obtained from the Netherlands Perinatal Registry (2000-2007). This group represents all women who had a choice between home and hospital birth. Two different analyses were performed: natural prospective approach (intention-to-treat-like analysis) and perfect guideline approach (per-protocol-like analysis). Unadjusted and adjusted odds ratios (ORs) were calculated. Case mix was based on the presence of at least one of the following: congenital abnormalities, small for gestational age, preterm birth, or low Apgar score. We also investigated the potential risk role of intended place of birth. Multivariate stepwise logistic regression was used to investigate the potential risk role of intended place of birth. Intrapartum and neonatal death at 0-7 days was observed in 0.15% of planned home compared with 0.18% in planned hospital births (crude relative risk 0.80, 95% confidence interval [CI] 0.71-0.91). After case mix adjustment, the relation is reversed, showing nonsignificant increased mortality risk of home birth (OR 1.05, 95% CI 0.91-1.21). In certain subgroups, additional mortality may arise at home if risk conditions emerge at birth (up to 20% increase). Home birth, under routine conditions, is generally not associated with increased intrapartum and early neonatal death, yet in subgroups, additional risk cannot be excluded.


Restoration of P-glycoprotein function is involved in the increase of natural killer activity with exogenous interleukin-15 in human immunodeficiency virus-infected individuals.
A depressed level of natural killer (NK) activity is one of the various immunologic abnormalities in human immunodeficiency virus (HIV) infection. Interleukin-15 (IL-15), an immunotherapeutic candidate in HIV infection, increases NK activity and induces the excretion of CC-chemokines from divergent immune cells, but the mechanisms of NK activity enhancement by IL-15 stimulation is not clearly established in HIV infection. This study examined whether CC-chemokines, which are known to increase NK activity, are secreted adequately in HIV-infected individuals, and also investigated whether P-glycoprotein is involved in NK activity enhancement after IL-15 administration. NK activity increased with IL-15 stimulation in NK cells of HIV-infected individuals, as it does in normal NK cells. IL-15 stimulates NK cells to secrete CC-chemokines, such as, macrophage inflammatory protein-1alpha (MIP-1alpha), macrophage chemotactic protein-1alpha (MCP-1alpha) and regulated upon activation, normal T cells expressed and secreted (RANTES) in both HIV-infected individuals and controls with no significant difference. P-glycoprotein expression and function is decreased in HIV-infected individuals and restored only in NK cells of HIV-infected individuals after IL-15 stimulation. P-glycoprotein may play a role in the mechanism of increased NK cell activity in HIV-infected individuals after IL-15 stimulation.


Computer navigation in orthopedic trauma: safer surgeries with less irradiation and more precision.
Exposure of patients and practitioners to ionizing radiation for diagnostic and therapeutic purposes has become the norm rather than the exception. This article discusses the findings from a literature review of intraoperative risks from ionizing radiation to patients and surgeons and the validity of substituting the conventional intraoperative fluoroscopy with computer-assisted orthopedic surgery (CAOS) in orthopedic trauma surgery. Diversity of study designs and measurements exists in reporting intraoperative ionizing radiation, making direct study comparisons difficult. CAOS can effectively reduce the amount of radiation exposure. There are definite advantages and disadvantages for using CAOS in the field of orthopedic trauma. Implementation of CAOS may hold the answer to better patient and surgeon intraoperative radiation safety with decreased operative time and increased procedure precision. The increased safety for patients and surgeons is a critical consideration in recommending CAOS in trauma surgery.


Systematic review of met and unmet need of surgical disease in rural sub-Saharan Africa.
Little is known about the burden of surgical disease in rural sub-Saharan Africa, where district and rural hospitals are the main providers of care. The present study sought to analyze what is known about the met and unmet need of surgical disease. The PubMed and EMBASE databases were searched for studies of surveys in rural areas, information on surgical admissions, and operations performed within rural and district hospitals. Data were extrapolated to calculate the amount of surgical disease per 100,000 population and the number of operations performed per 100,000 population. These extrapolations were used to estimate the total, the met, and the unmet need of surgical disease. The estimated overall incidence of nonfatal injury is at least 1,690/100,000 population per year. Morbidity as a result of injury is up to 190/100,000 population per year, and the annual mortality from injury is 53-92/100,000. District hospitals perform 6 fracture reductions (95% CI: 0.1-12)/100,000 population per year and 14 laparotomies (95% CI: 7-21)/100,000 per year. The incidence of peritonitis and bowel obstruction is unknown, although it may be as high as 1,364/100,000 population for the acute abdomen. The annual total need for inguinal hernia repair is estimated to be a minimum of 205/100,000 population. The average district hospital performs 30 hernia repairs (95% CI: 18-41)/100,000 population per year, leaving an unmet need of 175/100,000 population annually. District hospitals are not meeting the surgical needs of the populations they serve. Urgent intervention is required to build up their capacity, to train healthcare personnel in safe surgery and anesthesia, and to overcome obstacles to timely emergency care.


Continuous subcutaneous insulin infusion versus multiple daily injections of insulin for pregnant women with diabetes.
Diabetes results in a rise in blood glucose above normal physiological levels; if untreated this may cause damage to many systems including the cardiovascular and renal systems. Pregnancy increases resistance to insulin action; for those women who have pre-gestational diabetes, this results in an increasing insulin requirement. There are several methods of administering insulin. Conventionally, insulin has been administered subcutaneously, formally referred to as intensive conventional treatment, but now more usually referred to as multiple daily injections (MDI). An alternative method of insulin administration is the continuous subcutaneous insulin infusion pump (CSII). To compare CSII with MDI of insulin for pregnant women with pre-existing and gestational diabetes. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2016) and reference lists of retrieved studies. Randomised trials comparing CSII with MDI for pregnant women with diabetes. Three review authors independently assessed studies and two review authors extracted data. Disagreements were resolved through discussion with the third author. We assessed the quality of the evidence using the GRADE approach. We included five single-centre trials (undertaken in Italy) with 153 women and 154 pregnancies in this review.There were no clear differences in the primary outcomes reported between CSII and MDI in the included trials: caesarean section (risk ratio (RR) 1.09, 95% confidence interval (CI) 0.66 to 1.77; three trials, 71 women, evidence graded very low), large-for-gestational age (RR 4.15, 95% CI 0.49 to 34.95; three trials, 73 infants; evidence graded very low), and perinatal mortality (RR 2.33, 95% CI 0.38 to 14.32; four trials, 83 infants, evidence graded very low). Other primary outcomes were not reported in these trials (hypertensive disorders of pregnancy, development of type 2 diabetes, composite outcome of serious neonatal outcomes, and neurosensory disability).There was no clear evidence of differences in the maternal secondary outcomes: maternal weight gain during pregnancy, 24 hour mean blood glucose in each trimester, mean maternal HbA1c in each trimester, maternal hypoglycaemia, and maternal hyperglycaemia. The included studies did not report several GRADE outcomes: perineal trauma, return to pre-pregnancy weight, postnatal depression, induction of labour. Many maternal secondary outcomes were also not reported.In two trials, including a total of 61 infants, CSII was associated with an increase in mean birthweight compared with MDI (mean difference (MD) 220.56 g, 95% CI -2.09 g to 443.20 g; P = 0.05). However, the large CI including anything from a small reduction to an increase in mean birthweight and the lack of a difference in macrosomia rate (RR 3.20, CI 0.14 to 72.62; two trials, 61 infants) suggests uncertainty. Large-for-gestational age (see above), andsmall-for-gestational age also suggests uncertainty of effect. No significant differences were found in: gestation at delivery, preterm birth < 37 weeks' gestation, preterm birth < 32 weeks' gestation, neonatal hypoglycaemia (evidence graded very low), respiratory distress syndrome, neonatal hyperbilirubinaemia, and fetal anomaly. There were no data reported on many important infant outcomes, including the GRADE outcomes adiposity and diabetes. There was no follow-up of infants in childhood or adulthood, so longer-term outcomes were not reported.The only outcome reported for use of health service resources wasmaternal days hospitalised, which did not show a difference between groups in the small number of women included (MD 9.40, CI -6.04 to 24.84; one trial, 10 women).The methods used by the trials were poorly reported, for example although blinding of participants and clinicians regarding intervention allocation is impossible, it is possible to blind assessors and this along with other aspects of trial methods was not reported, which means that the trials are at an unclear or high risk of bias. We do not know if the women who participated were representative, and therefore if the results can be generalised. Most GRADE outcomes were not reported. For the GRADE outcomes that were reported, our assessment was that the evidence is very low quality (caesarean section, large-for-gestational age, perinatal mortality, andneonatal hypoglycaemia). This was due to design limitations in the included trials, small sample sizes in the trials contributing data, wide CIs crossing both the line of no effect and the line of appreciable benefit and/or harm, and often few events. We are therefore uncertain whether CSII or MDI improves outcomes for pregnant women with diabetes and their infants, and the results of further studies may differ substantially from those presented in this review. There is no evidence to support the use of one particular form of insulin administration over another for pregnant women with diabetes. There are only a small number of trials appropriate for meta-analysis, a small number of women included and questionable generalisability of the trial population.Pump technology has progressed since these trials were undertaken. Well-designed randomised trials are required to evaluate comparisons such as patch pumps against MDI and more conventional CSII against MDI. These trials should be adequately powered to assess the effect of interventions, and report the core set of outcomes used in Cochrane reviews of diabetes in pregnancy. Trials to assess the effects of pumps on birthweight and macrosomia rates are needed. It would be beneficial for future trials to undertake longer-term follow-up of participants and their infants, assess women's preferences, and conduct an economic evaluation.


Genetically encoded calcium indicators for multi-color neural activity imaging and combination with optogenetics.
Genetically encoded calcium indicators (GECIs) are powerful tools for systems neuroscience. Here we describe red, single-wavelength GECIs, "RCaMPs," engineered from circular permutation of the thermostable red fluorescent protein mRuby. High-resolution crystal structures of mRuby, the red sensor RCaMP, and the recently published red GECI R-GECO1 give insight into the chromophore environments of the Ca(2+)-bound state of the sensors and the engineered protein domain interfaces of the different indicators. We characterized the biophysical properties and performance of RCaMP sensors in vitro and in vivo in Caenorhabditis elegans, Drosophila larvae, and larval zebrafish. Further, we demonstrate 2-color calcium imaging both within the same cell (registering mitochondrial and somatic [Ca(2+)]) and between two populations of cells: neurons and astrocytes. Finally, we perform integrated optogenetics experiments, wherein neural activation via channelrhodopsin-2 (ChR2) or a red-shifted variant, and activity imaging via RCaMP or GCaMP, are conducted simultaneously, with the ChR2/RCaMP pair providing independently addressable spectral channels. Using this paradigm, we measure calcium responses of naturalistic and ChR2-evoked muscle contractions in vivo in crawling C. elegans. We systematically compare the RCaMP sensors to R-GECO1, in terms of action potential-evoked fluorescence increases in neurons, photobleaching, and photoswitching. R-GECO1 displays higher Ca(2+) affinity and larger dynamic range than RCaMP, but exhibits significant photoactivation with blue and green light, suggesting that integrated channelrhodopsin-based optogenetics using R-GECO1 may be subject to artifact. Finally, we create and test blue, cyan, and yellow variants engineered from GCaMP by rational design. This engineered set of chromatic variants facilitates new experiments in functional imaging and optogenetics.


Incorporating Inflammation into Mortality Risk in Pediatric Acute Respiratory Distress Syndrome.
In pediatric acute respiratory distress syndrome, lung injury is mediated by immune activation and severe inflammation. Therefore, we hypothesized that patients with elevated pro- and anti-inflammatory cytokines would have higher mortality rates and that these biomarkers could improve risk stratification of poor outcomes. Multicenter prospective observational study. We enrolled patients from five academic PICUs between 2008 and 2015. Patients were 1 month to 18 years old, used noninvasive or invasive ventilation, and met the American European Consensus Conference definition of acute respiratory distress syndrome. Eight proinflammatory and anti-inflammatory cytokines were measured on acute respiratory distress syndrome day 1 and correlated with mortality, ICU morbidity as measured by survivor Pediatric Logistic Organ Dysfunction score, and biomarkers of endothelial injury, including angiopoietin-2, von Willebrand Factor, and soluble thrombomodulin. We measured biomarker levels in 194 patients, including 38 acute respiratory distress syndrome nonsurvivors. Interleukin-6, interleukin-8, interleukin-10, interleukin-18, and tumor necrosis factor-R2 were each strongly associated with all-cause mortality, multiple markers of ICU morbidity, and endothelial injury. A multiple logistic regression model incorporating oxygenation index, interleukin-8, and tumor necrosis factor-R2 was superior to a model of oxygenation index alone in predicting the composite outcome of mortality or severe morbidity (area under the receiver operating characteristic, 0.77 [0.70-0.83] vs 0.70 [0.62-0.77]; p = 0.042). In pediatric acute respiratory distress syndrome, pro- and anti-inflammatory cytokines are strongly associated with mortality, ICU morbidity, and biochemical evidence of endothelial injury. These cytokines significantly improve the ability of the oxygenation index to discriminate risk of mortality or severe morbidity and may allow for identification and enrollment of high-risk subgroups for future studies.


The nucleotide sequence coding for major outer membrane protein OmpA of Shigella dysenteriae.
The nucleotide sequence of the ompA gene from Shigella dysenteriae has been determined and the amino acid sequence of the pro-OmpA protein predicted. Sequence comparison between the ompA genes of S.dysenteriae and Escherichia coli showed that features such as mRNA secondary structure and codon usage, as well as polypeptide function, have been conserved during evolution. The pro-OmpA protein of S.dysenteriae consists of 351 residues, as opposed to the 346 of the E.coli protein and also shows several amino acid changes. These changes have been used to interpret differences in the biological activity of the two proteins.


Face adaptation aftereffects reveal anterior medial temporal cortex role in high level category representation.
Previous studies have shown reductions of the functional magnetic resonance imaging (fMRI) signal in response to repetition of specific visual stimuli. We examined how adaptation affects the neural responses associated with categorization behavior, using face adaptation aftereffects. Adaptation to a given facial category biases categorization towards non-adapted facial categories in response to presentation of ambiguous morphs. We explored a hypothesis, posed by recent psychophysical studies, that these adaptation-induced categorizations are mediated by activity in relatively advanced stages within the occipitotemporal visual processing stream. Replicating these studies, we find that adaptation to a facial expression heightens perception of non-adapted expressions. Using comparable behavioral methods, we also show that adaptation to a specific identity heightens perception of a second identity in morph faces. We show both expression and identity effects to be associated with heightened anterior medial temporal lobe activity, specifically when perceiving the non-adapted category. These regions, incorporating bilateral anterior ventral rhinal cortices, perirhinal cortex and left anterior hippocampus are regions previously implicated in high-level visual perception. These categorization effects were not evident in fusiform or occipital gyri, although activity in these regions was reduced to repeated faces. The findings suggest that adaptation-induced perception is mediated by activity in regions downstream to those showing reductions due to stimulus repetition.


Formation and dissolution of bacterial colonies.
Many organisms form colonies for a transient period of time to withstand environmental pressure. Bacterial biofilms are a prototypical example of such behavior. Despite significant interest across disciplines, physical mechanisms governing the formation and dissolution of bacterial colonies are still poorly understood. Starting from a kinetic description of motile and interacting cells we derive a hydrodynamic equation for their density on a surface, where most of the kinetic coefficients are estimated from experimental data for N. gonorrhoeae bacteria. We use it to describe the formation of multiple colonies with sizes consistent with experimental observations. Finally, we show how the changes in the cell-to-cell interactions lead to the dissolution of the bacterial colonies. The successful application of kinetic theory to a complex far from equilibrium system such as formation and dissolution of living bacterial colonies potentially paves the way for the physical quantification of the initial stages of biofilm formation.


Evaluation of a fully automated end-tidal carbon monoxide instrument for breath analysis.
We evaluated a novel, portable breath sampler/CO-quantifying instrument [Baby's Breath Carbon Monoxide Analyzer (BB); Natus Medical], developed for use at the bedside or with gas samples collected into bags. Bench tests demonstrated that the CO measurements were linear, accurate, and precise when compared with gas chromatography (GC) results. In vivo tests (n = 30) performed with adults showed excellent correlation between end-tidal breath CO measurements (ETCO) corrected for inhaled CO (ETCOc) as determined by BB and GC. Breath sampling efficiency was 96%. ETCOc measurements and blood carboxyhemoglobin fractions (% of total hemoglobin) corrected for inhaled CO (COHbc) correlated strongly: COHbc = 0.25 ETCOc--0.01 microL/L CO (r2 = 0.97, Sy/x = 0.47, SE slope = 0.01, n = 30). The imprecision, assessed by the mean of the population's CV for triplicate determinations, was 11%. Measurements with healthy and hemolytic term newborns showed that ETCOc values of > 3 microL/L correlated with known hemolytic conditions. We conclude that this instrument is clinically reliable and can be used to noninvasively measure ETCO in neonates and adults.


When parent and teacher ratings don't agree: the Tracking Adolescents' Individual Lives Survey (TRAILS).
A commonly encountered situation for evaluating clinicians is a history of significant problems in one setting with little or no difficulties in another. This study aims to describe this phenomenon and to examine its relations with other child and family characteristics. A total of 1,730 children (mean age 11.05 years) was studied from the first wave of the Tracking Adolescents' Individual Lives Survey (TRAILS), a large population-based study of Dutch youth. Parent and teacher ratings of aggression, rule breaking, inattention, and hyperactivity were obtained. Children were assigned to groups according to the presence of clinically relevant problems at home only, at school only, or in both settings. The rate of setting specific problems was calculated and comparisons between groups were made. Setting specific, especially home-specific, problems were quite common. Among children whom parents rated as having at least borderline-clinical problems, teachers reported clear or very clear behaviors at school at the following rates: aggression (22%), rule breaking (12.5%), inattention (55%), and hyperactivity/impulsivity (33%). Compared with the school-specific group, the home-specific group contained a significantly higher percentage of girls with regard to inattention or hyperactivity and a significantly lower percentage of girls with regards to rule breaking. Logistic regression analyses revealed that home- versus school-specific problems were related to sex, child effortful control, and parental stress. Externalizing problems are frequently encountered only in one setting between home and school and are related to sex, child effortful control, and parental stress.


Information technologies in health care delivery and policy: giant steps and missteps.
The influences of information technology have touched almost all aspects of our lives, and health care delivery has been no exception. Law, policy, and regulation have driven the adoption of electronic medical records, particularly over the past decade, driving fundamental changes to the practice of medicine in general and dermatology in particular. This article reviews the history of these changes, the regulations that drove these changes, the intended and unintended consequences of these initiatives, and our insights into the appropriate roles for policy and regulation to drive positive change.


Imatinib mesylate in the treatment of chronic myeloid leukemia: a local experience.
This study was done to assess the overall response rate of imatinib mesylate in local patients with chronic myeloid leukaemia. A total of 69 patients were recruited with male/female ratio of 7:3. Of the 69 patients; 35% were in the chronic phase, 41% were in the accelerated phase, 17% were in blast crisis and the remaining 7% were after stem cell transplantation. Complete haematological response rates of patients in chronic phase, accelerated phase and blast crisis were 95.8%, 96.4% and 41.7% respectively. Thirty-eight percent of patients achieved complete cytogenetic response and 10% achieved partial cytogenetic response. The cytogenetic response rates were 80%, 41.7% and 18.2% in chronic, accelerated and blast crisis phase respectively (p < 0.005). Twenty-six percent of patients developed anaemia, 13% had neutropenia and 12% had thrombocytopenia after starting on treatment. In addition, 14% of patients developed peripheral oedema, 13% complained of musculoskeletal pain, 12% had gastrointestinal side effects which include nausea, vomiting and diarrhoea, 9% had grade 1 hepatotoxicity, 7% developed skin rashes and one patient had an abnormal renal function test. Patients taking 600mg or higher dosage of imatinib had more gastrointestinal side effects. Patients who weighed less than 60kg had a much higher risk of developing anaemia. Anaemia was a negative predictor of cytogenetic response. Presenting high white blood cell counts and absence of cytogenetic response were also negative predictors of survival. Overall survival was 87%. This was affected by the different phases of disease (chronic phase was better than accelerated and blast crisis) (p < 0.001). In conclusion, our local CML patients did well on treatment with imatinib.


Enhancing contraceptive choice for postpartum women in sub-Saharan Africa with the progesterone vaginal ring: a review of the evidence.
It is increasingly recognized that women who have just given birth have a high unmet need and require contraceptive protection in the first year postpartum. A majority of women in developing countries do breastfeed exclusively but for short durations, hence they may be sometimes unknowingly exposed to the risk of pregnancy if they are relying on nursing for contraceptive protection. The WHO's Medical Eligibility Criteria for Contraceptive Use recommends the use of different contraceptives in the first year postpartum depending on whether the woman is nursing or not and the time since delivery. Some of the options available for breastfeeding women include implants, IUDs and injectables, which can be obtained only from a trained family planning provider. Since 2013, Population Council has been carrying out a study in Senegal, Nigeria, and Kenya to assess the acceptability of progesterone vaginal ring (PVR) as a new contraceptive option designed specifically for use by breastfeeding women to extend the period of lactational amenorrhea and promote birth spacing. Breastfeeding in sub-Saharan Africa is near universal with fairly long durations, a situation that increases the effectiveness of PVR. Each ring delivers a daily dose of 10 mg of progesterone and can be used continuously up to 3 months with a woman being able to continue with its use up to 1 year (four rings used consecutively). Preliminary results indicate that many women who had used the method found it acceptable and their partners supported its use. Activities aimed at having PVR registered and made available in focal countries are ongoing. Integration of family planning and immunization services for mothers and their newborns will be a key strategy in introducing PVR into targeted health care markets. Given that the use of PVR does not require extensive clinical training, it will be easier to integrate it at all levels of the health system from tertiary health facilities to community-based services. The PVR has been recently included in the WHO Model List of Essential Medicines and the WHO's fifth edition of the Medical Eligibility Criteria for Contraceptive Use which should facilitate its introduction into the public and private sectors.


Morphological aspects of interactions between microparticles and mammalian cells: intestinal uptake and onward movement.
Uptake of ingested microparticles into small intestinal tissues and on to secondary organs has moved from being an anecdotal phenomenon to a recognised and quantifiable process, which is relevant to risk assessment of accidental exposure, treatment of multi-organ dysfunction syndrome and therapeutic uses of encapsulated drug or vaccine delivery. This review puts in context with the literature the findings of a morphological study of microparticle uptake, using two approaches. The first is a rat in vivo in situ model, appropriate to a study rooted in the exposure of human populations to microparticles. Latex microspheres 2 μm in diameter are the principal particle type used, although others are also investigated. Most data are based on microscopy, but analysis of macerated bulk tissue is also useful. Uptake occurs at early time points after a single dose and is shown to take place almost entirely at villous rather than Peyer's patch sites: however, multiple feeding and therefore a longer time-span produces a higher proportion of particles associated with Peyer's patches, albeit for very small total uptake at those later time points. Uptake is less affected by species, fasting and immunological competence than by age and reproductive status. The second approach uses in vitro methods to confirm the role of intercellular junctions in particle uptake. Particle-associated tight junction opening, in a Caco-2 monolayer, is reflected in changes in transepithelial resistance and particle uptake across the epithelial monolayer: Tight junction opening and particle uptake are both increased further by external irradiation, ethanol and sub-epithelial macrophages, but reduced by exposure to ice. An M cell model has looser tight junctions than Caco-2 cells, but a similar level of particle uptake. These results, along with the changes seen in junctional proteins after particle addition, confirm the role of tight junctions in uptake but suggest that adhering junctions are also important.


IgG1-3 MuSK Antibodies Inhibit AChR Cluster Formation, Restored by SHP2 Inhibitor, Despite Normal MuSK, DOK7, or AChR Subunit Phosphorylation.
Up to 50% of patients with myasthenia gravis (MG) without acetylcholine receptor antibodies (AChR-Abs) have antibodies to muscle-specific kinase (MuSK). Most MuSK antibodies (MuSK-Abs) are IgG4 and inhibit agrin-induced MuSK phosphorylation, leading to impaired clustering of AChRs at the developing or mature neuromuscular junction. However, IgG1-3 MuSK-Abs also exist in MuSK-MG patients, and their potential mechanisms have not been explored fully. C2C12 myotubes were exposed to MuSK-MG plasma IgG1-3 or IgG4, with or without purified agrin. MuSK, Downstream of Kinase 7 (DOK7), and βAChR were immunoprecipitated and their phosphorylation levels identified by immunoblotting. Agrin and agrin-independent AChR clusters were measured by immunofluorescence and AChR numbers by binding of 125I-α-bungarotoxin. Transcriptomic analysis was performed on treated myotubes. IgG1-3 MuSK-Abs impaired AChR clustering without inhibiting agrin-induced MuSK phosphorylation. Moreover, the well-established pathway initiated by MuSK through DOK7, resulting in βAChR phosphorylation, was not impaired by MuSK-IgG1-3 and was agrin-independent. Nevertheless, the AChR clusters did not form, and both the number of AChR microclusters that precede full cluster formation and the myotube surface AChRs were reduced. Transcriptomic analysis did not throw light on the pathways involved. However, the SHP2 inhibitor, NSC-87877, increased the number of microclusters and led to fully formed AChR clusters. MuSK-IgG1-3 is pathogenic but seems to act through a noncanonical pathway. Further studies should throw light on the mechanisms involved at the neuromuscular junction.


Triple knockdown of CDC37, HSP90-alpha and HSP90-beta diminishes extracellular vesicles-driven malignancy events and macrophage M2 polarization in oral cancer.
Evidence has been accumulating to indicate that extracellular vesicles (EVs), including exosomes, released by cancer cells can foster tumour progression. The molecular chaperones - CDC37, HSP90α and HSP90β play key roles in cancer progression including epithelial-mesenchymal transition (EMT), although their contribution to EVs-mediated cell-cell communication in tumour microenvironment has not been thoroughly examined. Here we show that triple depletion of the chaperone trio attenuates numerous cancer malignancy events exerted through EV release. Metastatic oral cancer-derived EVs (MEV) were enriched with HSP90α HSP90β and cancer-initiating cell marker CD326/EpCAM. Depletion of these chaperones individually induced compensatory increases in the other chaperones, whereas triple siRNA targeting of these molecules markedly diminished the levels of the chaperone trio and attenuated EMT. MEV were potent agents in initiating EMT in normal epithelial cells, a process that was attenuated by the triple chaperone depletion. The migration, invasion, and in vitro tumour initiation of oral cancer cells were significantly promoted by MEV, while triple depletion of CDC37/HSP90α/β reversed these MEV-driven malignancy events. In metastatic oral cancer patient-derived tumours, HSP90β was significantly accumulated in infiltrating tumour-associated macrophages (TAM) as compared to lower grade oral cancer cases. HSP90-enriched MEV-induced TAM polarization to an M2 phenotype, a transition known to support cancer progression, whereas the triple chaperone depletion attenuated this effect. Mechanistically, the triple chaperone depletion in metastatic oral cancer cells effectively reduced MEV transmission into macrophages. Hence, siRNA-mediated knockdown of the chaperone trio (CDC37/HSP90α/HSP90β) could potentially be a novel therapeutic strategy to attenuate several EV-driven malignancy events in the tumour microenvironment. CDC37: cell division control 37; EMT: epithelial-mesenchymal transmission; EV: extracellular vesicles; HNSCC: head and neck squamous cell carcinoma; HSP90: heat shock protein 90; TAM: tumour-associated macrophage.


Correlation of human sperm centrosomal proteins with fertility.
The centrosome is the microtubule organizing center (MTOC) paternally inherited by the zygote during fertilization. As the centrosome is located in the midpiece of the sperm tail, we presume that oligoasthenozoospermic sperm samples should also have abnormal concentrations of centrosomal proteins. This study therefore aims to determine if there is any correlation between sperm centrosomal proteins, centrin, α and γ-tubulin, in sperm samples from normozoospermic and oligoasthenozoospermic men. Proteins were extracted from the normozoospermic and oligoasthenozoospermic sperm samples and analyzed by Western Blot and ELISA for centrin, α and γ-tubulin. The levels of centrin, α and γ-tubulin are markedly lower in oligoasthenozoospermic sperm samples as compared to the normozoospermic sperm samples. Lower centrosomal protein expression in sperm samples of oligoasthenozoospermic infertile males may be a possible cause for their reduced fertility status. Further studies on these proteins are warranted to design rational approaches for the diagnosis and treatment of male infertility.


Involvement of Raf-1/MEK/ERK1/2 signaling pathway in zinc-induced injury in rat renal cortical slices.
Zinc is an essential nutrient that can also be toxic. We have previously reported that zinc-related renal toxicity is due, in part, to free radical generation in the renal epithelial cell line, LLC-PK(1) cells. We have also shown that an MEK1/2 inhibitor, U0126, markedly inhibits zinc-induced renal cell injury. In this study, we investigated the role of an upstream MEK/ERK pathway, Raf-1 kinase pathway, and the transcription factor and ERK substrate Elk-1, in rat renal cortical slices exposed to zinc. Immediately after preparing slices from rat renal cortex, the slices were incubated in medium containing Raf-1 and MEK inhibitors. ERK1/2 and Elk-1 activation were determined by Western blot analysis for phosphorylated ERK (pERK) 1/2 and phosphorylated Elk-1 (pElk-1) in nuclear fractions prepared from slices exposed to zinc. Zinc caused not only increases in 4-hydroxynonenal (4-HNE) modified protein and lipid peroxidation, as an index of oxidant stress, and decreases in PAH accumulation, as that of renal cell injury in the slices. Zinc also induced a rapid increase in ERK/Elk-1 activity accompanied by increased expressions of pERK and pElk-1 in the nuclear fraction. A Raf-1 kinase inhibitor and an MEK1/2 inhibitor U0126 significantly attenuated zinc-induced decreases PAH accumulation in the slices. The Raf-1 kinase inhibitor and U0126 also suppressed ERK1/2 activation in nuclear fractions prepared from slices treated with zinc. The present results suggest that a Raf-1/MEK/ERK1/2 pathway and the ERK substrate Elk-1 are involved in free radical-induced injury in rat renal cortical slices exposed to zinc.


Transient absorption in excimer-exposed silica.
The transient absorption produced in high-purity fused silica by exposure to a 193-nm excimer laser is investigated as a function of exposure, dissolved molecular hydrogen content, and hydrogen-related processing. Long-term recovery of transmittance was found to correlate with the dissolved molecular hydrogen concentration, whereas short-term fade was due to geminate recombination of an E? center with an H radical. The redarkening process was shown to be the result of photolysis of SiH, which regenerates color centers. When the silica was processed in a hydrogen atmosphere at high temperature and subsequently exposed at 193 nm, the glass was found to produce an absorption spike, a fast, recoverable decrease in transmittance. The origin of the spike was linked to the creation of a precursor produced in the thermal reaction of silica with hydrogen. The precursor can be identified by its signal in the Raman spectrum. It is suggested that the precursor has absorption at 193 nm.


Wearable Contact Lens Biosensors for Continuous Glucose Monitoring Using Smartphones.
Low-cost, robust, and reusable continuous glucose monitoring systems that can provide quantitative measurements at point-of-care settings is an unmet medical need. Optical glucose sensors require complex and time-consuming fabrication processes, and their readouts are not practical for quantitative analyses. Here, a wearable contact lens optical sensor was created for the continuous quantification of glucose at physiological conditions, simplifying the fabrication process and facilitating smartphone readouts. A photonic microstructure having a periodicity of 1.6 μm was printed on a glucose-selective hydrogel film functionalized with phenylboronic acid. Upon binding with glucose, the microstructure volume swelled, which modulated the periodicity constant. The resulting change in the Bragg diffraction modulated the space between zero- and first-order spots. A correlation was established between the periodicity constant and glucose concentration within 0-50 mM. The sensitivity of the sensor was 12 nm mM-1, and the saturation response time was less than 30 min. The sensor was integrated with commercial contact lenses and utilized for continuous glucose monitoring using smartphone camera readouts. The reflected power of the first-order diffraction was measured via a smartphone application and correlated to the glucose concentrations. A short response time of 3 s and a saturation time of 4 min was achieved in the continuous monitoring mode. Glucose-sensitive photonic microstructures may have applications in point-of-care continuous monitoring devices and diagnostics at home settings.


Evaluating surgical competency with the American Board of Surgery In-Training Examination, skill testing, and intraoperative assessment.
Evaluation of surgical competency should include assessment of knowledge, technical skill, and judgment. The purpose of this study was to determine the relationship between the American Board of Surgery In-Training Examination (ABSITE), skill testing, and intraoperative assessment. Postgraduate year 2 (PGY-2) and postgraduate year 3 (PGY-3) surgery residents (n = 33) were tested by means of (1) the ABSITE, (2) skill testing on a laparoscopic video-trainer, and (3) intra-operative global assessments during laparoscopic cholecystectomy. The Pearson correlation was used to determine the correlation between the ABSITE, skill testing, and intraoperative assessments. For the comparison of PGY-2 and PGY-3 resident performance, Wilcoxon rank sum tests were used. The ABSITE scores did not correlate with skill testing or intraoperative assessments (not significant). Skill testing correlated with the intraoperative composite score and with 4 of 8 operative performance criteria (P<.05). The ABSITE scores and skill testing were not different for PGY-2 and PGY-3 residents (not significant). Intraoperative assessments were better in 5 of 8 criteria and the composite score for PGY-3 versus PGY-2 residents (P<.05), which demonstrated construct validity. The ABSITE measures knowledge but does not correlate with technical skill or operative performance. Residency programs should use multiple assessment instruments to evaluate competency. There may be a role for both skill testing and intraoperative assessment in the evaluation of surgical competency.


Efficacy and safety of a novel beclomethasone dipropionate dry powder inhaler (Clickhaler) for the treatment of adult asthma. Amsterdam Clinical Study Group.
A randomized, double-blind, double-dummy protocol was used to compare the safety and efficacy of beclomethasone dipropionate (BDP) delivered by a novel dry powder inhaler (DPI, Clickhaler) or by a pressurized metered-dose inhaler (MDI) plus spacer. There was a four-week run-in period, completed by 240 adult patients, who received BDP via an MDI. Patients with stable asthma were then randomized into a 12-week treatment period and received BDP (< or =2 mg/day via DPI or MDI). There were no significant differences in morning peak expiratory flow (PEF) (primary endpoint), evening PEF, overall daytime or nighttime symptom scores, or lung function parameters (forced expiratory volume in 1 sec, forced vital capacity) between DPI and MDI. The safety profiles were similar and patient acceptability for Clickhaler was high. In conclusion, BDP administered via Clickhaler was found to be clinically equivalent to an optimally used MDI. Patients with stable asthma currently receiving BDP via MDI may be effectively switched to treatment via Clickhaler DPI.


Detecting novel bone density and bone size quantitative trait loci using a cross of MRL/MpJ and CAST/EiJ inbred mice.
Most previous studies to identify loci involved in bone mineral density (BMD) regulation have used inbred strains with high and low BMD in generating F(2) mice. However, differences in BMD may not be a requirement in selecting parental strains for BMD quantitative trait loci (QTL) studies. In this study, we intended to identify novel QTL using a cross of two strains, MRL/MpJ (MRL) and CAST/EiJ (CAST), both of which exhibit relatively high BMD when compared to previously used strains. In addition, CAST was genetically distinct. We generated 328 MRL x CAST F(2) mice of both sexes and measured femur BMD and periosteal circumference (PC) using peripheral quantitative computed tomography. Whole-genome genotyping was performed with 86 microsatellite markers. A new BMD QTL on chromosome 10 and another suggestive one on chromosome 15 were identified. A significant femur PC QTL identified on chromosome 9 and a suggestive one on chromosome 2 were similar to those detected in MRL x SJL. QTL were also identified for other femur and forearm bone density and bone size phenotypes, some of which were colocalized within the same chromosomal positions as those for femur BMD and femur PC. This study demonstrates the utility of crosses involving inbred strains of mice which exhibit a similar phenotype in QTL identification.


Negative regulation by glucocorticoids through interference with a cAMP responsive enhancer.
Although steroid hormone receptors are known to activate gene expression by binding to specific hormone-dependent enhancers, the mechanisms by which steroids inhibit the transcription of specific genes are unknown. It is shown here by gene transfer studies that the same glucocorticoid receptor that activates gene expression can negatively regulate expression of the human glycoprotein hormone alpha-subunit gene. Glucocorticoid inhibition was conferred by a 52-nucleotide region that also contains elements crucial both for adenosine 3',5'-monophosphate (cAMP) responsiveness and for placental-specific expression of this gene and was observed only under conditions in which these elements were functioning as enhancers. Purified glucocorticoid receptor was found to bind to DNA that overlap the cAMP responsive elements sites in this region. It is hypothesized that steroid receptors negatively regulate gene expression by interfering with the activity or binding of other important transcription factors.


Chain dynamics and nanoparticle motion in attractive polymer nanocomposites subjected to large deformations.
The effect of large deformation on the chain dynamics in attractive polymer nanocomposites was investigated using neutron scattering techniques. Quasi-elastic neutron backscattering measurements reveal a substantial reduction of polymer mobility in the presence of attractive, well-dispersed nanoparticles. In addition, large deformations are observed to cause a further slowing down of the Rouse rates at high particle loadings, where the interparticle spacings are slightly smaller than the chain dimensions, i.e. in the strongly confined state. No noticeable change, however, was observed for a lightly confined system. The reptation tube diameter, measured by neutron spin echo, remained unchanged after shear, suggesting that the level of chain-chain entanglements is not significantly affected. The shear-induced changes in the interparticle bridging reflect the slow nanoparticle motion measured by X-ray photon correlation spectroscopy. These results provide a first step for understanding how large shear can significantly affect the segmental motion in nanocomposites and open up new opportunities for designing mechanically responsive soft materials.


Long-term exposure to road traffic noise and all-cause and cause-specific mortality: a Danish Nurse Cohort study.
Long-term road traffic noise exposure is linked to cardio-metabolic disease morbidity, whereas evidence on mortality remains limited. We investigated association of long-term exposure to road traffic noise with all-cause and cause-specific mortality. We linked 22,858 females from the Danish Nurse Cohort (DNC), recruited into the Danish Register of Causes of Death up to 2014. Road traffic noise levels since 1970 were modelled by Nord2000 as the annual mean of a weighted 24 h average (Lden). Cox regression models examined the associations between Lden (5-year and 23-year means) and all-cause and cause-specific mortalities, adjusting for lifestyle and exposure to PM2.5 (particulate matter with diameter < 2.5 μm) and NO2 (nitrogen dioxide). During follow-up (mean 17.4 years), 3902 nurses died: 1622 from cancer, 922 from CVDs (289 from stroke), 338 from respiratory diseases (186 from chronic obstructive pulmonary disease, 114 from lower respiratory tract infections [ALRIs]), 234 from dementia, 95 from psychiatric disorders, and 79 from diabetes. Hazard ratios (95% confidence intervals) for all-cause mortality from fully-adjusted models were 1.06 (1.01, 1.11) and 1.09 (1.03, 1.15) per 10 dB of 5-year and 23-year mean Lden, respectively, which attenuated slightly in our main model (fully-adjusted plus PM2.5: 1.04 [1.00, 1.10]; 1.08 [1.02, 1.13]). Main model estimates suggested the strongest associations between 5-year mean Lden and diabetes (1.14: 0.81, 1.61), ALRIs (1.13: 0.84, 1.54), dementia (1.12: 0.90, 1.38), and stroke (1.10: 0.91, 1.31), whereas associations with 23-year mean Lden were suggested for respiratory diseases (1.15: 0.95, 1.39), psychiatric disorders (1.11: 0.78, 1.59), and all cancers (1.08: 0.99, 1.17). Among the female nurses from the DNC, we observed that long-term exposure to road traffic noise led to premature mortality, independently of air pollution, and its adverse effects may extend well beyond those on the cardio-metabolic system to include respiratory diseases, cancer, neurodegenerative and psychiatric disorders.


Management of posaconazole-induced pseudohyperaldosteronism.
Posaconazole-induced pseudohyperaldosteronism (PIPH) has been associated with elevated posaconazole serum concentrations. Clinicians are faced with the difficult task of managing patients with PIPH while maintaining the efficacy of antifungal therapy. Commonly, modifications to posaconazole therapy are utilized in managing PIPH, including dosage reduction of posaconazole or switch to an alternative antifungal. To characterize the management of patients diagnosed with PIPH and their response to various therapeutic interventions. We retrospectively reviewed 20 consecutive adult patients diagnosed with PIPH. Patient data collected included blood pressure, electrolytes, endocrine laboratory values and posaconazole serum concentrations collected before and after therapeutic intervention. Of 20 patients included, 17 patients (85%) underwent therapeutic modification, with posaconazole dose reduction (n = 11) as the most common change. Other modifications included discontinuation (n = 3), switch to an alternative antifungal (n = 2) and addition of spironolactone (n = 1). Clinical improvement (decrease in systolic blood pressure and increase in serum potassium) was observed in 9 of 17 patients (52.9%). An average decrease in systolic blood pressure of 7.1 mmHg and increase in serum potassium of 0.22 mmol/L was observed following therapeutic modification. We report our experience with PIPH management, for which there is no universally effective strategy. We utilized a stepwise approach for management, starting with posaconazole dose reduction and repeat assessment of clinical and laboratory parameters. If resolution of PIPH is not achieved, an alternative triazole antifungal or the addition of an aldosterone antagonist are additional potential interventions. It is possible for PIPH to persist after therapeutic modification despite these interventions. Thus, early diagnosis and continuous monitoring is warranted.


Meta-analysis, Simpson's paradox, and the number needed to treat.
There is debate concerning methods for calculating numbers needed to treat (NNT) from results of systematic reviews. We investigate the susceptibility to bias for alternative methods for calculating NNTs through illustrative examples and mathematical theory. Two competing methods have been recommended: one method involves calculating the NNT from meta-analytical estimates, the other by treating the data as if it all arose from a single trial. The 'treat-as-one-trial' method was found to be susceptible to bias when there were imbalances between groups within one or more trials in the meta-analysis (Simpson's paradox). Calculation of NNTs from meta-analytical estimates is not prone to the same bias. The method of calculating the NNT from a meta-analysis depends on the treatment effect used. When relative measures of treatment effect are used the estimates of NNTs can be tailored to the level of baseline risk. The treat-as-one-trial method of calculating numbers needed to treat should not be used as it is prone to bias. Analysts should always report the method they use to compute estimates to enable readers to judge whether it is appropriate.


Leptospirosis in domestic animals in France: serological results from 1988 to 2007.
Leptospirosis is a common infection in domestic animals. The microscopic agglutination test (MAT) is used for serological diagnosis. From 1988 to 2007, the Leptospira Medical and Molecular Bacteriology Laboratory at the Nantes National College of Veterinary Medicine, Food Science and Engineering used the MAT to test serum samples from more than 40,000 cattle, 40,000 pigs, 20,000 horses and 9,500 dogs. Five Leptospira serogroups were prominent, with specific variations within the four animal species: Icterohaemorrhagiae, Australis, Sejroë, Grippotyphosa and Autumnalis. The prevalence and incidence of each serogroup varied for each species over the 20-year period: some serogroups were emergent during some years but disappeared later. This study reports the complex epidemiological features of leptospirosis.


Influence of input rates on (+/-)-isradipine haemodynamics and concentration-effect relationship in healthy volunteers.
Since the magnitude of the response to a drug may depend upon the drug input rate, the concentration-effect relationship of the new dihydropyridine (+/-)-isradipine was investigated using different administration modalities. Ten normotensive healthy volunteers were given, double-blind and in a crossover fashion, isradipine as a 1 mg iv infusion, 5 mg oral solution, 5 mg standard tablet, 10 mg slow release formulation, and a placebo. Blood pressure, heart rate, and plasma isradipine concentrations were recorded for 24 h. The maximal fall in diastolic blood pressure was similar after the infusion (-11.40 mmHg), the oral solution (-15.20 mmHg), and the standard tablet (-12.50 mmHg). In healthy volunteers the slow release form had no significant effect on blood pressure. The concentration-effect plots showed an increasing slope in the order infusion, solution, and table, and anticlockwise hysteresis. This was partly due to marked heart rate counter-regulation, the corresponding mean maximal heart rate increases being 24, 19, and 17 beats.min-1. The pronounced counter-regulation of the heart rate implies that a slow isradipine input rate would be more effective in decreasing blood pressure.


Exercise, cachexia, and cancer therapy: a molecular rationale.
Evidence from recent publications indicates that repeated exercise may enhance the quality of life of cancer patients. The lack of reported negative effects and the consistency of the observed benefits lead one to conclude that physical exercise may provide a low-risk therapy that can improve patients' capacity to perform activities of daily living and improve their quality of life. Repeated physical activity may attenuate the adverse effects of cancer therapy, prevent or reverse cachexia, and reduce risk for a second cancer through suppression of inflammatory responses or enhancement of insulin sensitivity, rates of protein synthesis, and anti-oxidant and phase II enzyme activities. These results most likely come about through the ability of physical exercise to attenuate a chronic inflammatory signaling process and to transiently activate the mitogen-activated protein kinase, c-Jun NH2-terminal kinase, c-Jun NH2-terminal kinase-mitogen-activated protein kinase, and nuclear factor-kappa B pathways and through its ability to enhance insulin sensitivity. Expanded molecular-based research into these areas may provide new insights into the biological mechanisms associated with cancer rehabilitation and endogenous risk.


Organic field-effect transistor sensors: a tutorial review.
The functioning principles of electronic sensors based on organic semiconductor field-effect transistors (OFETs) are presented. The focus is on biological sensors but also chemical ones are reviewed to address general features. The field-induced electronic transport and the chemical and biological interactions for the sensing, each occurring at the relevant functional interface, are separately introduced. Once these key learning points have been acquired, the combined picture for the FET electronic sensing is proposed. The perspective use of such devices in point-of-care is introduced, after some basics on analytical biosensing systems are provided as well. This tutorial review includes also a necessary overview of the OFET sensing structures, but the focus will be on electronic rather than electrochemical detection. The differences among the structures are highlighted along with the implications on the performance level in terms of key analytical figures of merit such as: repeatability, sensitivity and selectivity.


Pre-hospital interventions: introduction to life support systems.
Pre-hospital interventions: introduction to life support systems. Crucial decisions in pre-hospital emergency care are often made; therefore, a tactical emergency medical support team (TEMS) should maintain the capacity to capture the situation instantaneously and in all circumstances. However, low exposure to severe trauma cases can be a weakness for emergency specialists, which makes pre-hospital assessment more difficult. Pre-hospital interventions (PHI) are usually classified in Western countries into BLS (basic life support) and ALS (ad- vanced life support) levels, according to the methods used. This review introduces tactical combat casualty care for medical personnel (TCCC) guidelines, designed for basic care management under fire or in a hostile environment. The phases of TCCC are: (1) care under fire (or in an unstable environment); (2) tactical field care; and (3) tactical evacuation care, and are mainly dependent on the different hazard zones (hot, warm or cold). In a mass casualty situation due to disaster or cataclysm, standardized protocol and triage are unquestionably required for identifying the environmental risks, for categorizing the casualties in accordance with medical care priorities, and for the initial management of casualty care. When considering conflict situations, or chemical, biological, radiological, or nuclear (CBRN) events, processes always start at the local level. Even before the detection and analysis of agents can be undertaken, zoning, triage, decontamination, and treatment should be initiated promptly. Otorhinolaryngologists should be aware of PHI procedures for completing preliminary assessment and management together with emergency specialists or TEMS.


Spirometric pulmonary function in 3- to 5-year-old children.
Forced expiratory maneuvers are routinely used in children, 6 years of age and older for the diagnosis and follow-up of respiratory diseases. Our objective was to establish normative data for an extensive number of parameters measured during forced spirometry in healthy 3- to 5-year-old children. Children aged between 3 and 5 years were tested in 11 daycare centers. Usual parameters, including FEV1, FVC, PEF, FEF(25-75), FEF25, FEF50, FEF75, and Aex were measured and analyzed in relation to sex, age, height, and weight. In addition, the same analysis was performed for FEV0.5 and FEV0.75. One hundred sixty-four children were recruited for testing including 87 girls and 77 boys. Thirty-five were 3 years old, 63 were 4 years old, and 66 were 5 years old. Overall, 143 children (87%) accepted to perform the test and 128 children (78%) were able to perform at least two technically acceptable expiratory maneuvers. Analyses using different regression models showed that height was the best predictor for every parameter. In conclusion, the present study confirms that most healthy 3-5 years old children can perform valid forced expiratory maneuvers. In agreement with other studies, we found that height is the most important single predictor of various parameters measured on forced spirometry. The present study is the first to establish normative values for FEV0.75, as well as to demonstrate that Aex can be easily performed in the majority of children aged 3-5 years. These are likely important parameters of lung function in this age range.


Increased nitric oxide in expired air in patients with Sjögren's syndrome. BHR study group. Bronchial hyperresponsiveness.
Nitric oxide has an important role in the regulation of airway function and can have pro-inflammatory effects. Bronchial hyperresponsiveness (BHR) and respiratory symptoms are common in patients with Sjögren's syndrome (SS). The aim of this study was to determine whether patients with SS have an increased amount of exhaled NO and whether this NO correlates with respiratory symptoms and BHR. Exhaled NO was measured in 18 patients with SS and 13 normal subjects on three different occasions with intervals of at least 3 days using a chemiluminescence method. Airway responsiveness was assessed with methacholine provocation. Serum levels of myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO) were measured. Exhaled NO was significantly higher in patients with SS than in controls (147+/-82 versus 88+/-52 nL x min(-1); mean+/-SD; p=0.041). Exhaled NO was correlated with age (partial r=0.52, p=0.006) and serum HNL (partial r=0.46, p=0.014). There were no significant correlations between exhaled NO and respiratory symptoms, BHR or serum MPO, ECP or EPO. Disease duration was negatively associated with serum MPO (r=-0.47, p=0.043). In patients with SS, a positive correlation was found between symptom score and serum ECP (partial r=0.65, p=0.003) and EPO (partial r=0.62, p=0.004) and a negative correlation with age (partial r=-0.60, p=0.005). In conclusion, elevated levels of exhaled nitric oxide in patients with Sjögren's syndrome were demonstrated. The mechanism underlying this increase in exhaled nitric oxide in Sjögren's syndrome is not known.


Assessing HPV vaccination perceptions with online social media in Italy.
Because of the widespread availability of the internet and social media, people often collect and disseminate news online making it important to understand the underlying mechanisms to steer promotional strategies in healthcare. The aim of this study is to analyze perceptions regarding the human papillomavirus (HPV) vaccine in Italy. From August 2015 to July 2016, articles, news, posts, and tweets were collected from social networks, posts on forums, blogs, and pictures about HPV. Using other keywords and specific semantic rules, we selected conversations presenting the negative or positive perceptions of HPV. We divided them into subgroups depending on the website, publication date, authors, main theme, and transmission modality. Most conversations occurred on social networks. Of all the conversations regarding HPV, more than 50% were about vaccination. With regard to conversations exclusively on the HPV vaccine, 47%, 32%, and 21% were positive, negative and neutral, respectively. Only 9% of the conversations mentioned the vaccine trade name and, in these conversations, perception was almost always negative. We observed many peaks in positive conversation trends compared with negative trends. The peaks were related to the web dissemination of particular news regarding HPV vaccination. In this study we have shown how mass media influences the diffusion of both negative and positive perceptions about HPV vaccines and suggest better ways to inform people about the importance of HPV vaccination.


Signaling the junctions in gut epithelium.
This Perspective summarizes recent developments in our understanding of the signaling pathways involved in the regulation of epithelial cell adhesion in the gut. The role of phosphatidylinositol 3-kinase signaling in the modulation of adherens junctions, and the connections between tight junctions and nuclear transcription factors, are discussed. The effect of gastrins on adherens and tight junctions is presented as an example of the regulation of adhesion by growth factors. The consequences of dysregulation of adherens junctions and tight junctions for human pathology are also considered.


Does the locus on chromosome 11 implicated in susceptibility to HLA-DR4 dependent type I diabetes mellitus also affect susceptibility to rheumatoid arthritis?
There is a polygenic component to rheumatoid arthritis (RA) in addition to the known association with HLA-DR4. It has previously been shown in another autoimmune disease (type I diabetes mellitus) that a gene on chromosome 11p can act with HLA-DR4 to enhance susceptibility (relative risk 5-6). It is therefore possible that this locus may also affect the development of RA. Genotype frequencies at this locus, defined by a dimorphic Fok 1 restriction site, were compared in 139 healthy controls and 213 patients with classical/definite RA. In contrast with diabetes there was no increase in genotypes lacking the Fok 1 site, either in the rheumatoid group overall (125/211 compared with 86/139 controls) or in the DR4 positive rheumatoid group (76/140 compared with controls). These results indicate that the interaction between DR4 and a locus on chromosome 11p is not common to all DR4 associated autoimmune diseases.


Decreased immune responses to influenza vaccination in patients with heart failure.
Heart failure (HF) patients are at risk for influenza despite widespread vaccination. Both humoral (antibody) and cytotoxic T-lymphocyte (CTL) responses are important for protection. We explored antibody- and CTL-mediated responses to the influenza vaccine in HF patients compared with healthy controls. We studied 29 HF patients (9 ischemic, 20 nonischemic) stable on HF therapies and 17 healthy controls. Participants had phlebotomy before and after influenza vaccination. Antibody production was measured in serum by hemagglutination inhibition assay and CTL responses (via interferon [IFN]-gamma and interleukin [IL]-10 production) were measured in isolated peripheral blood mononuclear cells with enzyme-linked immunosorbent assay. CTL responses demonstrated increased IL-10 production in HF patients after vaccination (P = .002), but similar IFN-gamma responses to healthy controls. All participants demonstrated antibody seroprotection; groups had similar rates of seroconversion (P = NS). Antibody-mediated response to the newest vaccine antigen, H3N2, was reduced in HF (P = .009). Patients with HF had higher vaccine induced IL-10 concentrations, suggesting a different CTL phenotype for vaccine responses. HF patients did not mount as vigorous of an antibody immune response to the newest vaccine viral strain compared with healthy individuals. These data suggest that immunologic memory may be important for vaccine protection in HF patients.


Population biology of Rhodnius domesticus Neiva & Pinto, 1923 (Hemiptera: Reduviidae) under laboratory conditions.
The entire life cycle of Rhodnius domesticus, fed weekly on mice, was studied under controlled conditions. Aspects related to hatching, life time, mortality, feeding behaviour and fecundity for each stage of the insect life-cycle were evaluated. The hatching rate observed in 100 eggs was 57% and the mean time of hatching was 15.6 days. Forty-six nymphs (80.7%) completed the cycle and the mean time from NI to adult was 93.8 days. The average span in days for each stage was 12.4 for NI, 9.8 for NII, 14.2 for NIII, 16.8 for NIV and 25.0 NV. the number of bloodmeals in each nymphal stage varied from 1 to 3. The mortality rate was 12.3% for NI, 3.5% for NII and 1.7% for NIII and NV nymphs. The mean number of eggs laid per female in a 9-month period was 333.1. Average adult survival rates were 287.6 + 133 and 328 + 73 days for males and females respectively.


Value of tumor stiffness measured with MR elastography for assessment of response of hepatocellular carcinoma to locoregional therapy.
The aim of the study was to correlate tumor stiffness (TS) measured with MR elastography (MRE) with degree of tumor enhancement and necrosis on contrast-enhanced T1-weighted imaging (CE-T1WI) in hepatocellular carcinomas (HCC) treated with Yttrium-90 radioembolization (RE) or transarterial chemoembolization plus radiofrequency ablation (TACE/RFA). This retrospective study was IRB-approved and the requirement for informed consent was waived. 52 patients (M/F 38/14, mean age 67 years) with HCC who underwent RE (n = 22) or TACE/RFA (n = 30) and 11 controls (M/F 6/5, mean age 64 years) with newly diagnosed untreated HCC were included. The MRI protocol included a 2D MRE sequence. TS and LS (liver stiffness) were measured on stiffness maps. Degree of tumor necrosis was assessed on subtraction images by two observers, and tumor enhancement ratios (ER) were calculated on CE-T1WI by one observer. 63 HCCs (mean size 3.2 ± 1.6 cm) were evaluated. TS was significantly lower in treated vs. untreated tumors (3.9 ± 1.8 vs. 6.9 ± 3.4 kPa, p = 0.006) and also compared to LS (5.3 ± 2.2 kPa, p = 0.002). There were significant correlations between TS and each of enhancement ratios (r = 0.514, p = 0.0001), and percentage of necrosis (r = -0.540, p = 0.0001). The observed correlations were stronger in patients treated with RE (TS vs. ER, r = 0.636, TS vs. necrosis, r = -0.711, both p = 0.0001). Percentage of necrosis and T1-signal in native T1WI were significant independent predictors of TS (p = 0.0001 and 0.001, respectively). TS measured with MRE shows a significant correlation with tumor enhancement and necrosis, especially in HCCs treated with RE.


Glucose requirement for postischemic recovery of perfused working heart.
The quantitative importance of glycolysis in cardiomyocyte reenergization and contractile recovery was examined in postischemic, preload-controlled, isolated working guinea pig hearts. A 25-min global but low-flow ischemia with concurrent norepinephrine infusion to exhaust cellular glycogen stores was followed by a 15-min reperfusion. With 5 mM pyruvate as sole reperfusion substrate, severe contractile failure developed despite normal sarcolemmal pyruvate transport rate and high intracellular pyruvate concentrations near 2 mM. Reperfusion dysfunction was characterized by a low cytosolic phosphorylation potential [( ATP]/[( ADP][Pi]) due to accumulations of inorganic phosphate (Pi) and lactate. In contrast, with 5 mM glucose plus pyruvate as substrates, but not with glucose as sole substrate, reperfusion phosphorylation potential and function recovered to near normal. During the critical ischemia-reperfusion transition at 30 s reperfusion the cytosolic creatine kinase appeared displaced from equilibrium, regardless of the substrate supply. When under these conditions glucose and pyruvate were coinfused, glycolytic flux was near maximum, the glyceraldehyde-3-phosphate dehydrogenase/3-phosphoglycerate kinase reaction was enhanced, accumulation of Pi was attenuated, ATP content was slightly increased, and adenosine release was low. Thus, glucose prevented deterioration of the phosphorylation potential to levels incompatible with reperfusion recovery. Immediate energetic support due to maximum glycolytic ATP production and enhancement of the glyceraldehyde-3-phosphate dehydrogenase/3-phosphoglycerate kinase reaction appeared to act in concert to prevent detrimental collapse of [ATP]/[( ADP][Pi]) during creatine kinase dysfunction in the ischemia-reperfusion transition. Dichloroacetate (2 mM) plus glucose stimulated glycolysis but failed fully to reenergize the reperfused heart; conversely, 10 mM 2-deoxyglucose plus pyruvate inhibited glycolysis and produced virtually instantaneous de-energization during reperfusion. The following conclusions were reached. (1) A functional glycolysis is required to prevent energetic and contractile collapse of the low-flow ischemic or reperfused heart (2). Glucose stabilization of energetics in pyruvate-perfused hearts is due in part to intensification of glyceraldehyde-3-phosphate dehydrogenase/3-phosphoglycerate kinase activity. (3) 2-Deoxyglucose depletes the glyceraldehyde-3-phosphate pool and effects intracellular phosphate fixation in the form of 2-deoxyglucose 6-phosphate, but the cytosolic phosphorylation potential is not increased and reperfusion failure occurs instantly. (4) Consistent correlations exist between cytosolic ATP phosphorylation potential and reperfusion contractile function. The findings depict glycolysis as a highly adaptive emergency mechanism which can prevent deleterious myocyte deenergization during forced ischemia-reperfusion transitions in presence of excess oxidative substrate.


Measuring physiological stress in the common marmoset (Callithrix jacchus): Validation of a salivary cortisol collection and assay technique.
Cortisol levels are often used as a physiological measure of the stress response in captive primates, with non-invasive measures of this being an important step in welfare assessment. We report a method of collecting saliva samples voluntarily from unrestrained captive common marmosets (Callithrix jacchus), and validate an enzyme-linked immunosorbent assay (ELISA) technique previously unused in this species. Saliva samples were collected from marmosets housed in pairs in a UK laboratory. The assay showed parallelism, precision, accuracy and sensitivity, meeting the criteria typically used to investigate the effectiveness of new analytical techniques. Use of Salimetrics® Oral Swabs considerably increased the amount of cortisol recovered in comparison with previous studies using cotton buds. However, while use of banana on the swabs can encourage chewing, it may influence results. Although increases in cortisol levels have traditionally been interpreted as an indicator of stress in primates, there are many factors that affect the hypothalamic-pituitary-adrenal axis, with some studies showing decreases in cortisol levels post-stressor. Following a likely stressful event (capture for weighing), we also found cortisol levels significantly decreased, possibly due to social buffering or 'blunting' of the HPA axis. Order of weighing also had an effect. The method therefore provided an effective non-invasive means of assessing acute changes in cortisol level that may be more useful than previous methods, improving our ability to study physiological aspects of welfare in primates. We discuss methodological considerations, as well as implications of using cortisol as a measure of stress.


The Eukaryotic Proteome Is Shaped by E3 Ubiquitin Ligases Targeting C-Terminal Degrons.
Degrons are minimal elements that mediate the interaction of proteins with degradation machineries to promote proteolysis. Despite their central role in proteostasis, the number of known degrons remains small, and a facile technology to characterize them is lacking. Using a strategy combining global protein stability (GPS) profiling with a synthetic human peptidome, we identify thousands of peptides containing degron activity. Employing CRISPR screening, we establish that the stability of many proteins is regulated through degrons located at their C terminus. We characterize eight Cullin-RING E3 ubiquitin ligase (CRL) complex adaptors that regulate C-terminal degrons, including six CRL2 and two CRL4 complexes, and computationally implicate multiple non-CRLs in end recognition. Proteome analysis revealed that the C termini of eukaryotic proteins are depleted for C-terminal degrons, suggesting an E3-ligase-dependent modulation of proteome composition. Thus, we propose that a series of "C-end rules" operate to govern protein stability and shape the eukaryotic proteome.


Modeling rotavirus-like particles production in a baculovirus expression vector system: Infection kinetics, baculovirus DNA replication, mRNA synthesis and protein production.
Rotavirus is the most common cause of severe diarrhoea in children worldwide, responsible for more than half a million deaths in children per year. Rotavirus-like particles (Rota VLPs) are excellent vaccine candidates against rotavirus infection, since they are non-infectious, highly immunogenic, amenable to large-scale production and safer to produce than those based on attenuated viruses. This work focuses on the analysis and modeling of the major events taking place inside Spodoptera frugiperda (Sf-9) cells infected by recombinant baculovirus that may be critical for the expression of rotavirus viral proteins (VPs). For model validation, experiments were performed adopting either a co-infection strategy, using three monocistronic recombinant baculovirus each one coding for viral proteins VP(2), VP(6) and VP(7), or single-infection strategies using a multigene baculovirus coding for the three proteins of interest. A characteristic viral DNA (vDNA) replication rate of 0.19+/-0.01 h(-1) was obtained irrespective of the monocistronic or multigene vector employed, and synthesis of progeny virus was found to be negligible in comparison to intracellular vDNA concentrations. The timeframe for vDNA, mRNA and VP synthesis tends to decrease with increasing multiplicity of infection (MOI) due to the metabolic burden effect. The protein synthesis rates could be ranked according to the gene size in the multigene experiments but not in the co-infection experiments. The model exhibits acceptable prediction power of the dynamics of intracellular vDNA replication, mRNA synthesis and VP production for the three proteins involved. This model is intended to be the basis for future Rota VLPs process optimisation and also a means to evaluating different baculovirus constructs for Rota VLPs production.


Comparison of emotional processing assessed with fear conditioning by interpersonal conflicts in patients with depression and schizophrenia.
While emotional processing is implicated in various psychiatric illnesses, its differences among diagnoses are unclear. We compared associative learning of social values in patients with depression and schizophrenia by measuring skin conductance response to interpersonal stimuli. We included 20 female outpatients each with depression and schizophrenia. They underwent Pavlovian conditioning experiments in response to a classical aversive sound, and an interpersonal stimulus that was designed to cause aversive social conditioning with actors' faces coupled with negative verbal messages. Multiple regression analysis was performed to examine the associations between the degree of conditioned response and the clinical characteristics of the participants. Conditioned responses during the acquisition phase in both conditions were higher in depression compared to schizophrenia. Patients with depression successfully showed fear conditioning in both conditions, and they exhibited slower extinction in the interpersonal condition. The conditioned response during the extinction phase showed a positive association with Emotion Regulation Questionnaire Expressive Suppression score, and a negative association with the Emotion Regulation Questionnaire Cognitive Reappraisal score and the use of antidepressants. Patients with schizophrenia did not become conditioned in either of the conditions. The Positive and Negative Syndrome Scale Negative Syndrome score was negatively associated with the degree of conditioned response during the acquisition phase in the interpersonal condition. Female patients with schizophrenia, especially those who prominently demonstrated negative symptoms, suggested their intrinsic impairments in the associative learning of social context. Antidepressants and adaptive emotional regulation strategy may enhance the extinction learning of aversive social conditioning in depression.


The paradox of moral focus.
When we evaluate moral agents, we consider many factors, including whether the agent acted freely, or under duress or coercion. In turn, moral evaluations have been shown to influence our (non-moral) evaluations of these same factors. For example, when we judge an agent to have acted immorally, we are subsequently more likely to judge the agent to have acted freely, not under force. Here, we investigate the cognitive signatures of this effect in interpersonal situations, in which one agent ("forcer") forces another agent ("forcee") to act either immorally or morally. The structure of this relationship allowed us to ask questions about both the "forcer" and the "forcee." Paradoxically, participants judged that the "forcer" forced the "forcee" to act immorally (i.e. X forced Y), but that the "forcee" was not forced to act immorally (i.e. Y was not forced by X). This pattern obtained only for human agents who acted intentionally. Directly changing participants' focus from one agent to another (forcer versus forcee) also changed the target of moral evaluation and therefore force attributions. The full pattern of judgments may provide a window into motivated moral reasoning and focusing bias more generally; participants may have been motivated to attribute greater force to the immoral forcer and greater freedom to the immoral forcee.


A single intersubunit salt bridge affects oligomerization and catalytic activity in a bacterial quinone reductase.
YhdA, a thermostable NADPH:FMN oxidoreductase from Bacillus subtilis, reduces quinones via a ping-pong bi-bi mechanism with a pronounced preference for NADPH. The enzyme occurs as a stable tetramer in solution. The two extended dimer surfaces are packed against each other by a 90 rotation of one dimer with respect to the other. This assembly is stabilized by the formation of four salt bridges between K109 and D137 of the neighbouring protomers. To investigate the importance of the ion pair contacts, the K109L and D137L single replacement variants, as well as the K109L/D137L and K109D/D137K double replacement variants, were generated, expressed, purified, crystallized and biochemically characterized. The K109L and D137L variants form dimers instead of tetramers, whereas the K109L/D137L and K109D/D137K variants appear to exist in a dimer-tetramer equilibrium in solution. The crystal structures of the K109L and D137L variants confirm the dimeric state, with the K109L/D137L and K109D/D137K variants adopting a tetrameric assembly. Interestingly, all protein variants show a drastically reduced quinone reductase activity in steady-state kinetics. Detailed analysis of the two half reactions revealed that the oxidative half reaction is not affected, whereas reduction of the bound FMN cofactor by NADPH is virtually abolished. Inspection of the crystal structures indicates that the side chain of K109 plays a dual role by forming a salt bridge to D137, as well as stabilizing a glycine-rich loop in the vicinity of the FMN cofactor. In all protein variants, this glycine-rich loop exhibits a much higher mobility, compared to the wild-type. This appears to be incompatible with NADPH binding and thus leads to abrogation of flavin reduction.


Nested capillary anti-resonant silica fiber with mid-infrared transmission and low bending sensitivity at 4000 nm.
We report a silica glass nested capillary anti-resonant nodeless fiber with transmission and low bending sensitivity in the mid-infrared around 4000 nm. The fiber is characterized in terms of transmission over 1700-4200 nm wavelengths, revealing a mid-infrared 3500-4200 nm transmission window, clearly observable for a 12 m long fiber. Bending loss around 4000 nm is 0.5 dB/m measured over three full turns with 40 mm radius, going up to 5 dB/m for full turns with 15 mm radius. Our results provide experimental evidence of hollow-core silica fibers in which nested, anti-resonant capillaries provide high bend resistance in the mid-infrared. This is obtained for a fiber with a large core diameter of over 60 μm relative to around 30 μm capillaries in the cladding, which motivates its application in gas fiber lasers or fiber-based mid-infrared spectroscopy of COx or NxO analytes.


Seeding of picosecond and femtosecond optical parametric amplifiers by weak single mode continuous lasers.
Optical parametric amplifiers are typically seeded with either parametric superfluorescence or broadband continuum pulses. We show both with picosecond and femtosecond pump pulses, that single longitudinal mode cw lasers with mW power can be well used to generate nearly Fourier-transform-limited output pulses. The 532 nm pumped picosecond system is seeded in the near infrared and fully tunable from 1260 to 1630 nm. The femtosecond system operates stable with just hundreds of seed photons. The output spectral width matches closely to the width of individual spectral features found in single shot spectra of parametric superfluorescence. Both systems provide interesting radiation sources for nonlinear optics experiments that need highly controlled and clean excitation.


Yearly changes of insecticide susceptibility and possible insecticide resistance mechanisms of Anopheles maculipennis Meigen (Diptera: Culicidae) in Turkey.
To evaluate the adulticide susceptibility and yearly changes of Anopheles maculipennis Meigen (Diptera: Culicidae) in Thrace, five mosquito populations were evaluated against the resistance status of four different adulticides. Three biochemical resistance mechanisms and yearly changes of activities were investigated. All the strains were highly resistant to DDT, and all the strains were placed in the resistance surveillance category for malathion, permethrin and deltamethrin in 2007. Although DDT mortality rates had increased from 2007 to 2008 except in the Seremkoy strain, malathion, permethrin and deltamethrin mortality rates have decreased in all of the tested strains. High rates of increase were determined for nonspecific esterases (NSEs) activity by using the substrate p-NPA and these results showed correlation with malathion mortality rates. All the strains showed high level of glutathione S transferases (GSTs), and their activity level had significantly increased from 2007 to 2008. Different insecticide susceptibility statuses were observed between localities, and high DDT resistance was observed although DDT was banned in the 1980s. Biochemical assay results suggest that NSEs and GSTs could play a role insecticide resistance in all tested strains. Malathion susceptibility has decreased in all the tested strains and NSE's activity is possibly the main enzymatic mechanism related to the insecticide resistance. DDT resistance is at a high degree in all the strains and GST's activity is probably related to this situation. GST's activity could play an important role for permethrin and deltamethrin susceptibility but needs to be confirmed for molecular studies. Our results provide important data on insecticide susceptibility and change over time for the Anopheles maculipennis populations in Turkey.


Impact of the COVID-19 pandemic on sports and exercise.
COVID-19 is a droplet-transmitted potentially fatal coronavirus pandemic affecting the world in 2020. The WHO recommended social distancing and human-to-human contact was discouraged to control the transmission. It has put many countries in a state of lockdown and sporting events (including the 2020 Olympics) have been affected. Participation in sports and exercise, typically regarded as healthy activities, were also debated. The local professional football leagues, governed by the Hong Kong Football Association, ultimately postponed all matches after much deliberation on the transmission risk for the spectators and on-field players. Large spectating crowds are well-known to be infectious hazards, but the infection risk for on-field players is less recognized. Aside from watching professionals exercise, many people opted to hike in the countryside during the weekends to avoid city crowds. This led to a widespread discussion on the issue of wearing a facemask during outdoor activities. A small sample of video footage of professional football players were analysed to track each players' time of close body contact and frequency of infection-risky behaviours to investigate the risk of virus transmission during football games.To investigate the physiological effect of wearing a facemask during exercise, we conducted a controlled laboratory, within-subject, repeated measures study of 23 healthy volunteers of various sporting backgrounds. They underwent graded treadmill walking at 4 km per hour for 6 min with and without wearing a surgical mask in a randomized order with sufficient resting time in between trials. The heart rate and the rate of perceived exertion (RPE) were recorded. In a 90 min match, the average duration of close contact between professional football players was 19 min and each player performed an average of 52 episodes of infection-risky behaviours. The heart rate and RPE of subjects wearing a facemask was 128 beats per minute and 12.7 respectively. In those without a facemask, the results were a heart rate of 124 beats per minute and a RPE of 10.8. This suggests that the infection risk was high for the players, even without spectators. The laboratory study to investigate the physiological effect of wearing a facemask found that it significantly elevated heart rate and perceived exertion. Those participating in exercise need to be aware that facemasks increase the physiological burden of the body, especially in those with multiple underlying comorbidities. Elite athletes, especially those training for the upcoming Olympics, need to balance and reschedule their training regime to balance the risk of deconditioning versus the risk of infection. The multiple infection-control measures imposed by the Hong Kong national team training centre was highlighted to help strike this balance. Amidst a global pandemic affecting millions; staying active is good, but staying safe is paramount.