Deep-etched sinusoidal polarizing beam splitter grating.
A sinusoidal-shaped fused-silica grating as a highly efficient polarizing beam splitter (PBS) is investigated based on the simplified modal method. The grating structure depends mainly on the ratio of groove depth to grating period and the ratio of incident wavelength to grating period. These ratios can be used as a guideline for the grating design at different wavelengths. A sinusoidal-groove PBS grating is designed at a wavelength of 1310 nm under Littrow mounting, and the transmitted TM and TE polarized waves are mainly diffracted into the zeroth order and the -1st order, respectively. The grating profile is optimized by using rigorous coupled-wave analysis. The designed PBS grating is highly efficient (>95.98%) over the O-band wavelength range (1260-1360 nm) for both TE and TM polarizations. The sinusoidal grating can exhibit higher diffraction efficiency, larger extinction ratio, and less reflection loss than the rectangular-groove PBS grating. By applying wet etching technology on the rectangular grating, which was manufactured by holographic recording and inductively coupled plasma etching technology, the sinusoidal grating can be approximately fabricated. Experimental results are in agreement with theoretical values.


Prophylactic administration of histamine 1 and/or histamine 2 receptor blockers in the prevention of heparin- and protamine-related haemodynamic effects.
The efficacy of prophylactic administration of H1 and H2 receptor blockers to prevent adverse haemodynamic responses to heparin and protamine was studied. The control group (n = 10) received no histamine receptor blocker, group H1 (n = 10) received oral terfenadine 60 mg, group H2 (n = 10) received oral ranitidine 300 mg, and group H1+H2 (n = 10) received both terfenadine and ranitidine on the night before the operation and on call to the operating room. Heparin sulphate 300 U/kg was injected directly into the right atrium, and protamine hydrochloride was administered at the conclusion of bypass over at least three minutes through a peripheral route. Following the injection of heparin, plasma histamine-like activity (H-LA) was increased significantly in all four groups. While systolic, diastolic, mean arterial and central venous pressures were decreased significantly in the control group, no significant changes were observed in the H1 and H2 groups. Protamine infusion did not lead to an increase in H-LA. Prophylactic administration of histamine receptor blockers (H1 or H2) attenuated the heparin-induced adverse haemodynamic response but did not change the protamine-related haemodynamic effects. Factors other than histamine may play a major role in protamine induced cardiovascular changes.


Energy transfer and photoluminescence properties of lanthanide-containing polyoxotitanate cages coordinated by salicylate ligands.
Polyoxotitanate (POT) cages have attracted considerable attention recently; much of this from the fact that they can be considered to be structural models for the technologically important semiconductor TiO2. Among the reported POT cages, lanthanide-containing (Ln-POT) cages are of particular interest owing to the fascinating luminescence properties of Ln3+ ions and the versatile coordination environments that they can adopt. In the present study, we report the energy transfer mechanism and photoluminescence properties of a series of isostructural Ln-POT cages coordinated by salicylate ligands, of general formula [LnTi6O3(OiPr)9(salicylate)6] (Ln-1, Ln = La to Er excluding Pm). Both visible (for Pr-1, Sm-1, Eu-1, Ho-1 and Er-1) and near-infrared (for Nd-1 and Er-1) Ln3+-centred photoluminescence can be sensitised in solution, and most importantly, their excitation bands all extend well into the visible region up to 475 nm. With the assistance of steady-state and time-resolved photoluminescence spectroscopy, an energy-transfer mechanism involving the salicylate-to-Ti4+ charge-transfer state is proposed to account for the largely red-shifted excitation wavelengths of these Ln-1 cages. The photoluminescence quantum yield of Nd-1 upon excitation via the charge-transfer state reaches 0.30 ± 0.01% in solution, making it among the highest reported values for Nd3+-complexes in the literature.


Catechol-O-methyltransferase val158met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex.
Catechol-O-methyltransferase (COMT) degrades the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. A functional polymorphism in the COMT gene (val158met) accounts for a fourfold variation in enzyme activity. The low-activity met158 allele has been associated with improved working memory but with higher risk for anxiety-related behaviors. Using functional magnetic resonance imaging, we assessed the effects of COMT genotype on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 35 healthy subjects. The analysis of genotype effects was restricted to brain areas with robust activation by the task. To determine genedose effects, the number of met158 alleles (0, 1, or 2) was correlated with the blood oxygen level-dependent (BOLD) response elicited by pleasant or unpleasant stimuli compared with neutral stimuli. COMT genotype had no significant impact on brain activation by pleasant stimuli but was related to the neural response to unpleasant stimuli: reactivity to unpleasant stimuli was significantly positively correlated with the number of met158 alleles in the limbic system (left hippocampus, right amygdala, right thalamus), connected prefrontal areas (bilateral ventrolateral prefrontal cortex, right dorsolateral prefrontal cortex), and the visuospatial attention system (bilateral fusiform gyrus, left inferior parietal lobule). Genotype explained up to 38% of interindividual variance in BOLD response elicited by unpleasant stimuli. We conclude that (1) genetic variations can account for a substantial part of interindividual variance in task-related brain activation and that (2) increased limbic and prefrontal activation elicited by unpleasant stimuli in subjects with more met158 alleles might contribute to the observed lower emotional resilience against negative mood states.


Increased expression of ferritin in cerebral cortex after human traumatic brain injury.
Despite numerous researches and improvements in the past few years, the precise mechanisms underlying secondary brain injury after trauma remain obscure. Iron is essential for almost all types of cells, including nerve cells. However, excess of iron has been proved to contribute to the brain injury following trauma in animal models. As a key iron-handling protein in the brain, ferritin might be involved in iron-induced pathophysiological process of various brain disorders. Therefore, the current study was aimed to investigate the expression of ferritin in the human contused brain. Nineteen contused brain samples were obtained from 19 patients undergoing surgery for brain contusions 3 h-17 d after trauma, and three normal temporal pole samples from 3 patients with petroclival meningioma were collected as controls. Expression of ferritin-H-chain was measured by quantitative real-time polymerase chain reaction (PCR), western blot and immunohistochemistry, respectively. Perl's reaction was taken for iron staining. The results showed that human traumatic brain injury (TBI) could up-regulate ferritin-H-chain in pericontusional cortex. A marked increase of ferritin was detected in the early group (≤12 h), and remained elevated for a long time till after 48 h post-injury. The location of ferritin-H-chain was found mainly at the neuron-like cells and seldom at glia-like cells. Perl's reaction showed that most of the iron-positive cells were glia-like cells. These findings suggested that iron and ferritin might be involved in the secondary brain injury and could be therapeutic targets for patients with TBI.


Protective mucosal immunity mediated by epithelial CD1d and IL-10.
The mechanisms by which mucosal homeostasis is maintained are of central importance to inflammatory bowel disease. Critical to these processes is the intestinal epithelial cell (IEC), which regulates immune responses at the interface between the commensal microbiota and the host. CD1d presents self and microbial lipid antigens to natural killer T (NKT) cells, which are involved in the pathogenesis of colitis in animal models and human inflammatory bowel disease. As CD1d crosslinking on model IECs results in the production of the important regulatory cytokine interleukin (IL)-10 (ref. 9), decreased epithelial CD1d expression--as observed in inflammatory bowel disease--may contribute substantially to intestinal inflammation. Here we show in mice that whereas bone-marrow-derived CD1d signals contribute to NKT-cell-mediated intestinal inflammation, engagement of epithelial CD1d elicits protective effects through the activation of STAT3 and STAT3-dependent transcription of IL-10, heat shock protein 110 (HSP110; also known as HSP105), and CD1d itself. All of these epithelial elements are critically involved in controlling CD1d-mediated intestinal inflammation. This is demonstrated by severe NKT-cell-mediated colitis upon IEC-specific deletion of IL-10, CD1d, and its critical regulator microsomal triglyceride transfer protein (MTP), as well as deletion of HSP110 in the radioresistant compartment. Our studies thus uncover a novel pathway of IEC-dependent regulation of mucosal homeostasis and highlight a critical role of IL-10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.


Parental experiences of uncertainty following an abnormal fetal anomaly scan: Insights using Han's taxonomy of uncertainty.
For a number of prospective parents, uncertainty during pregnancy starts when an anomaly is found during a routine fetal anomaly scan. This may be followed by numerous tests to determine the etiology and nature of the anomaly. In this study, we aimed to understand how prospective parents perceive and manage uncertainty after being confronted with a structural anomaly during their routine ultrasound. Han's taxonomy of uncertainty was used as a framework to identify and understand the different types of uncertainty experienced. Interviews were held in the UK (n = 8 women and n = 1 male partner) and in the Netherlands (n = 7 women) with participants who had experienced uncertainty in their pregnancy after a fetal scan. Data were analyzed using thematic analysis, and the uncertainties experienced by parents were mapped against the dimensions of the Han taxonomy (sources, issues, and locus). Participants' experience of uncertainty was relevant to all dimensions and subcategories of the Han taxonomy, showing its applicability in the prenatal setting. Sources of uncertainty included receiving probabilistic or ambiguous information about the anomaly, or information that was complex and challenging to understand. Issues of uncertainty included were those that were scientific-such as a probable diagnosis with no further information, personal-such as the emotional impact of uncertainty, and practical-such as limited information about medical procedures and practical aspects of care. Additionally, participants described what helped them to manage uncertainty. This included active coping strategies such as searching for information on the Internet, external coping resources such as seeking social support, and internal coping resources such as using positivity and hope. Several recommendations for the healthcare professional to minimize uncertainty and help the patient deal with uncertainty have been proposed based on these findings.


Removing artefacts from TMS-EEG recordings using independent component analysis: importance for assessing prefrontal and motor cortex network properties.
The combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) is emerging as a powerful tool for causally investigating cortical mechanisms and networks. However, various artefacts contaminate TMS-EEG recordings, particularly over regions such as the dorsolateral prefrontal cortex (DLPFC). The aim of this study was to substantiate removal of artefacts from TMS-EEG recordings following stimulation of the DLPFC and motor cortex using independent component analysis (ICA). 36 healthy volunteers (30.8 ± 9 years, 9 female) received 75 single TMS pulses to the left DLPFC or left motor cortex while EEG was recorded from 57 electrodes. A subset of 9 volunteers also received 50 sham pulses. The large TMS artefact and early muscle activity (-2 to ~15 ms) were removed using interpolation and the remaining EEG signal was processed in two separate ICA runs using the FastICA algorithm. Five sub-types of TMS-related artefacts were manually identified: remaining muscle artefacts, decay artefacts, blink artefacts, auditory-evoked potentials and other noise-related artefacts. The cause of proposed blink and auditory-evoked potentials was assessed by concatenating known artefacts (i.e. voluntary blinks or auditory-evoked potentials resulting from sham TMS) to the TMS trials before ICA and evaluating grouping of resultant independent components (ICs). Finally, we assessed the effect of removing specific artefact types on TMS-evoked potentials (TEPs) and TMS-evoked oscillations. Over DLPFC, ICs from proposed muscle and decay artefacts correlated with TMS-evoked muscle activity size, whereas proposed TMS-evoked blink ICs combined with voluntary blinks and auditory ICs with auditory-evoked potentials from sham TMS. Individual artefact sub-types characteristically distorted each measure of DLPFC function across the scalp. When free of artefact, TEPs and TMS-evoked oscillations could be measured following DLPFC stimulation. Importantly, characteristic TEPs following motor cortex stimulation (N15, P30, N45, P60, N100) could be recovered from artefactual data, corroborating the reliability of ICA-based artefact correction. Various different artefacts contaminate TMS-EEG recordings over the DLPFC and motor cortex. However, these artefacts can be removed with apparent minimal impact on neural activity using ICA, allowing the study of TMS-evoked cortical network properties.


Antimicrobial drugs for persistent diarrhoea of unknown or non-specific cause in children under six in low and middle income countries: systematic review of randomized controlled trials.
A high proportion of children with persistent diarrhoea in middle and low income countries die. The best treatment is not clear. We conducted a systematic review to evaluate the effectiveness of antimicrobial drug treatment for persistent diarrhoea of unknown or non-specific cause. We included randomized comparisons of antimicrobial drugs for the treatment of persistent diarrhoea of unknown or non-specific cause in children under the age of six years in low and middle income countries. We searched the electronic databases MEDLINE, EMBASE, LILACS, WEB OF SCIENCE, and the Cochrane Central Register of Controlled Trials (CENTRAL) to May 2008 for relevant randomized or quasi randomized controlled trials. We summarised the characteristics of the eligible trials, assessed their quality using standard criteria, and extracted relevant outcomes data. Where appropriate, we combined the results of different trials. Three trials from South East Asia and one from Guatemala were included, all were small, and three had adequate allocation concealment. Two were in patients with diarrhoea of unknown cause, and two were in patients in whom known bacterial or parasitological causes of diarrhoea had been excluded. No difference was demonstrated for oral gentamicin compared with placebo (presence of diarrhoea at 6 or 7 days; 2 trials, n = 151); and for metronidazole compared with placebo (presence of diarrhoea at 3, 5 and 7 days; 1 trial, n = 99). In one small trial, sulphamethoxazole-trimethoprim appeared better than placebo in relation to diarrhoea at seven days and total stool volume (n = 55). There is little evidence as to whether or not antimicrobials help treat persistent diarrhoea in young children in low and middle income countries.


Differential expression of ovine innate immune genes by preterm and neonatal lung epithelia infected with respiratory syncytial virus.
Preterm infants have increased susceptibility to severe manifestations of respiratory syncytial virus (RSV) infection. The cause(s) for this age-dependent vulnerability is/are not well-defined, but alterations in innate immune products have been implicated. In sheep, RSV disease severity has similar age-dependent characteristics and sheep have several related innate molecules for study during pulmonary infection including surfactant protein A (SP-A), surfactant protein D (SP-D), sheep beta defensin 1 (SBD1), monocyte chemotactic protein 1 (MCP1), and Toll-like receptor 4 (TLR4). However, the in vivo cellular gene expression as a response to RSV infection is poorly understood. In this study, the effect of RSV infection on expression of these innate immune genes was determined for bovine RSV-infected (bRSV+ fluorescence) epithelial cells, adjacent cells lacking bRSV antigen (adjoining cells lacking fluorescence), and control cells from non-infected lung using laser capture microdissection (LCM) and real-time RT-PCR. Control lambs had increased expression of innate immune molecules in full term (term) compared to preterm epithelia with statistical significance in SBD1, SP-D, and TLR4 mRNA. Infected cells (bRSV+ fluorescent cells) had consistently higher mRNA levels of SP-A (preterm and term), MCP1 (preterm and term), and SP-D (preterm). Interestingly, bRSV- cells of infected term lambs had significantly reduced SP-D mRNA expression compared to bRSV+ and control epithelia, suggesting that RSV infected cells may regulate the adjacent epithelial SP-D expression. This study defines specific innate immune components (e.g., SBD1, SP-D, and TLR4) that have differential age-dependent expression in the airway epithelia. Furthermore, cellular bRSV infection enhanced certain innate immune components while suppressing adjacent cellular SP-D expression in term animals. These in vivo gene expression results provide a framework for future studies on age-dependent susceptibility to RSV and RSV pathogenesis.


Detailed structural investigation of the grafting of [Ta(=CHtBu)(CH2tBu)3] and [Cp*TaMe4] on silica partially dehydroxylated at 700 degrees C and the activity of the grafted complexes toward alkane metathesis.
The reaction of [Ta(=CHtBu)(CH2tBu)3] or [Cp*Ta(CH3)4] with a silica partially dehydroxylated at 700 degrees C gives the corresponding monosiloxy surface complexes [([triple bond]SiO)Ta(=CHtBu)(CH2tBu)2] and [([triple bond]SiO)Ta(CH3)3Cp*] by eliminating a sigma-bonded ligand as the corresponding alkane (H-CH2tBu or H-CH3). EXAFS data show that an adjacent siloxane bridge of the surface plays the role of an extra surface ligand, which most likely stabilizes these complexes as in [([triple bond]SiO)Ta(=CHtBu)(CH2tBu)2([triple bond]SiOSi[triple bond])] (1a') and [([triple bond]SiO)Ta(CH3)3Cp*([triple bond]SiOSi[triple bond])] (2a'). In the case of [(SiO)Ta(=CHtBu)(CH2tBu)2([triple bond]SiOSi[triple bond])], the structure is further stabilized by an additional interaction: a C-H agostic bond as evidenced by the small J coupling constant for the carbenic C-H (JC-H = 80 Hz), which was measured by J-resolved 2D solid-state NMR spectroscopy. The product selectivity in propane metathesis in the presence of [([triple bond]SiO)Ta(=CHtBu)(CH2tBu)2([triple bond]SiOSi[triple bond])] (1a') as a catalyst precursor and the inactivity of the surface complex [([triple bond]SiO)Ta(CH3)3Cp*([triple bond]SiOSi[triple bond])] (2a') show that the active site is required to be highly electrophilic and probably involves a metallacyclobutane intermediate.


Corticosteroid use and bone mineral accretion in children with asthma: effect modification by vitamin D.
The adverse effects of corticosteroids on bone mineral accretion (BMA) have been well documented. Vitamin D insufficiency, a prevalent condition in the pediatric population, has also been associated with decreased bone mineral density (BMD). We sought to determine whether children with asthma who have lower vitamin D levels are more susceptible to the negative effects of corticosteroids on BMD over time. Children aged 5 to 12 years with mild-to-moderate asthma who participated in the Childhood Asthma Management Program were followed for a mean of 4.3 years. Total doses of inhaled corticosteroids and oral corticosteroids (OCSs) were recorded, serum 25-hydroxyvitamin D3 levels were measured at the beginning of the trial, and serial dual-energy x-ray absorptiometry scans of the lumbar spine were performed. Annual BMA rates were defined as follows: [(BMD at 4 years' follow-up - BMD at baseline)/4 years]. BMA was calculated for 780 subjects. In boys baseline vitamin D levels significantly modified the relationship between OCSs and BMA (vitamin D × OCS interaction, P= .023). Stratification by vitamin D levels showed a decrease in BMA with increased use of OCSs in vitamin D-insufficient boys only (P< .001). Compared with vitamin D-sufficient boys, vitamin D-insufficient boys exposed to more than 2 courses of OCSs per year had twice the decrease in BMA rate (relative to boys who were OCS unexposed). Vitamin D levels significantly modified the effect of OCSs on BMA in boys. Further research is needed to examine whether vitamin D supplementation in children with poorly controlled asthma might confer benefits to bone health.


[Neurorehabilitation in multiple sclerosis].
Neurorehabilitation is predominantly an educational, dynamic process based on the adaptation of the individual and his environment to the actual neurological impairment and focuses on decreasing the impact of disabling neurological conditions on the individual in order to achieve optimum quality of life. It has been suggested by some that neurorehabilitation is the only approach available to us which can improve the limitations in activity and restrictions in social participation of people with multiple sclerosis. The neurorehabilitation approach is a holistic one and is a fundamental part of neurological care; it should not be forgotten by neurologists, especially when dealing with people with chronic disabling conditions such as multiple sclerosis. Together with the social model of disability, the concept of restorative neurology, as a scientific and therapeutic attempt to minimize those impairments directly responsible for the disability presented by the person, is recently gaining ground among neuroscientists and clinicians. In this review the conceptual basis for neurorehabilitation will be presented together with a review of the literature concerning the biological aspects of neurorehabilitative therapy (neuroplasticity) and the clinical trials evaluating the effectiveness of neurorehabilitation in people with multiple sclerosis. Finally, we will consider the practical aspects of neurorehabilitation.


How the door opened: the peopling of the New World.
The timing, pathways, and number of migrations involved in the early peopling of the New World are examined from a variety of perspectives. Ultimately, the occupation of the Western Hemisphere was a direct result of boreal cultural adaptations in the Old World. Here, we discuss (1) the dates of appearance of these boreal cultural adaptations and their relevance to the peopling of America, (2) archeological and linguistic evidence bearing on the earliest peopling of the New World, (3) ecological and linguistic evidence on two alternative routes into the New World, and (4) the assumptions present in various migration models. The relative strengths of opposing hypotheses are analyzed by observing whether different approaches point to the same answers.


A call for action to establish a research agenda for building a future health workforce in Europe.
The importance of a sustainable health workforce is increasingly recognised. However, the building of a future health workforce that is responsive to diverse population needs and demographic and economic change remains insufficiently understood. There is a compelling argument to be made for a comprehensive research agenda to address the questions. With a focus on Europe and taking a health systems approach, we introduce an agenda linked to the 'Health Workforce Research' section of the European Public Health Association. Six major objectives for health workforce policy were identified: (1) to develop frameworks that align health systems/governance and health workforce policy/planning, (2) to explore the effects of changing skill mixes and competencies across sectors and occupational groups, (3) to map how education and health workforce governance can be better integrated, (4) to analyse the impact of health workforce mobility on health systems, (5) to optimise the use of international/EU, national and regional health workforce data and monitoring and (6) to build capacity for policy implementation. This article highlights critical knowledge gaps that currently hamper the opportunities of effectively responding to these challenges and advising policy-makers in different health systems. Closing these knowledge gaps is therefore an important step towards future health workforce governance and policy implementation. There is an urgent need for building health workforce research as an independent, interdisciplinary and multi-professional field. This requires dedicated research funding, new academic education programmes, comparative methodology and knowledge transfer and leadership that can help countries to build a people-centred health workforce.


Do worse baseline risk factors explain the association of healthy obesity with increased mortality risk? Whitehall II Study.
To describe 20-year risk factor trajectories according to initial weight/health status and investigate the extent to which baseline differences explain greater mortality among metabolically healthy obese (MHO) individuals than healthy non-obese individuals. The sample comprised 6529 participants in the Whitehall II study who were measured serially between 1991-1994 and 2012-2013. Baseline weight (non-obese or obese; body mass index (BMI) ≥30 kg/m2) and health status (healthy or unhealthy; two or more of hypertension, low high-density lipoprotein cholesterol (HDL-C), high triglycerides, high glucose, and high homeostatic model assessment of insulin resistance (HOMA-IR)) were defined. The relationships of baseline weight/health status with 20-year trajectories summarizing ~25,000 observations of systolic and diastolic blood pressures, HDL-C, triglycerides, glucose, and HOMA-IR were investigated using multilevel models. Relationships of baseline weight/health status with all-cause mortality up until July 2015 were investigated using Cox proportional hazards regression. Trajectories tended to be consistently worse for the MHO group compared to the healthy non-obese group (e.g., glucose by 0.21 (95% CI 0.09, 0.33; p < 0.001) mmol/L at 20-years of follow-up). Consequently, the MHO group had a greater risk of mortality (hazard ratio 2.11 (1.24, 3.58; p = 0.006)) when the referent group comprised a random sample of healthy non-obese individuals. This estimate, however, attenuated (1.34 (0.85, 2.13; p = 0.209)) when the referent group was matched to the MHO group on baseline risk factors. Worse baseline risk factors may explain any difference in mortality risk between obese and non-obese groups both labelled as healthy, further challenging the concept of MHO.


Time to first tumor progression as a predictor of efficacy of continued treatment with trastuzumab beyond progression in human epidermal growth factor receptor 2-positive metastatic breast cancer.
Trastuzumab demonstrates significant clinical benefits in HER2-positive metastatic breast cancer (MBC), and recent clinical trials suggest that trastuzumab should be continued in combination with other chemotherapy beyond progression. There is an urgent need to assess if patients could substantially benefit from continuing trastuzumab-based therapy. We reviewed 91 patients with HER2-positive MBC treated with trastuzumab and investigated correlations between survival and clinical response to first trastuzumab-based therapy and biological markers, time to first tumor progression (1st TTP), response rate (RR), estrogen receptor (ER), Ki-67, and p53 overexpression. With a median follow-up of 33 months, 76 patients had received two or more lines of consecutive trastuzumab-based therapy. Median 1st TTP was 8.6 months; patients who received trastuzumab with chemotherapy had a longer 1st TTP and better RR than those without chemotherapy. In terms of survival after first progression, patients with a longer 1st TTP (≥ 8.6 months) had significantly better survival compared with those who had a shorter 1st TTP (24.3 months vs. 15.4 months, P = 0.024), and multivariate analysis revealed that 1st TTP was a significant prognostic factor (HR 0.44, 95% CI 0.23-0.82, P = 0.01). There were no correlations between survival and ER or Ki-67; however, there was a correlation with p53 overexpression (HR 1.92, 95% CI 1.01-3.64, P = 0.045). 1st TTP is a significant prognostic factor for patients who receive subsequent trastuzumab-based therapy. This factor should be considered when determining the efficacy of continuing trastuzumab or switching to another anti-HER2 therapy beyond progression.


The effect of comorbidities on risk of intensive care readmission during the same hospitalization: a linked data cohort study.
The aim of this study is to assess the effect of comorbidities on risk of readmission to an intensive care unit (ICU) and the excess hospital mortality associated with ICU readmissions. A cohort study used clinical data from a 22-bed multidisciplinary ICU in a university hospital and comorbidity data from the Western Australian hospital morbidity database. From 16,926 consecutive ICU admissions between 1987 and 2002, and 654 (3.9%) of these patients were readmitted to ICU readmissions within the same hospitalization. Patients with readmission were older, more likely to be originally admitted from the operating theatre or hospital ward, had a higher Acute Physiology and Chronic Health Evaluation (APACHE)-predicted mortality, and had more comorbidities when compared with patients without readmission. The number of Charlson comorbidities was significantly associated with late readmission (>72 hours) but not early readmission (<or=72 hours) in the multivariate analysis. Both early and late ICU readmissions were associated with an increased risk of hospital mortality (odds ratio, 1.68; 95% confidence interval, 1.18-2.39; P = .004; odds ratio, 1.45; 95% confidence interval, 1.05-1.99; P = .022, respectively) after adjusting for age, admission source, type of admission, the APACHE-predicted mortality, and the number of Charlson comorbidities and APACHE chronic health conditions. Comorbidity was a risk factor for late ICU readmission. Comorbidities could not account for the excess mortality associated with ICU readmissions.


Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance.
Fatty acid oversupply is a key mediator of skeletal muscle insulin resistance in obesity, primarily via accumulation of fatty acid metabolites and activation of proinflammatory pathways. Herein, we demonstrate that fatty acid-induced insulin resistance in humans is completely prevented the day after 1 session of endurance exercise. Because skeletal muscle is the primary site for systemic glucose disposal and is highly susceptible to impaired insulin action by elevated fatty acid availability, we obtained skeletal muscle samples to investigate possible mechanisms mediating this protective effect of exercise. Prevention of fatty acid-induced insulin resistance after exercise accompanied enhanced skeletal muscle protein expression of key lipogenic enzymes and an increase in muscle triglyceride synthesis. Partitioning more fatty acids toward triglyceride synthesis within muscle reduced the accumulation of fatty acid metabolites and suppressed the proinflammatory response in skeletal muscle, as evidenced by decreased phosphorylation and activation of JNK and increased abundance of inhibitor of NF-kappaB alpha (I kappa B-alpha) and I kappa B-beta. We believe this is the first study to demonstrate that 1 session of exercise completely reverses fatty acid-induced insulin resistance in humans. Reversal of insulin resistance accompanied enhanced lipogenic capacity within skeletal muscle, reduced accumulation of highly bioactive fatty acid metabolites, and suppressed activation of proinflammatory pathways known to impair insulin action.


Glucocorticoids for the treatment of anaphylaxis.
Anaphylaxis is a serious hypersensitivity reaction that is rapid in onset and may result in death. Anaphylaxis guidelines recommend glucocorticoids for the treatment of people experiencing anaphylaxis. We sought to assess the benefits and harms of glucocorticoid treatment during episodes of anaphylaxis. In our previous version we searched the literature until September 2009. In this version we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (Ovid) (1956 to September 2011), EMBASE (Ovid) (1982 to September 2011), CINAHL (EBSCOhost) (to September 2011). We also searched the UK National Research Register and websites listing ongoing trials, and contacted international experts in anaphylaxis in an attempt to locate unpublished material. We planned to include randomized and quasi-randomized controlled trials comparing glucocorticoids with any control (either placebo, adrenaline (epinephrine), an antihistamine, or any combination of these). Two authors independently assessed articles for inclusion. We found no studies that satisfied the inclusion criteria. We are, based on this review, unable to make any recommendations for the use of glucocorticoids in the treatment of anaphylaxis.


Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma.
Symptomatic epilepsy is a common complication of glioblastoma and requires pharmacotherapy. Several uncontrolled retrospective case series and a post hoc analysis of the registration trial for temozolomide indicated an association between valproic acid (VPA) use and improved survival outcomes in patients with newly diagnosed glioblastoma. To confirm the hypothesis suggested above, a combined analysis of survival association of antiepileptic drug use at the start of chemoradiotherapy with temozolomide was performed in the pooled patient cohort (n = 1,869) of four contemporary randomized clinical trials in newly diagnosed glioblastoma: AVAGlio (Avastin in Glioblastoma; NCT00943826), CENTRIC (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Methylated Gene Promoter Status; NCT00689221), CORE (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Unmethylated Gene Promoter Status; NCT00813943), and Radiation Therapy Oncology Group 0825 (NCT00884741). Progression-free survival (PFS) and overall survival (OS) were compared between: (1) any VPA use and no VPA use at baseline or (2) VPA use both at start of and still after chemoradiotherapy. Results of Cox regression models stratified by trial and adjusted for baseline prognostic factors were analyzed. The same analyses were performed with levetiracetam (LEV). VPA use at start of chemoradiotherapy was not associated with improved PFS or OS compared with all other patients pooled (PFS: hazard ratio [HR], 0.91; 95% CI, 0.77 to 1.07; P = .241; OS: HR, 0.96; 95% CI, 0.80 to 1.15; P = .633). Furthermore, PFS and OS of patients taking VPA both at start of and still after chemoradiotherapy were not different from those without antiepileptic drug use at both time points (PFS: HR, 0.92; 95% CI, 0.74 to 1.15; P = .467; OS: HR, 1.10; 95% CI, 0.86 to 1.40; P = .440). Similarly, no association with improved outcomes was observed for LEV use. The results of this analysis do not justify the use of VPA or LEV for reasons other than seizure control in patients with newly diagnosed glioblastoma outside clinical trials.


Secondhand Tobacco Smoke and COPD Risk in Smokers: A COPDGene Study Cohort Subgroup Analysis.
Exposure to secondhand tobacco smoke (SHS) can be a risk factor for chronic obstructive pulmonary disease (COPD), but its role among relatively heavy smokers with potential co-exposure to workplace vapors, gas, dust, and fumes (VGDF) has not been studied. To estimate the contribution of SHS exposure to COPD risk, taking into account smoking effects and work-related exposures to VGDF, we quantified SHS based on survey responses for 1400 ever-employed subjects enrolled in the COPDGene study, all current or former smokers with or without COPD. Occupational exposures to VGDF were quantified based on a job exposure matrix. The associations between SHS and COPD were tested in multivariate logistic regression analyses adjusted for age, sex, VGDF exposure, and cumulative smoking. Exposures to SHS at work and at home during adulthood were associated with increased COPD risk: odds ratio (OR) = 1.12 (95% confidence interval [CI]: 1.02-1.23; p = 0.01) and OR = 1.09 (95%CI: 1.00-1.18; p = 0.04) per 10 years of exposure adjusted for smoking and other covariates, respectively. In addition, subjects with employment histories likely to entail exposure to VGDF were more likely to have COPD: OR = 1.52 (95%CI: 1.16-1.98; p < 0.01) (adjusted for other covariates). While adult home SHS COPD risk was attenuated among the heaviest smokers within the cohort, workplace SHS and job VGDF risks persisted in that stratum. Among smokers all with at least 10 pack-years, adult home and work SHS exposures and occupational VGDF exposure are all associated with COPD.


Characterization of the small exported Plasmodium falciparum membrane protein SEMP1.
Survival and virulence of the human malaria parasite Plasmodium falciparum during the blood stage of infection critically depend on extensive host cell refurbishments mediated through export of numerous parasite proteins into the host cell. The parasite-derived membranous structures called Maurer's clefts (MC) play an important role in protein trafficking from the parasite to the red blood cell membrane. However, their specific function has yet to be determined. We identified and characterized a new MC membrane protein, termed small exported membrane protein 1 (SEMP1). Upon invasion it is exported into the RBC cytosol where it inserts into the MCs before it is partly translocated to the RBC membrane. Using conventional and conditional loss-of-function approaches we showed that SEMP1 is not essential for parasite survival, gametocytogenesis, or PfEMP1 export under culture conditions. Co-IP experiments identified several potential interaction partners, including REX1 and other membrane-associated proteins that were confirmed to co-localize with SEMP1 at MCs. Transcriptome analysis further showed that expression of a number of exported parasite proteins was up-regulated in SEMP1-depleted parasites. By using Co-IP and transcriptome analysis for functional characterization of an exported parasite protein we provide a new starting point for further detailed dissection and characterisation of MC-associated protein complexes.


Electrochemical aptasensor for lung cancer-related protein detection in crude blood plasma samples.
The development of an aptamer-based electrochemical sensor for lung cancer detection is presented in this work. A highly specific DNA-aptamer, LC-18, selected to postoperative lung cancer tissues was immobilized onto a gold microelectrode and electrochemical measurements were performed in a solution containing the redox marker ferrocyanide/ferricyanide. The aptamer protein targets were harvested from blood plasma of lung cancer patients by using streptavidin paramagnetic beads and square wave voltammetry of the samples was performed at various concentrations. In order to enhance the sensitivity of the aptasensor, silica-coated iron oxide magnetic beads grafted with hydrophobic C8 and C4 alkyl groups were used in a sandwich detection approach. Addition of hydrophobic beads increased the detection limit by 100 times. The detection limit of the LC-18 aptasensor was enhanced by the beads to 0.023 ng/mL. The formation of the aptamer - protein - bead sandwich on the electrode surface was visualized by electron microcopy. As a result, the electrochemical aptasensor was able to detect cancer-related targets in crude blood plasma of lung cancer patients.


De novo next-generation sequencing, assembling and annotation of Arachis hypogaea L. Spanish botanical type whole plant transcriptome.
Peanut is a major agronomic crop within the legume family and an important source of plant oil, proteins, vitamins, and minerals for human consumption, as well as animal feed, bioenergy, and health products. Peanut genomic research effort lags that of other legumes of economic importance, mainly due to the shortage of essential genomic infrastructure, tools, resources, and the complexity of the peanut genome. This is a pioneering study that explored the peanut Spanish Group whole plant transcriptome and culminated in developing unigenes database. The study applied modern technologies, such as, normalization and next-generation sequencing. It overall sequenced 8,308,655,800 nucleotides and generated 26,048 unigenes amongst which 12,302 were annotated and 8,817 were characterized. The remainder, 13,746 (52.77 %) unigenes, had unknown functions. These results will be applied as the reference transcriptome sequences for expanded transcriptome sequencing of the remaining three peanut botanical types (Valencia, Runner, and Virginia), which is currently in progress, RNA-seq, exome identification, and genomic markers development. It will also provide important tools and resources for other legumes and plant species genomic research.


AFLP Analysis of Phytophthora cactorum Isolates from Strawberry and Other Hosts: Implications for Identifying the Primary Source of Inoculum.
Forty-seven isolates of Phytophthora cactorum from North America and Germany were subjected to amplified fragment length polymorphism (AFLP) analysis to investigate genetic diversity among isolates and geographical populations; 42 isolates were recovered from cultivated strawberry plants (Fragaria × ananassa), and five isolates had been recovered from plants in four other genera (Syringa, Abies, Malus, and Panax). From all isolates evaluated, 226 out of 264 markers (85.6%) were polymorphic and provided 42 unique AFLP profiles. The genetic diversity among isolates of P. cactorum from strawberry was greater than that among isolates from the other hosts. Isolates collected during recent crown rot epidemics in strawberry fields in South Carolina were genetically diverse and scattered among isolates from other geographical areas in an unweighted pair-group mean analysis (UPGMA) dendrogram. Isolates collected during recent crown rot epidemics in North Carolina also were genetically diverse, but most isolates clustered with isolates collected in 1997 from Florida strawberry fields. These data suggest that recent outbreaks of Phytophthora crown rot in the southeastern United States resulted from use of transplants already infected or infested with P. cactorum rather than from endemic populations of this pathogen, which would affect recommendations for disease management.


Autosomal dominant growth hormone deficiency disrupts secretory vesicles in vitro and in vivo in transgenic mice.
Autosomal dominant GH deficiency type II (IGHDII) is often associated with mutations in the human GH gene (GH1) that give rise to products lacking exon-3 ((Deltaexon3)hGH). In the heterozygous state, these act as dominant negative mutations that prevent the release of human pituitary GH (hGH). To determine the mechanisms of these dominant negative effects, we used a combination of transgenic and morphological approaches in both in vitro and in vivo models. Rat GC cell lines were generated expressing either wild-type GH1 (WT-hGH-GC) or a genomic GH1 sequence containing a G->A transition at the donor splice site of IVS3 ((Deltaexon3)hGH-GC). WT-hGH-GC cells grew normally and produced equivalent amounts of human and rGH packaged in dense-cored secretory vesicles (SVs). In contrast, (Deltaexon3)hGH-GC cells showed few SVs but accumulated secretory product in amorphous cytoplasmic aggregates. They produced much less rGH and grew more slowly than WT-hGH-GC cells. When cotransfected with an enhanced green fluorescent protein construct (GH-eGFP), which copackages with GH in SVs, WT-hGH-GC cells showed normal electron microscopy morphology and SV movements, tracked with total internal reflectance fluorescence microscopy. In contrast, coexpression of (Deltaexon3)hGH with GH-eGFP abolished the vesicular targeting of GH-eGFP, which instead accumulated in static aggregates. Transgenic mice expressing (Deltaexon3)hGH in somatotrophs showed an IGHD-II phenotype with mild to severe pituitary hypoplasia and dwarfism, evident at weaning in the most severely affected lines. Hypothalamic GHRH expression was up-regulated and somatostatin expression reduced in (Deltaexon3)hGH transgenic mice, consistent with their profound GHD. Few SVs were detectable in the residual pituitary somatotrophs in (Deltaexon3)hGH transgenic mice, and these cells showed grossly abnormal morphology. A low copy number transgenic line showed a mild effect relatively specific for GH, whereas two severely affected lines with higher transgene copy numbers showed early onset, widespread pituitary damage, macrophage invasion, and multiple hormone deficiencies. These new in vitro and in vivo models shed new light on the cellular mechanisms involved in IGHDII, as well as its phenotypic consequences in vivo.


Galectin-3 deficiency reduces the severity of experimental autoimmune encephalomyelitis.
Galectin-3 (Gal-3) is a member of the beta-galactoside-binding lectin family and plays an important role in inflammation. However, the precise role of Gal-3 in autoimmune diseases remains obscure. We have investigated the functional role of Gal-3 in experimental autoimmune encephalomyelitis (EAE) following immunization with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide. Gal-3 deficient (Gal-3-/-) mice developed significantly milder EAE and markedly reduced leukocyte infiltration in the CNS compared with similarly treated wild-type (WT) mice. Gal-3-/- mice also contained fewer monocytes and macrophages but more apoptotic cells in the CNS than did WT mice. Following Ag stimulation in vitro, lymph node cells from the immunized Gal-3-/- mice produced less IL-17 and IFN-gamma than did those of the WT mice. In contrast, Gal-3-/- mice produced more serum IL-10, IL-5, and IL-13 and contained higher frequency of Foxp3+ regulatory T cells in the CNS than did the WT mice. Furthermore, bone marrow-derived dendritic cells from Gal-3-/- mice produced more IL-10 in response to LPS or bacterial lipoprotein than did WT marrow-derived dendritic cells. Moreover, Gal-3-/- dendritic cells induced Ag-specific T cells to produce more IL-10, IL-5, and IL-12, but less IL-17, than did WT dendritic cells. Taken together, our data demonstrate that Gal-3 plays an important disease-exacerbating role in EAE through its multifunctional roles in preventing cell apoptosis and increasing IL-17 and IFN-gamma synthesis, but decreasing IL-10 production.


Permanent lymphoid lines from genetically marked lymphocytes: success with lymphocytes recovered from frozen storage.
Permanent human lymphoid cell lines were established successfully from peripheral blood lymphocytes which had been separated for HL-A typing and stored in liquid nitrogen for two years. Frozen lymphocytes were chosen from two siblings who were homozygous at the LA and FOUR HL-A loci. Thawed lymphocytes were transformed with EB virus produced by the marmoset lymphoid line B95-8. No chromosome abnormalities were seen on karyotypes prepared on cells from the established human lymphoid lines using G and Q banding techniques. HL-A typing showed the expected HL-A antigens plus a considerable number of additional reactions. Separation of lymphocytes and freezing them for possible future use requires a relatively small investment. This method of preserving cells can be applied to patients with interesting genetic disorders or other biochemical markers to provide cells which can be transformed and propagated years later.


Repeated exposure to neurotoxic levels of chlorpyrifos alters hippocampal expression of neurotrophins and neuropeptides.
Chlorpyrifos (CPF), an organophosphorus pesticide (OP), is one of the most widely used pesticides in the world. Subchronic exposures to CPF that do not cause cholinergic crisis are associated with problems in cognitive function (i.e., learning and memory deficits), but the biological mechanism(s) underlying this association remain speculative. To identify potential mechanisms of subchronic CPF neurotoxicity, adult male Long Evans (LE) rats were administered CPF at 3 or 10mg/kg/d (s.c.) for 21 days. We quantified mRNA and non-coding RNA (ncRNA) expression profiles by RNA-seq, microarray analysis and small ncRNA sequencing technology in the CA1 region of the hippocampus. Hippocampal slice immunohistochemistry was used to determine CPF-induced changes in protein expression and localization patterns. Neither dose of CPF caused overt clinical signs of cholinergic toxicity, although after 21 days of exposure, cholinesterase activity was decreased to 58% or 13% of control levels in the hippocampus of rats in the 3 or 10mg/kg/d groups, respectively. Differential gene expression in the CA1 region of the hippocampus was observed only in the 10mg/kg/d dose group relative to controls. Of the 1382 differentially expressed genes identified by RNA-seq and microarray analysis, 67 were common to both approaches. Differential expression of six of these genes (Bdnf, Cort, Crhbp, Nptx2, Npy and Pnoc) was verified in an independent CPF exposure study; immunohistochemistry demonstrated that CRHBP and NPY were elevated in the CA1 region of the hippocampus at 10mg/kg/d CPF. Gene ontology enrichment analysis suggested association of these genes with receptor-mediated cell survival signaling pathways. miR132/212 was also elevated in the CA1 hippocampal region, which may play a role in the disruption of neurotrophin-mediated cognitive processes after CPF administration. These findings identify potential mediators of CPF-induced neurobehavioral deficits following subchronic exposure to CPF at a level that inhibits hippocampal cholinesterase to less than 20% of control. An equally significant finding is that subchronic exposure to CPF at a level that produces more moderate inhibition of hippocampal cholinesterase (approximately 50% of control) does not produce a discernable change in gene expression.


Low-velocity gunshot injury of the abdominal aorta managed by debridement and re-anastomosis. A case report.
Penetrating injuries to the abdominal aorta are highly lethal despite increasing numbers of reports of successful treatment. A case of survival after a 0,25-calibre gunshot wound of the abdominal aorta is presented. The patient, a young male, also had associated injuries to the liver, stomach and jejunum. He was managed by vigorous resuscitation, emergency laparotomy, aortic debridement and end-to-end re-anastomosis. He was discharged from hospital on the 12th postoperative day.


Register-Based Evaluation of Relative Effectiveness of New Therapies: Biologics Versus Conventional Agents in Treatment of Psoriasis in Sweden.
The Swedish National Register for Systemic Treatment of Psoriasis (PsoReg) was established in 2006. This article analyzes the implementation phase of biologics in the treatment of moderate to severe psoriasis in Sweden in the period 2006-2012. Clinical studies have shown efficacy of biologic agents in psoriasis, but their relative effectiveness in real-world clinical practice has rarely been studied. To estimate the incremental changes in clinical health-related quality-of-life measures in patients receiving biologics versus conventional systemic agents. Patients fulfilling the clinical criteria for moderate to severe psoriasis were included. Average treatment effects were estimated from longitudinal data as incremental changes in: (1) the Psoriasis Area and Severity Index (PASI) score, (2) the Dermatology Life Quality Index (DLQI) score, and (3) the EQ-5D score, by matching patients switching to biologics with patients remaining on conventional systemic agents. The study included 239 biologic-treated patients and 378 conventionally treated patients. The matched patient groups were essentially equivalent in terms of important patient characteristics. The average treatment effects of biologics versus conventional systemic agents were 2.2 for PASI, 3.5 for DLQI, and 0.11 for EQ-5D. The estimated incremental benefits of biologics for the subgroup of patients not responding to their conventional systemic agent were even greater. Register-based research complements knowledge from randomized controlled trials regarding relative effectiveness in clinical practice. This information can be used to support health care decision making. This research suggests that there is both under- and overtreatment with biologics in Swedish clinical practice. Reallocation of biologics to more severe cases of psoriasis could improve overall health in the total patient population.


Pre-registration nursing students' experience of caring for cancer patients.
The preparation of nurses caring for cancer patients remains a topical subject. The recent emphasis on the preparation of an effective and informed workforce for cancer care at all nursing levels is significant, particularly as the majority of previous studies have traditionally focused on post-registration preparation of qualified nurses. Currently, there is limited information on the preparation of pre-registered nursing students and little is known about the experiences of these students, especially during their initial exposure to cancer patients. Recently, changes have also been made to the pre-registration nursing programmes in the UK in line with national recommendations leading to much earlier exposures to patient care in practice. This study provides information about nursing students' experiences of caring for cancer patients. Using self-report questionnaires each comprising of 21 Likert scale items, a survey was conducted on a total of 134 students (response rate: 88%) enrolled on the common foundation programme at the end of the first year of their undergraduate nursing programme. Data collected included information about the types of clinical settings where students were exposed to cancer patients, perceptions of their experiences with cancer patients and aspects of educational and clinical inputs perceived as helpful in preparing them to care for cancer patients. Additional insight into the students' experience was further obtained from semi-structured interviews conducted from a total of nine students drawn from the three categories of experiences they identified: positive, non-positive and mixed. The findings and implications for the preparation of pre-registration nursing students in caring for cancer patients were discussed in relation to the theoretical input, clinical support and the use of reflection in practice.


Treatment of ventilator-associated pneumonia and ventilator-associated tracheobronchitis in the intensive care unit. A national survey of clinicians and pharmacists in Saudi Arabia.
To assess current practices of different healthcare providers for treating extensively drug-resistant (XDR) Acinetobacter baumannii (AB) infections in tertiary-care centers in Saudi Arabia. This cross-sectional study was performed in tertiary-care centers of Saudi Arabia between March and June 2014. A questionnaire consisting of 3 parts (respondent characteristics; case scenarios on ventilator-associated pneumonia [VAP] and tracheobronchitis [VAT], and antibiotic choices in each scenario) was developed and sent electronically to participants in 34 centers across Saudi Arabia. One-hundred and eighty-three respondents completed the survey. Most of the respondents (54.6%) preferred to use colistin-based combination therapy to treat VAP caused by XDR AB, and 62.8% chose to continue treatment for 2 weeks. Most of the participants (80%) chose to treat VAT caused by XDR AB with intravenous antibiotics. A significant percentage of intensive care unit (ICU) fellows (41.3%) and clinical pharmacists (35%) opted for 2 million units (mu) of colistin every 8 hours without a loading dose, whereas 60% of infectious disease consultants, 45.8% of ICU consultants, and 44.4% of infectious disease fellows preferred a 9 mu loading dose followed by 9 mu daily in divided doses. The responses for the scenarios were different among healthcare providers (p less than 0.0001). Most of the respondents in our survey preferred to use colistin-based combination therapy and intravenous antibiotics to treat VAP and VAT caused by XDR AB. However, colistin dose and duration varied among the healthcare providers.


Automobile traffic around the home and attained body mass index: a longitudinal cohort study of children aged 10-18 years.
The objective of this study is to examine the relationship between measured traffic density near the homes of children and attained body mass index (BMI) over an eight-year follow up. Children aged 9-10 years were enrolled across multiple communities in Southern California in 1993 and 1996 (n=3318). Children were followed until age 18 or high school graduation to collect longitudinal information, including annual height and weight measurements. Multilevel growth curve models were used to assess the association between BMI levels at age 18 and traffic around the home. For traffic within 150 m around the child's home, there were significant positive associations with attained BMI for both sexes at age 18. With the 300 m traffic buffer, associations for both male and female growth in BMI were positive, but significantly elevated only in females. These associations persisted even after controlling for numerous potential confounding variables. This analysis yields the first evidence of significant effects from traffic density on BMI levels at age 18 in a large cohort of children. Traffic is a pervasive exposure in most cities, and our results identify traffic as a major risk factor for the development of obesity in children.


Isotopic composition of old ground water from lake agassiz: implications for late pleistocene climate.
A uniform oxygen isotope value of -25 per mil was obtained from old ground water at depths of 20 to 30 meters in a thick deposit of clay in the southern part of the glacial Lake Agassiz basin. The lake occupied parts of North Dakota and southern Manitoba at the end of the last glacial maximum and received water from the ice margin and the interior plains region of Canada. Ground water from thick late Pleistocene-age clay deposits elsewhere, a till in southern Saskatchewan, and a glaciolacustrine deposit in northern Ontario show the same value at similar depths. These sites are at about 50 degrees N latitude, span a distance of 2000 kilometers, and like the Lake Agassiz sites, have a ground-water velocity of less than a few millimeters per year. The value of -25 per mil is characteristic of meltwater impounded in the southern basin of Lake Agassiz. This value corresponds to an estimated air temperature of -16 degrees C, compared with the modern temperature of 0 degrees C for this area.


Numerical study of thermoviscous effects in ultrasound-induced acoustic streaming in microchannels.
We present a numerical study of thermoviscous effects on the acoustic streaming flow generated by an ultrasound standing-wave resonance in a long straight microfluidic channel containing a Newtonian fluid. These effects enter primarily through the temperature and density dependence of the fluid viscosity. The resulting magnitude of the streaming flow is calculated and characterized numerically, and we find that even for thin acoustic boundary layers, the channel height affects the magnitude of the streaming flow. For the special case of a sufficiently large channel height, we have successfully validated our numerics with analytical results from 2011 by Rednikov and Sadhal for a single planar wall. We analyzed the time-averaged energy transport in the system and the time-averaged second-order temperature perturbation of the fluid. Finally, we have made three main changes in our previously published numerical scheme to improve the numerical performance: (i) The time-averaged products of first-order variables in the time-averaged second-order equations have been recast as flux densities instead of as body forces. (ii) The order of the finite-element basis functions has been increased in an optimal manner. (iii) Based on the International Association for the Properties of Water and Steam (IAPWS 1995, 2008, and 2011), we provide accurate polynomial fits in temperature for all relevant thermodynamic and transport parameters of water in the temperature range from 10 to 50 °C.


Estimating liver perfusion from free-breathing continuously acquired dynamic gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced acquisition with compressed sensing reconstruction.
The purpose of this study was to estimate perfusion metrics in healthy and cirrhotic liver with pharmacokinetic modeling of high-temporal resolution reconstruction of continuously acquired free-breathing gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced acquisition in patients undergoing clinically indicated liver magnetic resonance imaging. In this Health Insurance Portability and Accountability Act-compliant prospective study, 9 cirrhotic and 10 noncirrhotic patients underwent clinical magnetic resonance imaging, which included continuously acquired radial stack-of-stars 3-dimensional gradient recalled echo sequence with golden-angle ordering scheme in free breathing during contrast injection. A total of 1904 radial spokes were acquired continuously in 318 to 340 seconds. High-temporal resolution data sets were formed by grouping 13 spokes per frame for temporal resolution of 2.2 to 2.4 seconds, which were reconstructed using the golden-angle radial sparse parallel technique that combines compressed sensing and parallel imaging. High-temporal resolution reconstructions were evaluated by a board-certified radiologist to generate gadolinium concentration-time curves in the aorta (arterial input function), portal vein (venous input function), and liver, which were fitted to dual-input dual-compartment model to estimate liver perfusion metrics that were compared between cirrhotic and noncirrhotic livers. The cirrhotic livers had significantly lower total plasma flow (70.1 ± 10.1 versus 103.1 ± 24.3 mL/min per 100 mL; P < 0.05), lower portal venous flow (33.4 ± 17.7 versus 89.9 ± 20.8 mL/min per 100 mL; P < 0.05), and higher arterial perfusion fraction (52.0% ± 23.4% versus 12.4% ± 7.1%; P < 0.05). The mean transit time was higher in the cirrhotic livers (24.4 ± 4.7 versus 15.7 ± 3.4 seconds; P < 0.05), and the hepatocellular uptake rate was lower (3.03 ± 2.1 versus 6.53 ± 2.4 100/min; P < 0.05). Liver perfusion metrics can be estimated from free-breathing dynamic acquisition performed for every clinical examination without additional contrast injection or time. This is a novel paradigm for dynamic liver imaging.


Whole-body Magnetic Resonance Imaging in Inflammatory Arthritis: Systematic Literature Review and First Steps Toward Standardization and an OMERACT Scoring System.
Whole-body magnetic resonance imaging (WB-MRI) is a relatively new technique that can enable assessment of the overall inflammatory status of people with arthritis, but standards for image acquisition, definitions of key pathologies, and a quantification system are required. Our aim was to perform a systematic literature review (SLR) and to develop consensus definitions of key pathologies, anatomical locations for assessment, a set of MRI sequences and imaging planes for the different body regions, and a preliminary scoring system for WB-MRI in inflammatory arthritis. An SLR was initially performed, searching for WB-MRI studies in arthritis, osteoarthritis, spondyloarthritis, or enthesitis. These results were presented to a meeting of the MRI in Arthritis Working Group together with an MR image review. Following this, preliminary standards for WB-MRI in inflammatory arthritides were developed with further iteration at the Working Group meetings at the Outcome Measures in Rheumatology (OMERACT) 2016. The SLR identified 10 relevant original articles (7 cross-sectional and 3 longitudinal, mostly focusing on synovitis and/or enthesitis in spondyloarthritis, 4 with reproducibility data). The Working Group decided on inflammation in peripheral joints and entheses as primary focus areas, and then developed consensus MRI definitions for these pathologies, selected anatomical locations for assessment, agreed on a core set of MRI sequences and imaging planes for the different regions, and proposed a preliminary scoring system. It was decided to test and further develop the system by iterative multireader exercises. These first steps in developing an OMERACT WB-MRI scoring system for use in inflammatory arthritides offer a framework for further testing and refinement.


Nonviral oncogenic antigens and the inflammatory signals driving early cancer development as targets for cancer immunoprevention.
Cancer immunoprevention is an emerging field that holds much promise. Within the past 20 years, prophylactic vaccines have been implemented on the population level for the immunoprevention of carcinomas induced by viruses, specifically hepatitis B virus (HBV) and human papillomavirus (HPV) infection. Armed with the success of prophylactic vaccines that prevent viral-induced tumors, the field must overcome its next hurdle: to develop robust prophylactic vaccines that prevent the remaining >80% of human cancers not induced by viral infection. In this review, we discuss some of the most promising non-virus-associated prophylactic vaccines that target endogenous neoantigens, including the earliest oncogene products, altered mucin 1 (MUC1) and α-enolase (ENO1), all of which produce new targets in the earliest stages of nonviral-induced tumorigenesis. We also highlight a novel attenuated Listeria monocytogenes-based vaccine expressing mutant oncogene Kras(G12D) (LM-Kras) effective in a pancreatic cancer model. A novel chimeric human/rat HER-2 plasmid vaccine (HuRT-DNA vaccine) effective in a breast cancer model is also discussed. In addition to prophylactic vaccine developments, this review highlights the potential use of classic drugs, such as aspirin and metformin, as chemopreventive agents that can potentially be used as adjuvants to enhance the anticancer immunogenicity and efficacy of noninfectious prophylactic vaccines by modulating the inflammatory pathways within the early tumor microenvironment (TME) that propels tumorigenesis. Finally, timing of prophylactic vaccine administration is critical to its immunopreventive efficacy, providing a necessary role of current and emerging biomarkers for cancer screening and early cancer detection.


The structure of the extended psychosis phenotype in early adolescence--a cross-sample replication.
The extended psychosis phenotype, or the expression of nonclinical positive psychotic experiences, is already prevalent in adolescence and has a dose-response risk relationship with later psychotic disorder. In 2 large adolescent general population samples (n = 5422 and n = 2230), prevalence and structure of the extended psychosis phenotype was investigated. Positive psychotic experiences, broadly defined, were reported by the majority of adolescents. Exploratory analysis with Structural Equation Modelling (Exploratory Factor Analysis followed by Confirmatory Factor Analysis [CFA]) in sample 1 suggested that psychotic experiences were best represented by 5 underlying dimensions; CFA in sample 2 provided a replication of this model. Dimensions were labeled Hallucinations, Delusions, Paranoia, Grandiosity, and Paranormal beliefs. Prevalences differed strongly, Hallucinations having the lowest and Paranoia having the highest rates. Girls reported more experiences on all dimensions, except Grandiosity, and from age 12 to 16 years rates increased. Hallucinations, Delusions, and Paranoia, but not Grandiosity and Paranormal beliefs, were associated with distress and general measures of psychopathology. Thus, only some of the dimensions of the extended psychosis phenotype in young people may represent a continuum with more severe psychopathology and predict later psychiatric disorder.


Periodontitis associated bacteria in supragingival plaque of dental hygienists: stability of carrier state and clinical development.
The purpose of this study was the clinical and microbiological re-examination of dental hygienists, who, 30 months before, had shown remarkably high supragingival levels of periodontitis-associated micro-organisms. Interdental plaque was collected from the same molar sites and investigated by the same immunofluorescence assay with taxa-specific monoclonal antibodies as at the initial examination. On average, the 15 re-examined subjects showed slightly increased plaque levels but unchanged bleeding on probing scores (0.3-1.4). Pocket formation was restricted to a single subject. Prevotella intermedia/P. nigrescens and Peptostreptococcus micros were present in every plaque sample. Prevalences of Actinobacillus actinomycetemcomitans, Bacteroides forsythus and Campylobacter rectus were again between 20-40%, but some fluctuation within subjects was noted. The data confirm supragingival plaque as a natural habitat for periodontitis-associated bacteria in periodontially healthy persons, and indicate that colonization with A. actinomycetemcomitans, B. forsythus or C. rectus is mostly stable in spite of better than average personal plaque control.


The hydrolysis and biogas production of complex cellulosic substrates using three anaerobic biomass sources.
In this study, the ability of various sludges to digest a diverse range of cellulose and cellulose-derived substrates was assessed at different temperatures to elucidate the factors affecting hydrolysis. For this purpose, the biogas production was monitored and the specific biogas activity (SBA) of the sludges was employed to compare the performance of three anaerobic sludges on the degradation of a variety of complex cellulose sources, across a range of temperatures. The sludge with the highest performance on complex substrates was derived from a full-scale bioreactor treating sewage at 37 °C. Hydrolysis was the rate-limiting step during the degradation of complex substrates. No activity was recorded for the synthetic cellulose compound carboxymethylcellulose (CMC) using any of the sludges tested. Increased temperature led to an increase in hydrolysis rates and thus SBA values. The non-granular nature of the mesophilic sludge played a positive role in the hydrolysis of solid substrates, while the granular sludges proved more effective on the degradation of soluble compounds.


Moral Enhancement Meets Normative and Empirical Reality: Assessing the Practical Feasibility of Moral Enhancement Neurotechnologies.
Moral enhancement refers to the possibility of making individuals and societies better from a moral standpoint. A fierce debate has emerged about the ethical aspects of moral enhancement, notably because steering moral enhancement in a particular direction involves choosing amongst a wide array of competing options, and these options entail deciding which moral theory or attributes of the moral agent would benefit from enhancement. Furthermore, the ability and effectiveness of different neurotechnologies to enhance morality have not been carefully examined. In this paper, we assess the practical feasibility of moral enhancement neurotechnologies. We reviewed the literature on neuroscience and cognitive science models of moral judgment and analyzed their implications for the specific target of intervention (cognition, volition or affect) in moral enhancement. We also reviewed and compared evidence on available neurotechnologies that could serve as tools of moral enhancement. We conclude that the predictions of rationalist, emotivist, and dual process models are at odds with evidence, while different intuitionist models of moral judgment are more likely to be aligned with it. Furthermore, the project of moral enhancement is not feasible in the near future as it rests on the use of neurointerventions, which have no moral enhancement effects or, worse, negative effects.


Measurement variability of plasma beta-sitosterol and campesterol, two new biomarkers for cancer prevention.
Phytosterols are plant sterols that are structurally similar to cholesterol and are characterized by anti-carcinogenic and anti-atherogenic properties. Beta-sitosterol and campesterol are the predominant phytosterols in blood. The present study aimed to analyse the reproducibility and overtime reliability of plasma beta-sitosterol and campesterol measurements. In order to study the reproducibility of the measurement (technical variability), three healthy premenopausal women donated a sample of their blood. Each blood sample was subdivided into six aliquots and analysed within the same run by the same laboratory technician. The intraclass correlation coefficients (ICCs) of the assay for plasma beta-sitosterol and campesterol were 0.88 and 0.94 (95% confidence intervals low bounds (95% CI(low)) were 0.66 and 0.82), respectively. To study the reliability of beta-sitosterol and campesterol measurement over time, seven premenopausal women were recruited. Over a 6-month period, each woman provided a fasting blood sample once a month at the same time of day, and the same numerical day of the luteal phase of her menstrual cycle (between the 20th and 24th day of her menstrual cycle). All plasma samples from the same individual were processed together at the same time by the same technician at the end of the 6-month period. The overtime ICCs of plasma beta-sitosterol and campesterol were 0.91 (95% CI(low) 0.49) and 0.58 (95% CI(low) 0.31), respectively. The high reproducibility and good overtime reliability of plasma beta-sitosterol and campesterol measurements indicate that they may be suitable for potential clinical and population-based studies on cancer prevention.


Electrospun nerve guide scaffold of poly(ε-caprolactone)/collagen/nanobioglass: an in vitro study in peripheral nerve tissue engineering.
Among various methods, nerve tissue engineering (NTE) is one of the applicable methods to reconstruct damaged nerve tissues. Electrospinning technique and biomaterials are often considered to fabricate fibrous tissue engineered conduits which have great similarity to the extracellular matrix on fiber structure. Polymer blending is one of the most effective methods for the production of new materials with outstanding features. In this study, conduit structures as main part of the peripheral nerve regeneration based on polymer blend nanocomposites poly(ε-caprolactone)/collagen/nanobioglass (PCL/collagen/NBG) were manufactured by electrospinning technique. Various properties of electrospun mats were investigated by using contact angle, tensile, degradation time, porosity, scanning electron microscopy (SEM), Fourier-transform infrared (FTIR), and wide-angle X-ray scattering (WAXS). The SEM analysis was shown that size range and average pore size of polymer blend nanocomposite nanofibers were about 250-400 nm and 0.7 µm, respectively, with an optimum porosity of 62.5%. The XRD result was shown that synthesized nanoparticles of NBG had amorphous structures. Also, FTIR analysis indicated that good interaction between polymer-polymer macromolecules and polymer particles. The contact angle and tensile tests were indicated that electrospun webs showed good hydrophilicity and toughness properties. According to SEM, MTT assay and DAPI staining technique, the ability to support cell attachment and viability of samples were characterized. In vitro study indicated electrospun collagen/PCL/NBG nanofibrous conduit promoted Human Endometrial Stem cells (hEnSCs) adhesion and proliferation. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1960-1972, 2017.


Interleukin-7 influences FOXP3+CD4+ regulatory T cells peripheral homeostasis.
Mechanisms governing peripheral CD4+ FOXP3+ regulatory T cells (Treg) survival and homeostasis are multiple suggesting tight and complex regulation of regulatory T cells homeostasis. Some specific factors, such as TGF-β, interleukin-2 (IL-2) and B7 costimulatory molecules have been identified as essentials for maintenance of the peripheral Treg compartment. Conversely, Treg dependency upon classical T cell homeostatic factors such as IL-7 is still unclear. In this work, we formally investigated the role of IL-7 in Treg homeostasis in vivo in murine models. We demonstrated that IL-7 availability regulated the size of peripheral Treg cell pool and thus paralleled the impact of IL-7 on conventional T cell pool. Moreover, we showed that IL-7 administration increased Treg cell numbers by inducing thymic-independent Treg peripheral expansion. Importantly the impact of IL-7 on Treg expansion was detected whether conventional T cells were present or absent as IL-7 directly participates to the peripheral expansion of Treg after adoptive transfer into lymphopenic hosts. Our results definitively identify IL-7 as a central factor contributing to Treg peripheral homeostasis, thus reassembling Treg to other T cell subsets in respect of their need for IL-7 for their peripheral maintenance.


Prognostic significance of circumferential resection margin involvement following oesophagectomy for cancer.
The factors affecting long-term survival following oesophagectomy for oesophageal cancer are poorly understood. We examined the significance of microscopic tumour involvement at the circumferential resection margin (CRM) on postoperative survival following oesophagectomy. The case notes of 329 patients who underwent a potentially curative oesophagectomy for squamous or adenocarcinoma were reviewed retrospectively. As part of the procedure, all patients underwent an en-bloc resection of their periesophageal tissue. The presence of tumour either at, or within, 1 mm of the CRM was recorded and correlated with their TNM and survival data. A total of 67 patients (20%) were noted to have a positive CRM, of which 40 cases (12%) had tumour at the resection margin and the remainder had tumour within 1 mm of the margin. Univariate analysis showed no statistically significant association between survival and either category of CRM involvement. Multivariate analysis showed that only T-stage, nodal status and tumour grade were prognostic markers. In conclusion, the presence of microscopic tumour at the CRM following an en-bloc oesophagectomy is not a significant prognostic marker.


Changes in Cardiac Varices and Their Clinical Significance after Eradication of Esophageal Varices by Band Ligation.
Background and Aims. Cardiac varices (CVs) in patients with type 1 gastroesophageal varices (GOV1s) usually disappear with treatment for esophageal varices (EVs) by endoscopic injection sclerotherapy (EIS). However, whether this applies to patients treated with endoscopic band ligation (EBL) for EVs remains unclear. We evaluated the effect of EVs eradication by EBL on CVs. Methods. We included cirrhotic patients whose EVs had been eradicated using EBL and excluded those who had been treated using EIS, those who had received endoscopic therapy for CVs, and those who were combined with hepatocellular carcinoma. Results. A total of 123 patients were enrolled. The age was 59.7 ± 11.7 years, and 96 patients (78.0%) were men. Thirty-eight patients (30.9%) had EVs only, while 85 (69.1%) had GOV1s. After EVs eradication, the CVs disappeared in 55 patients (64.7%). EVs recurred in 40 patients, with recurrence rates at 1, 2, and 3 years of 16.0%, 29.6%, and 35.6%, respectively, the recurrence being more frequent in patients who had undergone EBL for secondary prophylaxis and in those with persisting CVs after EVs eradication (P = 0.003). Conclusions. CVs frequently disappeared when EVs were eradicated using EBL in patients with GOV1s. Persistence of CVs after EVs eradication by EBL was associated with EVs recurrence.


NCI in vitro and in silico anticancer screen, cell cycle pertubation and apoptosis-inducing potential of new acylated, benzylidene and isopropylidene derivatives of andrographolide.
Andrographolide (AGP) is the main bioactive constituent isolated from the traditional medicinal, Andrographis paniculata which contributes towards its various biological activities, including anticancer property. In this study, a series of new AGP derivatives were semi-synthesised and screened against the NCI in vitro 60 cell lines. From the screening results, we had identified SRS07 as the most potent AGP derivative, against breast and colon cancer cell lines. Subsequently, SRS07 was tested for its capability to induce cell cycle arrest and apoptosis in MCF-7 and HCT116 cancer cells. SRS07 effectively induced G1 cell cycle arrest in both cell lines and ultimately apoptosis by inducing DNA fragmentation in HCT116 cells. The apoptotic cell death induced by SRS07 was confirmed via FITC Annexin-V double staining. Western blot analysis of SRS07-treated HCT116 cells revealed that the compound induced apoptosis be activating caspase 8 which in turn cleaved Bid to t-Bid to initiate cell death cascade. Prediction of the possible mode of action of SRS07 by utilising NCI COMPARE analysis failed to reveal a distinct mechanism category. Hence, it is speculated that SRS07 possesses novel mechanism of action. In conclusion, SRS07 demonstrated superior in vitro anticancer profiles and emerged as a potential lead anticancer candidate.


Antibacterial activities of flavonoids: structure-activity relationship and mechanism.
Flavonoids are well known as antibacterial agents against a wide range of pathogenic microorganism. With increasing prevalence of untreatable infections induced by antibiotic resistance bacteria, flavonoids have attracted much interest because of the potential to be substitutes for antibiotics. In this review, the structure-relationship of flavonoids as antibacterial agents is summarized, and the recent advancements on the antibacterial mechanisms of flavonoids are also discussed. It is concluded that hydroxyls at special sites on the aromatic rings of flavonoids improve the activity. However, the methylation of the active hydroxyl groups generally decreases the activity. Besides, the lipopholicity of the ring A is vital for the activity of chalcones. The hydrophobic substituents such as prenyl groups, alkylamino chains, alkyl chains, and nitrogen or oxygen containing heterocyclic moieties usually enhance the activity for all the flavonoids. The proposed antibacterial mechanisms of flavonoids are as follows: inhibition of nucleic acid synthesis, inhibition of cytoplasmic membrane function, inhibition of energy metabolism, inhibition of the attachment and biofilm formation, inhibition of the porin on the cell membrane, alteration of the membrane permeability, and attenuation of the pathogenicity.


Setting of import tolerances, modification of existing maximum residue levels and evaluation of confirmatory data following the Article 12 MRL review for flupyradifurone and DFA.
In accordance with Article 6 of Regulation (EC) No 396/2005, the applicants Bayer CropScience AG and Bayer SAS submitted two requests to the competent national authority in the Netherlands to set import tolerances and to modify existing EU maximum residue levels (MRLs) for the active substance flupyradifurone and its metabolite difluoroacetic acid (DFA) in various crops. The application also included the request to evaluate the confirmatory data related to residues that were identified in the framework of the peer review of flupyradifurone under Regulation (EC) No 1107/2009 as not available. The data submitted in support of intended and authorised uses were found to be sufficient to derive MRL proposals for flupyradifurone and DFA in all crops under consideration except for prickly pear and hops; for grapefruit, pome fruits, grape leaves and witloof, further risk management discussion is recommended to decide on the appropriate MRL. Furthermore, EFSA recommended risk management discussion to examine different options to deal with DFA residues in crops that can be grown in crop rotation. The calculated livestock dietary burdens indicated that existing EU MRLs for flupyradifurone and DFA in animal commodities need to be modified. Adequate analytical methods for enforcement are available to control the residues of flupyradifurone and the DFA in plant and animal matrices. The submitted data are considered sufficient to address the data gaps related to residues which were identified in the framework of the EU pesticides peer review, and thus, the footnotes set for DFA and flupyradifurone MRLs in the Commission Regulation (EU) 2016/1902 can be deleted. Based on the consumer exposure assessment, acute consumer exposure concerns could not be excluded for tomatoes, melons, celery and processed escaroles. Hence, the raising of the existing MRLs for flupyradifurone in these crops is not recommended. For these four crops, MRL proposals for DFA were derived, which reflect the uptake of residues via soil resulting from previous use of flupyradifurone. For the remaining commodities of plant and animal origin, EFSA concludes that the intended EU uses and authorised US and Canadian uses of flupyradifurone and resulting residues of DFA will not result in chronic or acute consumer exposure exceeding the toxicological reference values and therefore is unlikely to pose a risk to consumers' health.


Evaluating the risk of ovarian cancer before surgery using the ADNEX model to differentiate between benign, borderline, early and advanced stage invasive, and secondary metastatic tumours: prospective multicentre diagnostic study.
To develop a risk prediction model to preoperatively discriminate between benign, borderline, stage I invasive, stage II-IV invasive, and secondary metastatic ovarian tumours. Observational diagnostic study using prospectively collected clinical and ultrasound data. 24 ultrasound centres in 10 countries. Women with an ovarian (including para-ovarian and tubal) mass and who underwent a standardised ultrasound examination before surgery. The model was developed on 3506 patients recruited between 1999 and 2007, temporally validated on 2403 patients recruited between 2009 and 2012, and then updated on all 5909 patients. Histological classification and surgical staging of the mass. The Assessment of Different NEoplasias in the adneXa (ADNEX) model contains three clinical and six ultrasound predictors: age, serum CA-125 level, type of centre (oncology centres v other hospitals), maximum diameter of lesion, proportion of solid tissue, more than 10 cyst locules, number of papillary projections, acoustic shadows, and ascites. The area under the receiver operating characteristic curve (AUC) for the classic discrimination between benign and malignant tumours was 0.94 (0.93 to 0.95) on temporal validation. The AUC was 0.85 for benign versus borderline, 0.92 for benign versus stage I cancer, 0.99 for benign versus stage II-IV cancer, and 0.95 for benign versus secondary metastatic. AUCs between malignant subtypes varied between 0.71 and 0.95, with an AUC of 0.75 for borderline versus stage I cancer and 0.82 for stage II-IV versus secondary metastatic. Calibration curves showed that the estimated risks were accurate. The ADNEX model discriminates well between benign and malignant tumours and offers fair to excellent discrimination between four types of ovarian malignancy. The use of ADNEX has the potential to improve triage and management decisions and so reduce morbidity and mortality associated with adnexal pathology.


A prospective study assessing the effects of introducing the female condom in a sex worker population in Mombasa, Kenya.
To assess the impact and costs of adding female condoms to a male condom promotion and distribution peer education programme for sex workers in Mombasa, Kenya. A 12 month, prospective study of 210 female sex workers. We interviewed participants about their sexual behaviour every 2 months for a total of seven times and introduced female condoms after the third interview. We also collected cost data and calculated the cost and cost effectiveness of adding the female condom component to the existing programme. Introduction of the female condom in an HIV/AIDS prevention project targeting sex workers led to small, but significant, increases in consistent condom use with all sexual partners. However, there was a high degree of substitution of the female condom for male condoms. The cost per additional consistent condom user at a programme level is estimated to be 2160 dollars (1169 pounds sterling, 1711 euros) (95% CI: 1338 to 11 179). The female condom has some potential for reducing unprotected sex among sex workers. However, given its high cost, and the marginal improvements seen here, governments should limit promotion of the female condom in populations that are already successfully using the male condom. More research is needed to identify effective methods of encouraging sex workers to practise safer sex with their boyfriends.


Postexertional malaise in women with chronic fatigue syndrome.
Postexertional malaise (PEM) is a defining characteristic of chronic fatigue syndrome (CFS) that remains a source of some controversy. The purpose of this study was to explore the effects of an exercise challenge on CFS symptoms from a patient perspective. This study included 25 female CFS patients and 23 age-matched sedentary controls. All participants underwent a maximal cardiopulmonary exercise test. Subjects completed a health and well-being survey (SF-36) 7 days postexercise. Subjects also provided, approximately 7 days after testing, written answers to open-ended questions pertaining to physical and cognitive responses to the test and length of recovery. SF-36 data were compared using multivariate analyses. Written questionnaire responses were used to determine recovery time as well as number and type of symptoms experienced. Written questionnaires revealed that within 24 hours of the test, 85% of controls indicated full recovery, in contrast to 0 CFS patients. The remaining 15% of controls recovered within 48 hours of the test. In contrast, only 1 CFS patient recovered within 48 hours. Symptoms reported after the exercise test included fatigue, light-headedness, muscular/joint pain, cognitive dysfunction, headache, nausea, physical weakness, trembling/instability, insomnia, and sore throat/glands. A significant multivariate effect for the SF-36 responses (p < 0.001) indicated lower functioning among the CFS patients, which was most pronounced for items measuring physiological function. The results of this study suggest that PEM is both a real and an incapacitating condition for women with CFS and that their responses to exercise are distinctively different from those of sedentary controls.


Predictive ability of a modified Örebro Musculoskeletal Pain Questionnaire in an acute/subacute low back pain working population.
The original 'Örebro Musculoskeletal Pain Questionnaire' (original-ÖMPQ) has been shown to have limitations in practicality, factor structure, face and content validity. This study addressed these concerns by modifying its content producing the 'Örebro Musculoskeletal Screening Questionnaire' (ÖMSQ). The ÖMSQ and original-ÖMPQ were tested concurrently in acute/subacute low back pain working populations (pilot n = 44, main n = 106). The ÖMSQ showed improved face and content validity, which broadened potential application, and improved practicality with two-thirds less missing responses. High reliability (0.975, p < 0.05, ICC: 2.1), criterion validity (Spearman's r = 0.97) and internal consistency (α = 0.84) were achieved, as were predictive ability cut-off scores from ROC curves (112-120 ÖMSQ-points), statistically different ÖMSQ scores (p < 0.001) for each outcome trait, and a strong correlation with recovery time (Spearman's, r = 0.71). The six-component factor structure reflected the constructs originally proposed. The ÖMSQ can be substituted for the original-ÖMPQ in this population. Further research will assess its applicability in broader populations.


Factors Associated with Opioid Use in a Cohort of Patients Presenting for Surgery.
Objectives. Patients taking opioids prior to surgery experience prolonged postoperative opioid use, worse clinical outcomes, increased pain, and more postoperative complications. We aimed to compare preoperative opioid users to their opioid naïve counterparts to identify differences in baseline characteristics. Methods. 107 patients presenting for thoracotomy, total knee replacement, total hip replacement, radical mastectomy, and lumpectomy were investigated in a cross-sectional study to characterize the associations between measures of pain, substance use, abuse, addiction, sleep, and psychological measures (depressive symptoms, Posttraumatic Stress Disorder symptoms, somatic fear and anxiety, and fear of pain) with opioid use. Results. Every 9-point increase in the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) score was associated with 2.37 (95% CI 1.29-4.32) increased odds of preoperative opioid use (p = 0.0005). The SOAPP-R score was also associated with 3.02 (95% CI 1.36-6.70) increased odds of illicit preoperative opioid use (p = 0.007). Also, every 4-point increase in baseline pain at the future surgical site was associated with 2.85 (95% CI 1.12-7.27) increased odds of legitimate preoperative opioid use (p = 0.03). Discussion. Patients presenting with preoperative opioid use have higher SOAPP-R scores potentially indicating an increased risk for opioid misuse after surgery. In addition, legitimate preoperative opioid use is associated with preexisting pain.


The Venus flytrap attracts insects by the release of volatile organic compounds.
Does Dionaea muscipula, the Venus flytrap, use a particular mechanism to attract animal prey? This question was raised by Charles Darwin 140 years ago, but it remains unanswered. This study tested the hypothesis that Dionaea releases volatile organic compounds (VOCs) to allure prey insects. For this purpose, olfactory choice bioassays were performed to elucidate if Dionaea attracts Drosophila melanogaster. The VOCs emitted by the plant were further analysed by GC-MS and proton transfer reaction-mass spectrometry (PTR-MS). The bioassays documented that Drosophila was strongly attracted by the carnivorous plant. Over 60 VOCs, including terpenes, benzenoids, and aliphatics, were emitted by Dionaea, predominantly in the light. This work further tested whether attraction of animal prey is affected by the nutritional status of the plant. For this purpose, Dionaea plants were fed with insect biomass to improve plant N status. However, although such feeding altered the VOC emission pattern by reducing terpene release, the attraction of Drosophila was not affected. From these results it is concluded that Dionaea attracts insects on the basis of food smell mimicry because the scent released has strong similarity to the bouquet of fruits and plant flowers. Such a volatile blend is emitted to attract insects searching for food to visit the deadly capture organ of the Venus flytrap.


In situ sediment treatment using activated carbon: a demonstrated sediment cleanup technology.
This paper reviews general approaches for applying activated carbon (AC) amendments as an in situ sediment treatment remedy. In situ sediment treatment involves targeted placement of amendments using installation options that fall into two general approaches: 1) directly applying a thin layer of amendments (which potentially incorporates weighting or binding materials) to surface sediment, with or without initial mixing; and 2) incorporating amendments into a premixed, blended cover material of clean sand or sediment, which is also applied to the sediment surface. Over the past decade, pilot- or full-scale field sediment treatment projects using AC-globally recognized as one of the most effective sorbents for organic contaminants-were completed or were underway at more than 25 field sites in the United States, Norway, and the Netherlands. Collectively, these field projects (along with numerous laboratory experiments) have demonstrated the efficacy of AC for in situ treatment in a range of contaminated sediment conditions. Results from experimental studies and field applications indicate that in situ sequestration and immobilization treatment of hydrophobic organic compounds using either installation approach can reduce porewater concentrations and biouptake significantly, often becoming more effective over time due to progressive mass transfer. Certain conditions, such as use in unstable sediment environments, should be taken into account to maximize AC effectiveness over long time periods. In situ treatment is generally less disruptive and less expensive than traditional sediment cleanup technologies such as dredging or isolation capping. Proper site-specific balancing of the potential benefits, risks, ecological effects, and costs of in situ treatment technologies (in this case, AC) relative to other sediment cleanup technologies is important to successful full-scale field application. Extensive experimental studies and field trials have shown that when applied correctly, in situ treatment via contaminant sequestration and immobilization using a sorbent material such as AC has progressed from an innovative sediment remediation approach to a proven, reliable technology.