Reporting characteristics of non-primary publications of results of randomized trials: a cross-sectional review.
For a randomized trial, the primary publication is usually the one which reports the results of the primary outcome and provides consolidated data from all study centers. Other aspects of a randomized trial's findings (that is, non-primary results) are often reported in subsequent publications. We carried out a cross-sectional review of the characteristics and type of information reported in non-primary reports (n = 69) of randomized trials (indexed in PubMed core clinical journals in 2009) and whether they report pre-specified or exploratory analyses. We also compared consistency of information in non-primary publications with that reported in the primary publication. The majority (n = 56; 81%) of non-primary publications were large, multicenter trials, published in specialty journals. Most reported subgroup analyses (n = 27; 39%), analyzing a specific subgroup of patients from the randomized trial, or reported on secondary outcomes (n = 29; 42%); 19% (n = 13) reported extended follow-up. Less than half reported details of trial registration (n = 30; 43%) or the trial protocol (n = 27; 39%) and in 41% (n = 28) it was unclear from reading the abstract that the report was not the primary publication for the trial. Non-primary publications often analyzed and reported multiple different outcomes (16% reported >20 outcomes) and in 10% (n = 7) it was unclear how many outcomes had actually been assessed; in 42% (n = 29) it was unclear whether the analyses reported were pre-specified or exploratory. Only 39% (n = 27) of non-primary publications described the primary outcome of the randomized trial, 6% (n = 4) reported its numerical results and 9% (n = 6) details of how participants were randomized. Non-primary publications often lack important information about the randomized trial and the type of analyses conducted and whether these were pre-specified or exploratory to enable readers to accurately identify and assess the validity and reliably of the study findings. We provide recommendations for what information authors should include in non-primary reports of randomized trials.


Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity.
Very preterm infants often require respiratory support and are therefore exposed to an increased risk of bronchopulmonary dysplasia (chronic lung disease) and later neurodevelopmental disability. Caffeine is widely used to prevent and treat apnea (temporal cessation of breathing) associated with prematurity and facilitate extubation. Though widely recognized dosage regimes have been used for decades, higher doses have been suggested to further improve neonatal outcomes. However, observational studies suggest that higher doses may be associated with harm. To determine the effects of higher versus standard doses of caffeine on mortality and major neurodevelopmental disability in preterm infants with (or at risk of) apnea, or peri-extubation. We searched CENTRAL, MEDLINE, Embase, CINAHL, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and clinicaltrials.gov in May 2022. The reference lists of relevant articles were also checked to identify additional studies. We included randomized (RCTs), quasi-RCTs and cluster-RCTs, comparing high-dose to standard-dose strategies in preterm infants. High-dose strategies were defined as a high-loading dose (more than 20 mg of caffeine citrate/kg) or a high-maintenance dose (more than 10 mg of caffeine citrate/kg/day). Standard-dose strategies were defined as a standard-loading dose (20 mg or less of caffeine citrate/kg) or a standard-maintenance dose (10 mg or less of caffeine citrate/kg/day). We specified three additional comparisons according to the indication for commencing caffeine: 1) prevention trials, i.e. preterm infants born at less than 34 weeks' gestation, who are at risk for apnea; 2) treatment trials, i.e. preterm infants born at less than 37 weeks' gestation, with signs of apnea; 3) extubation trials: preterm infants born at less than 34 weeks' gestation, prior to planned extubation. We used standard methodological procedures expected by Cochrane. We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data and mean, standard deviation (SD), and mean difference (MD) for continuous data. MAIN RESULTS: We included seven trials enrolling 894 very preterm infants (reported in Comparison 1, i.e. any indication). Two studies included infants for apnea prevention (Comparison 2), four studies for apnea treatment (Comparison 3) and two for extubation management (Comparison 4); in one study, indication for caffeine administration was both apnea treatment and extubation management (reported in Comparison 1, Comparison 3 and Comparison 4). In the high-dose groups, loading and maintenance caffeine doses ranged from 30 mg/kg to 80 mg/kg, and 12 mg/kg to 30 mg/kg, respectively; in the standard-dose groups, loading and maintenance caffeine doses ranged from 6 mg/kg to 25 mg/kg, and 3 mg/kg to 10 mg/kg, respectively. Two studies had three study groups: infants were randomized in three different doses (two of them matched our definition of high dose and one matched our definition of standard dose); high-dose caffeine and standard-dose caffeine were compared to theophylline administration (the latter is included in a separate review). Six of the seven included studies compared high-loading and high-maintenance dose to standard-loading and standard-maintenance dose, whereas in one study standard-loading dose and high-maintenance dose was compared to standard-loading dose and standard-maintenance dose. High-dose caffeine strategies (administration for any indication) may have little or no effect on mortality prior to hospital discharge (risk ratio (RR) 0.86, 95% confidence of interval (CI) 0.53 to 1.38; risk difference (RD) -0.01, 95% CI -0.05 to 0.03; I² for RR and RD = 0%; 5 studies, 723 participants; low-certainty evidence). Only one study enrolling 74 infants reported major neurodevelopmental disability in children aged three to five years (RR 0.79, 95% CI 0.51 to 1.24; RD -0.15, 95% CI -0.42 to 0.13; 46 participants; very low-certainty evidence). No studies reported the outcome mortality or major neurodevelopmental disability in children aged 18 to 24 months and 3 to 5 years. Five studies reported bronchopulmonary dysplasia at 36 weeks' postmenstrual age (RR 0.75, 95% CI 0.60 to 0.94; RD -0.08, 95% CI -0.15 to -0.02; number needed to benefit (NNTB) = 13; I² for RR and RD = 0%; 723 participants; moderate-certainty evidence). High-dose caffeine strategies may have little or no effect on side effects (RR 1.66, 95% CI 0.86 to 3.23; RD 0.03, 95% CI -0.01 to 0.07; I² for RR and RD = 0%; 5 studies, 593 participants; low-certainty evidence). The evidence is very uncertain for duration of hospital stay (data reported in three studies could not be pooled in meta-analysis because outcomes were expressed as medians and interquartile ranges) and seizures (RR 1.42, 95% CI 0.79 to 2.53; RD 0.14, 95% CI -0.09 to 0.36; 1 study, 74 participants; very low-certainty evidence). We identified three ongoing trials conducted in China, Egypt, and New Zealand. High-dose caffeine strategies in preterm infants may have little or no effect on reducing mortality prior to hospital discharge or side effects. We are very uncertain whether high-dose caffeine strategies improves major neurodevelopmental disability, duration of hospital stay or seizures. No studies reported the outcome mortality or major neurodevelopmental disability in children aged 18 to 24 months and 3 to 5 years. High-dose caffeine strategies probably reduce the rate of bronchopulmonary dysplasia. Recently completed and future trials should report long-term neurodevelopmental outcome of children exposed to different caffeine dosing strategies in the neonatal period. Data from extremely preterm infants are needed, as this population is exposed to the highest risk for mortality and morbidity. However, caution is required when administering high doses in the first hours of life, when the risk for intracranial bleeding is highest. Observational studies might provide useful information regarding potential harms of the highest doses.


Canadian Internal Medicine Ultrasound (CIMUS) Expert Consensus Statement on the Use of Lung Ultrasound for the Assessment of Medical Inpatients With Known or Suspected Coronavirus Disease 2019.
To develop a consensus statement on the use of lung ultrasound (LUS) in the assessment of symptomatic general medical inpatients with known or suspected coronavirus disease 2019 (COVID-19). Our LUS expert panel consisted of 14 multidisciplinary international experts. Experts voted in 3 rounds on the strength of 26 recommendations as "strong," "weak," or "do not recommend." For recommendations that reached consensus for do not recommend, a fourth round was conducted to determine the strength of those recommendations, with 2 additional recommendations considered. Of the 26 recommendations, experts reached consensus on 6 in the first round, 13 in the second, and 7 in the third. Four recommendations were removed because of redundancy. In the fourth round, experts considered 4 recommendations that reached consensus for do not recommend and 2 additional scenarios; consensus was reached for 4 of these. Our final recommendations consist of 24 consensus statements; for 2 of these, the strength of the recommendations did not reach consensus. In symptomatic medical inpatients with known or suspected COVID-19, we recommend the use of LUS to: (1) support the diagnosis of pneumonitis but not diagnose COVID-19, (2) rule out concerning ultrasound features, (3) monitor patients with a change in the clinical status, and (4) avoid unnecessary additional imaging for patients whose pretest probability of an alternative or superimposed diagnosis is low. We do not recommend the use of LUS to guide admission and discharge decisions. We do not recommend routine serial LUS in patients without a change in their clinical condition.


Targeted therapies in combination with chemotherapy in non-small cell lung cancer.
With rare exceptions, attempts to combine so-called targeted agents with standard cytotoxic chemotherapy in advanced non-small cell lung cancer have yielded disappointing results. The reasons underlying these spectacular failures are not always fully understood, but certainly the lack of careful patient selection is a major contributing factor. In addition, recent preclinical and clinical studies indicate that antagonism may exist between the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy primarily in tumor cells with wild-type EGFR. By contrast, tumor cells harboring somatic mutations in EGFR experience massive apoptosis when exposed to the EGFR tyrosine kinase inhibitors. Therefore, in theory, mutant tumor cells should exhibit enhanced cell kill when treated with concomitant chemotherapy and EGFR tyrosine kinase inhibitors akin to what is observed with chemotherapy and trastuzumab in breast cancer. Clinical data from the recently completed TRIBUTE trial support the latter possibility. Ideally, future studies of EGFR tyrosine kinase inhibitors and other targeted drugs will use careful patient selection criteria based on well-characterized and validated predictive markers. However, in the absence of such biomarkers, clinical judgment, common sense, and innovative clinical trial design are necessary to avoid undue delay in drug development.


Cautions about the reliability of pairwise gene correlations based on expression data.
Rapid growth in the availability of genome-wide transcript abundance levels through gene expression microarrays and RNAseq promises to provide deep biological insights into the complex, genome-wide transcriptional behavior of single-celled organisms. However, this promise has not yet been fully realized. We find that computation of pairwise gene associations (correlation; mutual information) across a set of 2782 total genome-wide expression samples from six diverse bacteria produces unexpectedly large variation in estimates of pairwise gene association-regardless of the metric used, the organism under study, or the number and source of the samples. We pinpoint the cause to sampling bias. In particular, in repositories of expression data (e.g., Gene Expression Omnibus, GEO), many individual genes show small differences in absolute gene expression levels across the set of samples. We demonstrate that these small differences are due mainly to "noise" instead of "signal" attributable to environmental or genetic perturbations. We show that downstream analysis using gene expression levels of genes with small differences yields biased estimates of pairwise association. We propose flagging genes with small differences in absolute, RMA-normalized, expression levels (e.g., standard deviation less than 0.5), as potentially yielding biased pairwise association metrics. This strategy has the potential to substantially improve the confidence in genome-wide conclusions about transcriptional behavior in bacterial organisms. Further work is needed to further refine strategies to identify genes with small difference in expression levels prior to computing gene-gene association metrics.


Estimated effect of ventilation and filtration on chronic health risks in U.S. offices, schools, and retail stores.
We assessed the chronic health risks from inhalation exposure to volatile organic compounds (VOCs) and particulate matter (PM2.5) in U.S. offices, schools, grocery, and other retail stores and evaluated how chronic health risks were affected by changes in ventilation rates and air filtration efficiency. Representative concentrations of VOCs and PM2.5 were obtained from available data. Using a mass balance model, changes in exposure to VOCs and PM2.5 were predicted if ventilation rate were to increase or decrease by a factor of two, and if higher efficiency air filters were used. Indoor concentrations were compared to health guidelines to estimate percentage exceedances. The estimated chronic health risks associated with VOC and PM2.5 exposures in these buildings were low relative to the risks from exposures in homes. Chronic health risks were driven primarily by exposures to PM2.5 that were evaluated using disease incidence of mortality, chronic bronchitis, and non-fatal stroke. The leading cancer risk factor was exposure to formaldehyde. Using disability-adjusted life years (DALYs) to account for both cancer and non-cancer effects, results suggest that increasing ventilation alone is ineffective at reducing chronic health burdens. Other strategies, such as pollutant source control and the use of particle filtration, should also be considered.


[Serendipity in medicine and anesthesiology.].
This study has evaluated more than a hundred of the most fortunate couplings of a brilliant mind with fortunate luck (serendipity), through the re-reading of most relevant histories on science-related (n = 46) and anesthesiology-related (n = 16) inventions and discoveries. This educational article encourages anesthesiologists to appreciate events related to scientific inventions and discoveries, showing that serendipity is possible, provided it is expected. Each discovery or invention includes history, references and scientific or anecdotal explanation. In addition to traditional discoveries, such as wine, gravity, photograph, Velcro, airbag, etc., there are other Medicine-related (microscope, X-rays, vaccine, penicillin, insulin, laser, Paps smear, etc.) and Anesthesiology-related (isometry, gloves, N2O, ether, barbiturates, benzodiazepines, blood patch, etc.) discoveries. Creativity and serendipity may act as cornerstones for clinical and basic research of pioneer inventions for medical and anesthesiologic advances. In fact, topics related to biology, anatomy, physics, chemistry, physiology, pharmacology, astronomy and archeology should be master and lots of luck. Although research and operating room accidents are regrettable, some of them happen and may sometimes lead to spectacular advances, such as heroic treatments and even Nobel Prizes. Open-mindedness is a common trait to those willing to count on grand prize, as American physicist Henry would state (1842): 'Seeds of discovery are constantly floating around us, but the onlytake roots in minds well prepared to receive them'.


Development of an Australian cardiovascular disease mortality risk score using multiple imputation and recalibration from national statistics.
To develop and recalibrate an Australian 5-year cardiovascular disease (CVD) mortality risk score to produce contemporary predictions of risk. Data were pooled from six Australian cohort studies (n = 54,829), with baseline data collected between 1989 and 2003. Participants included were aged 40-74 years and free of CVD at baseline. Variables were harmonised across studies and missing data were imputed using multiple imputation. Cox proportional hazards models were used to estimate the risk of CVD mortality associated with factors mutually independently predictive (p < 0.05) and a 5-year risk prediction algorithm was constructed. This algorithm was recalibrated to reflect contemporary national levels of CVD mortality and risk factors using national statistics. Over a mean 16.6 years follow-up, 1375 participants in the six studies died from CVD. The prediction model included age, sex, smoking, diabetes, systolic blood pressure, total and high-density lipoprotein cholesterol (HDLC), a social deprivation score, estimated glomerular filtration rate and its square and interactions of sex with diabetes, HDLC and deprivation score, and of age with systolic blood pressure and smoking. This model discriminated well when applied to a Scottish study population (c-statistic (95% confidence interval): 0.751 (0.709, 0.793)). Recalibration generally increased estimated risks, but well below those predicted by the European SCORE models. The resulting risk score, which includes markers of both chronic kidney disease and socioeconomic deprivation, is the first CVD mortality risk prediction tool for Australia to be derived using Australian data. The primary model, and the method of recalibration, is applicable elsewhere.


Acute hemodynamic changes during carotid artery stenting.
To determine the clinical significance of acute hemodynamic disturbances during stenting in the carotid sinus region, we assessed the relation between intraprocedural changes in heart rate (HR) and blood pressure (BP) and adverse neurologic and cardiac outcomes. Eighteen patients underwent carotid stenting with the Wallstent (Schneider Inc). Suitable candidates had at least 60% diameter stenosis of the carotid artery by angiography. Initial and nadir HR and BP were recorded during the predilatation, stent delivery, and postdilatation periods. Bradycardia was defined as HR < or =60 beats/min and hypotension as systolic BP < or =100 mm Hg. Nineteen Wallstents were successfully deployed in all 19 carotid arteries. Some degree of bradycardia or hypotension occurred in 68% of carotid stent procedures, but administration of vasoactive medications was necessary in only 7 patients (37%) with more persistent hemodynamic disturbances. Hypotension or the need for continuous vasopressor therapy was significantly more common during postdilatation (32%) than in the predilatation period (5%) (p = 0.02). Bradycardia was not reduced by prophylactic atropine. In 1 patient the hemodynamic response to stenting may have contributed to an adverse neurologic and cardiac outcome. Thus, despite frequent fluctuations in HR and BP, most carotid stenting procedures were performed with excellent overall results, even in patients at high risk.


Ethanol exposure affects gene expression in the embryonic organizer and reduces retinoic acid levels.
Fetal Alcohol Spectrum Disorder (FASD) is a set of developmental malformations caused by alcohol consumption during pregnancy. Fetal Alcohol Syndrome (FAS), the strongest manifestation of FASD, results in short stature, microcephally and facial dysmorphogenesis including microphthalmia. Using Xenopus embryos as a model developmental system, we show that ethanol exposure recapitulates many aspects of FAS, including a shortened rostro-caudal axis, microcephally and microphthalmia. Temporal analysis revealed that Xenopus embryos are most sensitive to ethanol exposure between late blastula and early/mid gastrula stages. This window of sensitivity overlaps with the formation and early function of the embryonic organizer, Spemann's organizer. Molecular analysis revealed that ethanol exposure of embryos induces changes in the domains and levels of organizer-specific gene expression, identifying Spemann's organizer as an early target of ethanol. Ethanol also induces a defect in convergent extension movements that delays gastrulation movements and may affect the overall length. We show that mechanistically, ethanol is antagonistic to retinol (Vitamin A) and retinal conversion to retinoic acid, and that the organizer is active in retinoic acid signaling during early gastrulation. The model suggests that FASD is induced in part by an ethanol-dependent reduction in retinoic acid levels that are necessary for the normal function of Spemann's organizer.


Killing of Plasmodium falciparum in vitro by nitric oxide derivatives.
We have investigated the in vitro susceptibility of the human malaria parasite Plasmodium falciparum to killing by nitric oxide and related molecules. A saturated solution of nitric oxide did not inhibit parasite growth, but two oxidation products of nitric oxide (nitrite and nitrate ions) were toxic to the parasite in millimolar concentrations. Nitrosothiol derivatives of cysteine and glutathione were found to be about a thousand times more active (50% growth inhibitory concentration, approximately 40 microM) than nitrite.


Variation between hospitals in inpatient admission practices for self-harm patients and its impact on repeat presentation.
Self-harm patient management varies markedly between hospitals, with fourfold differences in the proportion of patients who are admitted to a medical or psychiatric inpatient bed. The current study aimed to investigate whether differences in admission practices are associated with patient outcomes (repeat self-harm) while accounting for differences in patient case mix. Data came from the National Self-Harm Registry Ireland. A prospective cohort of 43,595 self-harm patients presenting to hospital between 2007 and 2012 were included. As well as conventional regression analysis, instrumental variable (IV) methods utilising between hospital differences in rates of hospital admission were used in an attempt to gain unbiased estimates of the association of admission with risk of repeat self-harm. The proportion of self-harm patients admitted to a medical bed varied from 10 to 74 % between hospitals. Conventional regression and IV analysis suggested medical admission was not associated with risk of repeat self-harm. Psychiatric inpatient admission was associated with an increased risk of repeat self-harm in both conventional and IV analyses. This increased risk persisted in analyses stratified by gender and when restricted to self-poisoning patients only. No strong evidence was found to suggest medical admission reduces the risk of repeat self-harm. Models of health service provision that encourage prompt mental health assessment in the emergency department and avoid unnecessary medical admission of self-harm patients appear warranted. Psychiatric inpatient admission may be associated with a heightened risk of repeat self-harm in some patients, but these findings could be biased by residual confounding and require replication.


Apamin attenuated cerulein-induced acute pancreatitis by inhibition of JNK pathway in mice.
We have previously reported that bee venom (BV) has a protective role against acute pancreatitis (AP). However, the effects of apamin, the major compound of BV, on AP have not been determined. The aim of this study was to evaluate the effects of apamin on cerulein-induced AP. AP was induced via intraperitoneal injection of supramaximal concentrations of the stable cholecystokinin analogue cerulein (50 μg/kg) every hour for 6 times. In the apamin treatment group, apamin was administered subcutaneously (10, 50, or 100 μg/kg) at both 18 and 1 h before the first cerulein injection. The mice were sacrificed at 6 h after the final cerulein injection. Blood samples were obtained to determine serum amylase and lipase levels, as well as cytokine production. The pancreas and lung were rapidly removed for morphologic and histological examination, myeloperoxidase (MPO) assay, and real-time reverse transcription-polymerase chain reaction. Furthermore, we isolated the pancreatic acinar cells to specify the role of apamin in AP. Pre-treatment with apamin inhibited histological damage, pancreatic weight/body weight ratio, serum level of amylase and lipase, MPO activity, and cytokine production. In addition, apamin treatment significantly inhibited cerulein-induced pancreatic acinar cell death. Furthermore, apamin treatment inhibited the cerulein-induced activation of c-Jun NH2-terminal kinases (JNK). These results could suggest that apamin could protect against AP by inhibition of JNK activation.


Alpha-lipoic acid and cardiovascular disease.
Alpha-lipoic acid (ALA) has been identified as a powerful antioxidant found naturally in our diets, but appears to have increased functional capacity when given as a supplement in the form of a natural or synthetic isolate. ALA and its active reduced counterpart, dihydrolipoic acid (DHLA), have been shown to combat oxidative stress by quenching a variety of reactive oxygen species (ROS). Because this molecule is soluble in both aqueous and lipid portions of the cell, its biological functions are not limited solely to one environment. In addition to ROS scavenging, ALA has been shown to be involved in the recycling of other antioxidants in the body including vitamins C and E and glutathione. Not only have the antioxidant qualities of this molecule been studied, but there are also several reports pertaining to its blood lipid modulating characteristics, protection against LDL oxidation and modulation of hypertension. Therefore, ALA represents a possible protective agent against risk factors of cardiovascular disease (CVD). The objective of this review is to examine the literature pertaining to ALA in relation to CVD and describe the most powerful actions and potential uses of this naturally occurring antioxidant. Despite the numerous studies on ALA, many questions remain relating to the use of ALA as a supplement. There is no consensus on dosage, dose frequency, form of administration, and/or preferred form of ALA. However, collectively the literature increases our understanding of the potential uses for supplementation with ALA and identifies key areas for future research.


JP8 exposure and neurocognitive performance among US Air Force personnel.
Petroleum-based fuels such as jet propellant (JP) 4, JP5, JP8, and jet A1 (JetA) are among the most common occupational chemical exposures encountered by military and civilian workforces. Although acute toxicity following high-level exposures to JP8 and similar chemical mixtures has been reported, the relationship between persistent low-level occupational exposures to jet fuels and both acute and longer-term central nervous system (CNS) function has been comparatively less well characterized. This paper describes results of neurocognitive assessments acquired repeatedly across a work week study design (Friday to Friday) as part of the Occupational JP8 Exposure Neuroepidemiology Study (OJENES) involving U.S. Air Force (AF) personnel with varying levels of exposure to jet fuel (JP8). JP8 exposure levels were quantified using both personal air monitoring and urinary biomarkers of exposure. Neurocognitive performance was evaluated using an objective, standardized battery of tests. No significant associations with neurocognitive performances were observed between individuals having regular contact and those with minimal/no direct contact with JP8 (measured by average work week levels of personal breathing zone exposure). Also, no significant findings were noted between repeated measures of absorbed dose (multi-day pre-shift urinary 1- and 2-naphthol) and reduced proficiency on neurocognitive tasks across the work week. Results suggest that occupational exposure to lower (than regulated standards) levels of JP8 do not appear to be associated with acute, measurable differences or changes in neurocognitive performance.


Effects of soybean (Glycine max) germination on biologically active components, nutritional values of seeds, and biological characteristics in rats.
We briefly reviewed the effects of soybean germination on biologically active components, nutritive value of seed and biological characteristics in rats. The purpose of this review is to evaluate the effects of soybean germination on nutritional values of seeds and the potential importance for the use of germinated soybeans, from a contemporary conception, in food preparation as well as on soybean possible influence in optimal health. Germination induced a substantial increase in the content of saponin, oestrogenic compounds and almost all phytosterols, particularly beta-sitosterol of seeds. Lecithin content increased slightly and gradually during germination process. Lipase and alpha-galactosidase activities increased whereas lipoxygenase activities reduced after a short period of germination (< or = 72 h). Therefore, the substantial odour and flavour scores of germinated soybean flour were improved. Germinated seeds were also beneficial to heat penetration, their thermolabile antinutritional factors were easier to inhibit than those of dry beans, also the seeds did not require a long cooking time to be palatable. Duration of the germination process greatly influenced the nutritional value and palatability of seeds and biological characteristics in rats. In rat bioassay, one-day germination of soybeans induced a significant increase of daily body weight gain, daily protein intake in rats and protein efficiency ratio (PER) of seed meal. Palatability of seeds was also improved whereas a 5-day germination resulted in a decrease of PER of seed meal (less than the value of unheated seeds) and induced thyroid enlargement in rats. A vapour thermal treatment (100 degrees C, 20 min) eliminated thyroid-active agents and improved PER of seed meal, food intake and final weight of rats. Well prepared germinated soybeans can be used as a good alternate to animal proteins for more balanced nutritional diet. Development of food products from germinated soybean may be another way to further increase the versatility and utility of soybeans for both developing and industrialized countries, as germination induced the modification of certain specific biologically active components, palatability and nutritive value of seeds.


Comparative Effectiveness of β-Blocker Use Beyond 3 Years After Myocardial Infarction and Long-Term Outcomes Among Elderly Patients.
The benefit of β-blocker use beyond 3 years after a myocardial infarction (MI) has not been clearly determined. Using data from the CRUSADE Registry (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) linked with Medicare claims, we studied patients ≥65 years of age with MI, discharged on β-blocker therapy and alive 3 years later without a recurrent MI to evaluate β-blocker use and dose (none, <50%, and ≥50% of the recommended target) at 3 years. Using inverse probability of treatment weighting, we then examined the adjusted association between β-blocker use (and dose) at 3 years and the cardiovascular composite of all-cause mortality, hospitalization for recurrent MI, ischemic stroke, or heart failure over the subsequent 5 years. Of the 6893 patients ≥65 years age, β-blocker use at 3 years was 72.2% (n=4980); 43% (n=2162) of these were treated with ≥50% of the target β-blocker dose. β-blocker use was not associated with a significant difference on the composite outcome (52.4% versus 55.4%, adjusted hazard ratio, 0.95; 95% CI, 0.88-1.03; P=0.23). Neither low dose (<50% target dose) nor high dose (≥50% target dose) β-blocker use was associated with a significant difference in risk when compared with no β-blocker use. Results were also consistent in patients with and without heart failure or systolic dysfunction ( P interaction =0.30). In this observational analysis, β-blocker use beyond 3 years post-MI, regardless of the dose achieved, was not associated with improved outcomes. The role of prolonged β-blocker use, particularly in older adults, needs further investigation.


A cadmium-sensitive, glutathione-deficient mutant of Arabidopsis thaliana.
The roots of the cadmium-sensitive mutant of Arabidopsis thaliana, cad1-1, become brown in the presence of cadmium. A new cadmium-sensitive mutant affected at a second locus, cad2, has been identified using this phenotype. Genetic analysis has grown that the sensitive phenotype is recessive to the wild type and segregates as a single Mendelian locus. Assays of cadmium accumulation by intact plants indicated that the mutant is deficient in its ability to sequester cadmium. Undifferentiated callus tissue was also cadmium sensitive, suggesting that the mutant phenotype is expressed at the cellular level. The level of cadmium-binding complexes formed in vivo was decreased compared with the wild type and accumulation of phytochelatins was about 10% of that in the wild type. The level of glutathione, the substrate for phytochelatin biosynthesis, in tissues of the mutant was decreased to about 15 to 30% of that in the wild type. Thus, the deficiency in phytochelatin biosynthesis can be explained by a deficiency in glutathione.


Self-control and its relation to emotions and psychobiology: evidence from a Day Reconstruction Method study.
This study aimed to ascertain whether self-control predicts heart rate, heart rate variability, and the cortisol slope, and to determine whether health behaviors and affect patterns mediate these relationships. A sample of 198 adults completed the Self-Control Scale (Tangney in J Pers 72:271-322, 2004), and reported their exercise levels, and cigarette and alcohol use. Participants provided a complete account of their emotional experiences over a full day, along with morning and evening salivary cortisol samples and a continuous measure of cardiovascular activity on the same day. High trait self-control predicted low resting heart rate, high heart rate variability, and a steep cortisol slope. Those with high self-control displayed stable emotional patterns which explained the link between self-control and the cortisol slope. The self-controlled smoked less and this explained their low heart rates. The capacity to sustain stable patterns of affect across diverse contexts may be an important pathway through which self-control relates to psychophysiological functioning and potentially health.


A comorbidity index for mortality prediction in Chinese patients with ESRD receiving hemodialysis.
Chinese patients with ESRD have different comorbidity patterns than white patients with ESRD and require a validated comorbidity index. The objective of this study was to develop a new index for mortality prediction in 2006-2009 Taiwanese incident hemodialysis patients. Data were retrieved from 2005 to 2010 Taiwan National Health Insurance claim records, and follow-up was available until December 31, 2010. The same comorbid conditions as the US Renal Data System (USRDS) index that occurred during a 12-month period from 9 months before to 3 months after dialysis initiation were used to construct the index. Integer weight of the comorbid conditions was derived from coefficient estimates of Cox regression for all-cause mortality, and the index was internally validated. The performance of the index was assessed by discrimination, calibration, and reclassification. A total of 30,303 hemodialysis patients were included in this study. The weight for individual comorbid conditions of this index differed from that of the USRDS index. The performance of this index was similar to that of USRDS and Charlson indices in terms of model fit statistics, overall predictive ability, discrimination, and calibration. Hosmer-Lemeshow test showed that all three indices demonstrated significant differences between predicted and observed mortality rates. When patients were categorized by the predicted 2.5-year survival probabilities, the index achieved a net reclassification improvement of 4.71% (P<0.001), referenced to USRDS index. Compared with USRDS index, this new index demonstrated better reclassification ability, but future studies should address the clinical significance.


Recent trends in molecular diagnostics of yeast infections: from PCR to NGS.
The incidence of opportunistic yeast infections in humans has been increasing over recent years. These infections are difficult to treat and diagnose, in part due to the large number and broad diversity of species that can underlie the infection. In addition, resistance to one or several antifungal drugs in infecting strains is increasingly being reported, severely limiting therapeutic options and showcasing the need for rapid detection of the infecting agent and its drug susceptibility profile. Current methods for species and resistance identification lack satisfactory sensitivity and specificity, and often require prior culturing of the infecting agent, which delays diagnosis. Recently developed high-throughput technologies such as next generation sequencing or proteomics are opening completely new avenues for more sensitive, accurate and fast diagnosis of yeast pathogens. These approaches are the focus of intensive research, but translation into the clinics requires overcoming important challenges. In this review, we provide an overview of existing and recently emerged approaches that can be used in the identification of yeast pathogens and their drug resistance profiles. Throughout the text we highlight the advantages and disadvantages of each methodology and discuss the most promising developments in their path from bench to bedside.


Conformational control of Pd2L4 assemblies with unsymmetrical ligands.
With increasing interest in the potential utility of metallo-supramolecular architectures for applications as diverse as catalysis and drug delivery, the ability to develop more complex assemblies is keenly sought after. Despite this, symmetrical ligands have been utilised almost exclusively to simplify the self-assembly process as without a significant driving foa mixture of isomeric products will be obtained. Although a small number of unsymmetrical ligands have been shown to serendipitously form well-defined metallo-supramolecular assemblies, a more systematic study could provide generally applicable information to assist in the design of lower symmetry architectures. Pd2L4 cages are a popular class of metallo-supramolecular assembly; research seeking to introduce added complexity into their structure to further their functionality has resulted in a handful of examples of heteroleptic structures, whilst the use of unsymmetrical ligands remains underexplored. Herein we show that it is possible to design unsymmetrical ligands in which either steric or geometric constraints, or both, can be incorporated into ligand frameworks to ensure exclusive formation of single isomers of three-dimensional Pd2L4 metallo-supramolecular assemblies with high fidelity. In this manner it is possible to access Pd2L4 cage architectures of reduced symmetry, a concept that could allow for the controlled spatial segregation of different functionalities within these systems. The introduction of steric directing groups was also seen to have a profound effect on the cage structures, suggesting that simple ligand modifications could be used to engineer structural properties.


Elevated levels of bilirubin and long-term exposure impair human brain microvascular endothelial cell integrity.
The pathogenesis of encephalopathy by unconjugated bilirubin (UCB) seems to involve the passage of high levels of the pigment across the blood-brain barrier (BBB) and the consequent damage of neuronal cells. However, it remains to be clarified if and how the disruption of BBB occurs by UCB. We used confluent monolayers of human brain microvascular endothelial cells (HBMEC) to explore the sequence of events produced by UCB. A cell line and primary cultures of HBMEC were exposed to 50 or 100 µM UCB, in the presence of 100 µM human serum albumin, to mimic moderate and severe jaundice, for 1-72 h. UCB caused loss of cell viability in a concentration-dependent manner. UCB inhibited the secretion of interleukin-6, interleukin-8, monocyte chemoattractant protein-1 and vascular endothelial growth factor at early time points, but enhanced their secretion at later time points. Upregulation of mRNA expression, particularly by 100 µM UCB, preceded cytokine secretion. Other early events include the disruption of glutathione homeostasis and the increase in endothelial nitric oxide synthase expression followed by nitrite production. Prolonged exposure to UCB upregulated the expression of β-catenin and caveolin-1. In conclusion, elevated concentrations of UCB affect the integrity of HBMEC monolayers mediated by oxidative stress and cytokine release. UCB also induced increased expression of caveolin-1, which has been associated with BBB breakdown, and β-catenin, probably as an attempt to circumvent that impairment. These findings provide a basis for target-directed therapy against brain endothelial injury caused by UCB.


Synthesis, characterization and ethylene polymerization behaviour of binuclear nickel halides bearing 4,5,9,10-tetra(arylimino)pyrenylidenes.
Pyrene-4,5,9,10-tetraone was prepared via the oxidation of pyrene, and reacted with various anilines to afford a series of 4,5,9,10-tetra(arylimino)pyrenylidene derivatives (L1-L4). The tetraimino-pyrene compounds L1 and L2 were reacted with two equivalents of (DME)NiBr2 in CH2Cl2 to afford the corresponding dinickel bromide complexes (Ni1 and Ni2). The organic compounds were fully characterized, whilst the bi-metallic complexes were characterized by FT-IR spectra and elemental analysis. The molecular structures of representative organic and nickel compounds were confirmed by single-crystal X-ray diffraction studies. These nickel complexes exhibited high activities towards ethylene polymerization in the presence of either MAO or Me2AlCl, maintaining a high activity over a prolonged period (longer than previously reported dinickel complex pre-catalysts). The polyethylene obtained was characterized by GPC, DSC and FT-IR spectroscopy and was found to possess branched features.


ENaC activity is regulated by calpain-2 proteolysis of MARCKS proteins.
We previously demonstrated a role for the myristoylated alanine-rich C kinase substrate (MARCKS) to serve as an adaptor protein in the anionic phospholipid phosphate-dependent regulation of the epithelial sodium channel (ENaC). Both MARCKS and ENaC are regulated by proteolysis. Calpains are a family of ubiquitously expressed intracellular Ca2+-dependent cysteine proteases involved in signal transduction. Here we examine the role of calpain-2 in regulating MARCKS and ENaC in cultured renal epithelial cells and in the mouse kidney. Using recombinant fusion proteins, we show that MARCKS, but not the ENaC subunits, are a substrate of calpain-2 in the presence of Ca2+ Pharmacological inhibition of calpain-2 alters MARCKS protein expression in light-density sucrose gradient fractions from cell lysates of mouse cortical collecting duct cells. Calpain-dependent cleaved products of MARCKS are detectable in cultured renal cells. Ca2+ mobilization and calpain-2 inhibition decrease the association between ENaC and MARCKS. The inhibition of calpain-2 reduces ENaC activity as demonstrated by single-channel patch-clamp recordings and transepithelial current measurements. These results suggest that calpain-2 proteolysis of MARCKS promotes its interaction with lipids and ENaC at the plasma membrane to allow for the phosphatidylinositol 4,5-bisphosphate (PIP2)-dependent regulation of ENaC activity in the kidney.


Cancer incidence among pesticide applicators exposed to butylate in the Agricultural Health Study (AHS).
Although limited, epidemiologic studies suggest possible associations between butylate use and cancer risk, specifically prostate cancer and non-Hodgkin lymphoma (NHL). We examined butylate use and cancer risk more broadly in the AHS, a cohort of licensed pesticide applicators in Iowa and North Carolina. Pesticide use information was collected using self-administered questionnaires. Poisson regression was used to calculate rate ratios (RR) and 95% confidence intervals (CI). Two exposure metrics were used: lifetime exposure days (LD) and intensity-weighted lifetime exposure days (IWLD). We used two referent groups: unexposed to butylate and the lowest butylate usage category. This analysis included 19,655 applicators with complete butylate use information; 5297 applicators were exposed to butylate, making this the largest study of butylate to date. The mean follow-up time since enrollment was 9 years. Prostate cancer risk was significantly elevated among applicators in the highest LD category in both referent groups (low-exposed referent: RR(LD)=2.09, 95% CI=1.27-3.44). We observed a significantly elevated joint effect of prostate cancer family history and high butylate usage across both exposure metrics and both referent groups (low-exposed referent: RR(LD)=2.00, 95% CI=1.07-3.74), and a non-significant, elevated interaction between butylate use and prostate cancer family history, similar to a previous AHS finding. Statistically significant increased risks and exposure-response trends were seen for all lymphohematopoietic cancers (AL) and NHL for both exposure metrics and referent groups (low-exposed referent: AL:RR(LD)=2.27, 95% CI=1.18-4.37; NHL: RR(LD)=3.44, 95% CI=1.29-9.21). Our analysis did not find meaningful associations for other cancers analyzed. Further study is warranted for AL, NHL and prostate cancers.


Large-scale variation among human and great ape genomes determined by array comparative genomic hybridization.
Large-scale genomic rearrangements are a major force of evolutionary change and the ascertainment of such events between the human and great ape genomes is fundamental to a complete understanding of the genetic history and evolution of our species. Here, we present the results of an evolutionary analysis utilizing array comparative genomic hybridization (array CGH), measuring copy-number gains and losses among these species. Using an array of 2460 human bacterial artificial chromosomes (BACs) (12% of the genome), we identified a total of 63 sites of putative DNA copy-number variation between humans and the great apes (chimpanzee, bonobo, gorilla, and orangutan). Detailed molecular characterization of a subset of these sites confirmed rearrangements ranging from 40 to at least 175 kb in size. Surprisingly, the majority of variant sites differentiating great ape and human genomes were found within interstitial euchromatin. These data suggest that such large-scale events are not restricted solely to subtelomeric or pericentromeric regions, but also occur within genic regions. In addition, 5/9 of the verified variant sites localized to areas of intrachromosomal segmental duplication within the human genome. On the basis of the frequency of duplication in humans, this represents a 14-fold positional bias. In contrast to previous cytogenetic and comparative mapping studies, these results indicate extensive local repatterning of hominoid chromosomes in euchromatic regions through a duplication-driven mechanism of genome evolution.


Time-resolved multichannel imaging of fluorescent objects embedded in turbid media.
We present a multichannel detection technique for three-dimensional imaging of objects embedded in turbid media by using time-resolved fluorescence. By using a streak camera, we can obtain the experimental data in a single measurement. The data, analyzed by means of a triangulation algorithm, provide accurate localization of a fluorescent object for path lengths of up to 120 scattering mean free paths. The results demonstrate the feasibility of combining fluorescence spectroscopy with time-resolved optical tomography for localizing and identifying embedded objects.


Platelet efflux of noradrenaline in patients with type 1 diabetes mellitus.
1. Endogenous noradrenaline release from washed platelets incubated under resting conditions and in the presence of thrombin was examined in 14 normal subjects and 10 subjects with type 1 (insulin-dependent) diabetes. 2. Irreversible aggregation of platelets from both normal and diabetic subjects was induced by thrombin (0.3 unit/ml). Platelets from diabetic subjects were more sensitive than platelets from normal subjects, extents of aggregation being 89% and 76%, respectively (P less than 0.002). 3. Stimulation with thrombin (0.3 unit/ml) elicited marked platelet release of noradrenaline to the incubation medium in both normal and diabetic subjects. Supernatant noradrenaline concentrations obtained under thrombin-stimulated conditions did not significantly differ between normal and diabetic subjects. However, under resting conditions noradrenaline levels were significantly greater (+93%, P less than 0.02) for diabetic than normal subjects. 4. Measurement of platelet noradrenaline contents after thrombin stimulation revealed no difference between normal and diabetic subjects. Under resting conditions, however, platelet noradrenaline levels were significantly lower (-46%, P less than 0.02) for diabetic than normal subjects. Thus, in the diabetic subjects increased resting platelet efflux of noradrenaline is mirrored by a decreased platelet noradrenaline content. 5. A consequence of increases in resting catecholamine efflux may be enhanced platelet activity resulting in increased platelet aggregation.


Comparison of land use regression and random forests models on estimating noise levels in five Canadian cities.
Chronic exposure to environment noise is associated with sleep disturbance and cardiovascular diseases. Assessment of population exposed to environmental noise is limited by a lack of routine noise sampling and is critical for controlling exposure and mitigating adverse health effects. Land use regression (LUR) model is newly applied in estimating environmental exposures to noise. Machine-learning approaches offer opportunities to improve the noise estimations from LUR model. In this study, we employed random forests (RF) model to estimate environmental noise levels in five Canadian cities and compared noise estimations between RF and LUR models. A total of 729 measurements and 33 built environment-related variables were used to estimate spatial variation in environmental noise at the global (multi-city) and local (individual city) scales. Leave one out cross-validation suggested that noise estimates derived from the RF global model explained a greater proportion of variation (R2: RF = 0.58, LUR = 0.47) with lower root mean squared errors (RF = 4.44 dB(A), LUR = 4.99 dB(A)). The cross-validation also indicated the RF models had better general performance than the LUR models at the city scale. By applying the global models to estimate noise levels at the postal code level, we found noise levels were higher in Montreal and Longueuil than in other major Canadian cities.


Investigation of SLC2A1 gene variants in genetic generalized epilepsy patients with eyelid myoclonia.
In addition to a complex inheritance pattern in genetic generalized epilepsy (GGE) syndromes, some studies have recently identified SLC2A1 variants which lead to glucose transporter type 1 (GLUT1) defects, in patients diagnosed with GGE. Here, we investigated the possible role of SLC2A1 variants in GGE patients with eyelid myoclonia (EM) which is a rare generalized seizure type associated with drug resistance and cognitive dysfunction. After polymerase chain reaction with designed primers, sequencing of all SLC2A1 exons was performed for 25 GGE-EM patients, as well as a control group of 15 GGE patients with absence seizures. Although various single nucleotide polymorphisms clustered in the ninth exon were detected, no variant was found in the two groups with GGE. Even though the patient number in this study is small, the data suggest that SLC2A1 variants do not play any causative role in GGE associated with EM.


The doubly labeled water method produces highly reproducible longitudinal results in nutrition studies.
The doubly labeled water (DLW) method is considered the reference method for the measurement of energy expenditure under free-living conditions. However, the reproducibility of the DLW method in longitudinal studies is not well documented. This study was designed to evaluate the longitudinal reproducibility of the DLW method using 2 protocols developed and implemented in a multicenter clinical trial-the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE). To document the longitudinal reproducibility of the DLW method, 2 protocols, 1 based on repeated analysis of dose dilutions over the course of the clinical trial (dose-dilution protocol) and 1 based on repeated but blinded analysis of randomly selected DLW studies (test-retest protocol), were carried out. The dose-dilution protocol showed that the theoretical fractional turnover rates for (2)H and (18)O and the difference between the 2 fractional turnover rates were reproducible to within 1% and 5%, respectively, over 4.5 y. The Bland-Altman pair-wise comparisons of the results generated from 50 test-retest DLW studies showed that the fractional turnover rates and isotope dilution spaces for (2)H and (18)O, and total energy expenditure, were highly reproducible over 2.4 y. Our results show that the DLW method is reproducible in longitudinal studies and confirm the validity of this method to measure energy expenditure, define energy intake prescriptions, and monitor adherence and body composition changes over the period of 2.5-4.4 y. The 2 protocols can be adopted by other laboratories to document the longitudinal reproducibility of their measurements to ensure the long-term outcomes of interest are meaningful biologically. This trial was registered at clinicaltrials.gov as NCT00427193.


Agreement study of keratometric values measured by Biograph/LENSTAR, auto-kerato-refractometer and Pentacam: decision for IOL calculation.
The aim was to determine the agreement in keratometric readings measured with the Biograph/LENSTAR, the Pentacam and an auto-kerato-refractometer in a 40- to 64-year-old population. This report is part of the first phase of the population-based Shahroud Cohort Eye Study. In virgin eyes, agreement among keratometry readings of three devices was examined in 7,260 eyes using the Bland-Altman method. The inter-device 95 per cent limits of agreement (95% LoA) and 95% confidence interval for upper and lower limits of agreement were calculated. Comparisons were made for keratometric readings of the flat and steep meridians as maximum keratometry (max-K), minimum keratometry (min-K) and their average (mean-K). Based on Biograph/LENSTAR measurements, averages of max-K, min-K and mean-K were 44.70 ± 1.64, 43.87 ± 1.54 and 44.28 ± 1.58 D, respectively. The quantile-quantile plot revealed that all three variables had normal distributions in this population. Agreement between the Biograph/LENSTAR and the auto-kerato-refractometer (max-K difference: -0.03 D, 95% LoA: -0.81 to 0.75; min-K difference: -0.08 D, 95% LoA: -0.85 to 0.68) was better than the agreement between the Biograph/LENSTAR and the Pentacam (max-K difference: 0.50 D, 95% LoA: -3.24 to 4.25; min-K difference: 0.59 D, 95% LoA: -3.00 to 4.17). The agreement between the Pentacam and the auto-kerato-refractometer (max-K difference: 0.54 D, 95% LoA: -3.16 to 4.24; min-K difference: 0.66 D, 95% LoA: -0.77 to 0.53) was worse than the other two pairs. These three devices are not interchangeable in terms of keratometry for calculation of the intraocular lens power. Agreement between the Biograph/LENSTAR and the auto-kerato-refractometer can be increased with regression models but this is not true in case of Biograph/LENSTAR and Pentacam.


Regulation of icosahedral virion capsid size by the in vivo activity of a cloned gene product.
Determination of icosahedral virion capsid size can be directly studied during helper-dependent lytic development of satellite P4 because the assembly pathway specified by the P2 helper virus is altered to yield smaller-sized capsids. Size determination (sid) mutations identify a P4-encoded function regulating this process. To determine whether the sid gene product is necessary and sufficient to redirect the assembly pathway, we (i) cloned the sid structural gene in a plasmid vector (pMA30) under the control of an inducible promoter and (ii) constructed a packaging substrate (pMA1), a P4 genome-sized plasmid containing only that region of P4, the cos site, necessary for encapsidation. Superinfection by P2 of a host carrying pMA30 under induced conditions resulted in a shift from large to small capsid production. P2 superinfection of a host carrying the cos plasmid pMA1 plus pMA30 under induced conditions yielded pMA1-transducing particles of P4 capsid size. These cloning-based analyses directly demonstrate that sid protein is the only P4 gene product required for small-capsid size determination. In the absence of the P2 O gene product no capsids of any size are assembled during solo infection by P2. Nevertheless, P2 Oam mutant superinfection of a host carrying pMA1 and pMA30 under induced conditions yielded small P4-sized transducing particles. We therefore propose that (i) the sid gene product competes with the O gene product to determine the assembly of small vs. large capsid sizes and (ii) both gene products probably function as temporary scaffolding proteins.


A Review of Surgical Nuances and Outcomes of the Reverse Stapedotomy.
The stapes surgery has evolved through different eras of technical and technological development. The current standard of care is creating a stapedotomy with piston placement, and both these aspects have multiple variations and show well-established technological advances. The conventional technique has been fairly standardized,and it offers gratifying results to both the surgeon and the patient. To overcome certain procedural risks and potential complications, the reversal of steps technique was developed and streamlined by Ugo Fisch in the early 1980s. Since its beginning, the technique has been adopted by various centers, and surgical outcomes have been demonstrated to be at par with the conventional technique, with a reduced risk of complications. The aim of the present review is to detail the various surgical nuances and outcomes of this particular technique in a comprehensive narrative manner.


From positive screen to engagement in treatment: a preliminary study of the impact of a new model of care for prisoners with serious mental illness.
The high prevalence of serious mental illness (SMI) in prisons remains a challenge for mental health services. Many prisoners with SMI do not receive care. Screening tools have been developed but better detection has not translated to higher rates of treatment. In New Zealand a Prison Model of Care (PMOC) was developed by forensic mental health and correctional services to address this challenge. The PMOC broadened triggers for referrals to mental health teams. Referrals were triaged by mental health nurses leading to multidisciplinary team assessment within specified timeframes. This pathway for screening, referral and assessment was introduced within existing resources. The PMOC was implemented across four prisons. An AB research design was used to explore the extent to which mentally ill prisoners were referred to and accepted by prison in-reach mental health teams and to determine the proportion of prison population receiving specialist mental health care. The number of prisoners in the study in the year before the PMOC (n = 9,349) was similar to the year after (n = 19,421). 24.6 % of prisoners were screened as per the PMOC in the post period. Referrals increased from 491 to 734 in the post period (Z = -7.23, p < 0.0001). A greater number of triage assessments occurred after the introduction of the PMOC (pre = 458; post = 613, Z = 4.74, p < 0.0001) leading to a significant increase in the numbers accepted onto in-reach caseloads (pre = 338; post = 426, Z = 3.16, p < 0.01). Numbers of triage assessments completed within specified time frames showed no statistically significant difference before or after implementation. The proportion of prison population on in-reach caseloads increased from 5.6 % in the pre period to 7.0 % in the year post implementation while diagnostic patterns did not change, indicating more prisoners with SMI were identified and engaged in treatment. The PMOC led to increased prisoner numbers across screening, referral, treatment and engagement. Gains were achieved without extra resources by consistent processes and improved clarity of professional roles and tasks. The PMOC described a more effective pathway to specialist care for people with SMI entering prison.


Theta burst stimulation reduces disability during the activities of daily living in spatial neglect.
Left-sided spatial neglect is a common neurological syndrome following right-hemispheric stroke. The presence of spatial neglect is a powerful predictor of poor rehabilitation outcome. In one influential account of spatial neglect, interhemispheric inhibition is impaired and leads to a pathological hyperactivity in the contralesional hemisphere, resulting in a biased attentional allocation towards the right hemifield. Inhibitory transcranial magnetic stimulation can reduce the hyperactivity of the contralesional, intact hemisphere and thereby improve spatial neglect symptoms. However, it is not known whether this improvement is also relevant to the activities of daily living during spontaneous behaviour. The primary aim of the present study was to investigate whether the repeated application of continuous theta burst stimulation trains could ameliorate spatial neglect on a quantitative measure of the activities of daily living during spontaneous behaviour. We applied the Catherine Bergego Scale, a standardized observation questionnaire that can validly and reliably detect the presence and severity of spatial neglect during the activities of daily living. Eight trains of continuous theta burst stimulation were applied over two consecutive days on the contralesional, left posterior parietal cortex in patients suffering from subacute left spatial neglect, in a randomized, double-blind, sham-controlled design, which also included a control group of neglect patients without stimulation. The results showed a 37% improvement in the spontaneous everyday behaviour of the neglect patients after the repeated application of continuous theta burst stimulation. Remarkably, the improvement persisted for at least 3 weeks after stimulation. The amelioration of spatial neglect symptoms in the activities of daily living was also generally accompanied by significantly better performance in the neuropsychological tests. No significant amelioration in symptoms was observed after sham stimulation or in the control group without stimulation. These results provide Class I evidence that continuous theta burst stimulation is a viable add-on therapy in neglect rehabilitation that facilitates recovery of normal everyday behaviour.


Endoscopic eradication therapy for mucosal neoplasia in Barrett's esophagus.
Endoscopic eradication therapy is frequently used to treat dysplasia and early cancers in Barrett's esophagus. This review addresses some of the recent developments in the field of endoscopic eradication therapy for Barrett's esophagus. Data on the effectiveness of Barrett's esophagus ablation programs have been published recently, with excellent results for dysplasia eradication. Studies describing long-term results have shed light on the durability of endoscopic ablation, with recurrence of Barrett's esophagus and neoplasia seen in some cases, particularly at the gastroesophageal junction. Risk factors for failed ablation include longer Barrett's esophagus segments and persistent gastroesophageal reflux. New developments include studies combining radiofrequency ablation (RFA) and endoscopic mucosal resection into a single endoscopic session, endoscopic submucosal dissection for Barrett's esophagus neoplasia, and a simplified RFA algorithm. New data on the cost-effectiveness of RFA have also been published, suggesting that RFA is cost-effective for both high-grade and low-grade dysplasia, but not for nondysplastic Barrett's esophagus. A systematic review has shown that lymph node metastases are rare (∼2%) with intramucosal adenocarcinoma, supporting the use of endoscopic eradication for that lesion. Research and clinical experience with the endoscopic therapies for Barrett's esophagus continue to grow. Proper patient selection and technique are critical for ensuring a good outcome. Endoscopic surveillance after any of the ablative therapies still appears to be necessary.


Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice.
The gut microbiome is linked to inflammatory bowel disease (IBD) severity and altered in late-stage disease. However, it is unclear how gut microbial communities change over the course of IBD development, especially in regard to function. To investigate microbiome-mediated disease mechanisms and discover early biomarkers of IBD, we conducted a longitudinal metagenomic investigation in an established mouse model of IBD, where damped transforming growth factor β (TGF-β) signaling in T cells leads to peripheral immune activation, weight loss, and severe colitis. IBD development is associated with abnormal gut microbiome temporal dynamics, including damped acquisition of functional diversity and significant differences in abundance trajectories for KEGG modules such as glycosaminoglycan degradation, cellular chemotaxis, and type III and IV secretion systems. Most differences between sick and control mice emerge when mice begin to lose weight and heightened T cell activation is detected in peripheral blood. However, levels of lipooligosaccharide transporter abundance diverge prior to immune activation, indicating that it could be a predisease indicator or microbiome-mediated disease mechanism. Taxonomic structure of the gut microbiome also significantly changes in association with IBD development, and the abundances of particular taxa, including several species of Bacteroides, correlate with immune activation. These discoveries were enabled by our use of generalized linear mixed-effects models to test for differences in longitudinal profiles between healthy and diseased mice while accounting for the distributions of taxon and gene counts in metagenomic data. These findings demonstrate that longitudinal metagenomics is useful for discovering the potential mechanisms through which the gut microbiome becomes altered in IBD. IMPORTANCE IBD patients harbor distinct microbial communities with functional capabilities different from those seen with healthy people. But is this cause or effect? Answering this question requires data on changes in gut microbial communities leading to disease onset. By performing weekly metagenomic sequencing and mixed-effects modeling on an established mouse model of IBD, we identified several functional pathways encoded by the gut microbiome that covary with host immune status. These pathways are novel early biomarkers that may either enable microbes to live inside an inflamed gut or contribute to immune activation in IBD mice. Future work will validate the potential roles of these microbial pathways in host-microbe interactions and human disease. This study was novel in its longitudinal design and focus on microbial pathways, which provided new mechanistic insights into the role of gut microbes in IBD development.


Antixenosis resistance to Oulema melanopus (Coleoptera: Chrysomelidae) in central Asian wheat germplasm.
ABSTRACT The cereal leaf beetle, Oulema melanopus (L.) (Coleoptera: Chrysomelidae), which is Eurasian in origin, is an emerging pest of agriculturally important cereal crops in western Canada, including wheat, oat, and barley. Among these crops, wheat (Triticum aestivum L.) has the highest number of resistant genotypes to O. melanopus infestation. Here we explored six genotypes from central Asia with putative resistance to the beetle in comparison with a widely grown Canadian wheat variety. We noted the highest oviposition on the susceptible control genotype, CDC GO, and the lowest on one of the central Asian genotypes (NN-100) in both choice and no-choice tests. Two of the other Asian genotypes (NN-78 and NN-105) were also less attractive for oviposition than the CDC GO check. Feeding trials also indicated less damage on some of the Asian genotypes (NN-100, NN-105, and NN-78) relative to CDC GO, but other Asian genotypes (NN-41, NN-45, and NN-27) were highly attractive for feeding and oviposition and did not exhibit stronger resistance to O. melanopus infestation than moderately resistant central Asian genotypes (NN-103, NN-78, or NN-105). There were no significant differences in the amount of feeding by overwintered and teneral adults. The results indicated that some wheat genotypes developed in central Asia have categories of nonpreference for feeding and oviposition worth considering in further development of host-plant resistance and integrated management of this pest.


Hedgehog organises the pattern and polarity of epidermal cells in the Drosophila abdomen.
The abdomen of adult Drosophila, like that of other insects, is formed by a continuous epithelium spanning several segments. Each segment is subdivided into an anterior (A) and posterior (P) compartment, distinguished by activity of the selector gene engrailed (en) in P but not A compartment cells. Here we provide evidence that Hedgehog (Hh), a protein secreted by P compartment cells, spreads into each A compartment across the anterior and the posterior boundaries to form opposing concentration gradients that organize cell pattern and polarity. We find that anteriorly and posteriorly situated cells within the A compartment respond in distinct ways to Hh: they express different combinations of genes and form different cell types. They also form polarised structures that, in the anterior part, point down the Hh gradient and, in the posterior part, point up the gradient - therefore all structures point posteriorly. Finally, we show that ectopic Hh can induce cells in the middle of each A compartment to activate en. Where this happens, A compartment cells are transformed into an ectopic P compartment and reorganise pattern and polarity both within and around the transformed tissue. Many of these results are unexpected and lead us to reassess the role of gradients and compartments in patterning insect segments.


Frequency-selective 3-D integration of nanoplasmonic circuits on a Si platform.
Vertical integration of nanoplasmonic circuits through the use of vertically coupled nanoring resonators was examined. The devices are shown to be capable of frequency selective signal transfer between device layers with planar device footprints on the order of 1.00 μm². The frequency selectivity of the devices is shown to be tunable through altering the radius of the coupled nanoring resonators. Coupling efficiencies of up to 39% between adjacent device layers are reached for two and three-levels coupling.


Enhancing the Physical Properties and Lifespan of Bacterial Quorum Quenching Media through Combination of Ionic Cross-Linking and Dehydration.
Quorum quenching (QQ) bacteria entrapped in a polymeric composite hydrogel (QQ medium) have been successfully applied in membrane bioreactors (MBRs) for effective biofouling control. However, in order to bring QQ technology closer to practice, the physical strength and lifetime of QQ media should be improved. In this study, enforcement of physical strength, as well as an extension of the lifetime of a previously reported QQ bacteria entrapping hollow cylinder (QQ-HC), was sought by adding a dehydration procedure following the cross-linking of the polymeric hydrogel by inorganic compounds like Ca2+ and boric acid. Such prepared medium demonstrated enhanced physical strength possibly through an increased degree of physical cross-linking. As a result, a longer lifetime of QQ-HCs was confirmed, which led to improved biofouling mitigation performance of QQ-HC in an MBR. Furthermore, QQ-HCs stored under dehydrated condition showed higher QQ activity when the storage time lasted more than 90 days owing to enhanced cell viability. In addition, the dormant QQ activity after the dehydration step could be easily restored through reactivation with real wastewater, and the reduced weight of the dehydrated media is expected to make handling and transportation of QQ media highly convenient and economical in practice.


Genomics and biology of Rudiviruses, a model for the study of virus-host interactions in Archaea.
Archaeal viruses, especially viruses that infect hyperthermophilic archaea of the phylum Crenarchaeota, constitute one of the least understood parts of the virosphere. However, owing to recent substantial research efforts by several groups, archaeal viruses are starting to gradually reveal their secrets. In the present review, we summarize the current knowledge on one of the emerging model systems for studies on crenarchaeal viruses, the Rudiviridae. We discuss the recent advances towards understanding the function and structure of the proteins encoded by the rudivirus genomes, their role in the virus life cycle, and outline the directions for further research on this model system. In addition, a revised genome annotation of SIRV2 (Sulfolobus islandicus rod-shaped virus 2) is presented. Future studies on archaeal viruses, combined with the knowledge on viruses of bacteria and eukaryotes, should lead to a better global understanding of the diversity and evolution of virus-host interactions in the viral world.


Internet-based cognitive behavior therapy for procrastination: study protocol for a randomized controlled trial.
Procrastination, to voluntarily delay an intended course of action despite expecting to be worse-off for the delay, is a persistent behavior pattern that can cause major psychological suffering. Approximately half of the student population and 15%-20% of the adult population are presumed having substantial difficulties due to chronic and recurrent procrastination in their everyday life. However, preconceptions and a lack of knowledge restrict the availability of adequate care. Cognitive behavior therapy (CBT) is often considered treatment of choice, although no clinical trials have previously been carried out. The aim of this study will be to test the effects of CBT for procrastination, and to investigate whether it can be delivered via the Internet. Participants will be recruited through advertisements in newspapers, other media, and the Internet. Only people residing in Sweden with access to the Internet and suffering from procrastination will be included in the study. A randomized controlled trial with a sample size of 150 participants divided into three groups will be utilized. The treatment group will consist of 50 participants receiving a 10-week CBT intervention with weekly therapist contact. A second treatment group with 50 participants receiving the same treatment, but without therapist contact, will also be employed. The intervention being used for the current study is derived from a self-help book for procrastination written by one of the authors (AR). It includes several CBT techniques commonly used for the treatment of procrastination (eg, behavioral activation, behavioral experiments, stimulus control, and psychoeducation on motivation and different work methods). A control group consisting of 50 participants on a wait-list control will be used to evaluate the effects of the CBT intervention. For ethical reasons, the participants in the control group will gain access to the same intervention following the 10-week treatment period, albeit without therapist contact. The current study is believed to result in three important findings. First, a CBT intervention is assumed to be beneficial for people suffering from problems caused by procrastination. Second, the degree of therapist contact will have a positive effect on treatment outcome as procrastination can be partially explained as a self-regulatory failure. Third, an Internet based CBT intervention is presumed to be an effective way to administer treatment for procrastination, which is considered highly important, as the availability of adequate care is limited. The current study is therefore believed to render significant knowledge on the treatment of procrastination, as well as providing support for the use of Internet based CBT for difficulties due to delayed tasks and commitments. To our knowledge, the current study is the first clinical trial to examine the effects of CBT for procrastination, and is assumed to render significant knowledge on the treatment of procrastination, as well as investigating whether it can be delivered via the Internet. ClinicalTrials.gov: NCT01842945; http://clinicaltrials.gov/show/NCT01842945 (Archived by WebCite at http://www.webcitation.org/6KSmaXewC).


Halogen-bonding in a new family of tris(haloanilato)metallate(III) magnetic molecular building blocks.
Here we report on new tris(haloanilato)metallate(III) complexes with general formula [A]3[M(X2An)3] (A = (n-Bu)4N(+), (Ph)4P(+); M = Cr(III), Fe(III); X2An = 3,6-dihalo derivatives of 2,5-dihydroxybenzoquinone (H4C6O4), chloranilate (Cl2An(2-)), bromanilate (Br2An(2-)) and iodanilate (I2An(2-))), obtained by a general synthetic strategy, and their full characterization. The crystal structures of these Fe(III) and Cr(III) haloanilate complexes consist of anions formed by homoleptic complexes formulated as [M(X2An)3](3-) and (Et)3NH(+), (n-Bu)4N(+), or (Ph4)P(+) cations. All complexes exhibit octahedral coordination geometry with metal ions surrounded by six oxygen atoms from three chelate ligands. These complexes are chiral according to the metal coordination of three bidentate ligands, and both Λ and Δ enantiomers are present in their crystal lattice. The packing of [(n-Bu)4N]3[Cr(I2An)3] (5a) shows that the complexes form supramolecular dimers that are held together by two symmetry related I···O interactions (3.092(8) Å), considerably shorter than the sum of iodine and oxygen van der Waals radii (3.50 Å). The I···O interaction can be regarded as a halogen bond (XB), where the iodine behaves as the XB donor and the oxygen atom as the XB acceptor. This is in agreement with the properties of the electrostatic potential for [Cr(I2An)3](3-) that predicts a negative charge accumulation on the peripheral oxygen atoms and a positive charge accumulation on the iodine. The magnetic behaviour of all complexes, except 5a, may be explained by considering a set of paramagnetic non-interacting Fe(III) or Cr(III) ions, taking into account the zero-field splitting effect. The presence of strong XB interactions in 5a are able, instead, to promote antiferromagnetic interactions among paramagnetic centers at low temperature, as shown by the fit with the Curie-Weiss law, in agreement with the formation of halogen-bonded supramolecular dimers.


Genetic Factors That Could Affect Concussion Risk in Elite Rugby.
Elite rugby league and union have some of the highest reported rates of concussion (mild traumatic brain injury) in professional sport due in part to their full-contact high-velocity collision-based nature. Currently, concussions are the most commonly reported match injury during the tackle for both the ball carrier and the tackler (8-28 concussions per 1000 player match hours) and reports exist of reduced cognitive function and long-term health consequences that can end a playing career and produce continued ill health. Concussion is a complex phenotype, influenced by environmental factors and an individual's genetic predisposition. This article reviews concussion incidence within elite rugby and addresses the biomechanics and pathophysiology of concussion and how genetic predisposition may influence incidence, severity and outcome. Associations have been reported between a variety of genetic variants and traumatic brain injury. However, little effort has been devoted to the study of genetic associations with concussion within elite rugby players. Due to a growing understanding of the molecular characteristics underpinning the pathophysiology of concussion, investigating genetic variation within elite rugby is a viable and worthy proposition. Therefore, we propose from this review that several genetic variants within or near candidate genes of interest, namely APOE, MAPT, IL6R, COMT, SLC6A4, 5-HTTLPR, DRD2, DRD4, ANKK1, BDNF and GRIN2A, warrant further study within elite rugby and other sports involving high-velocity collisions.


Image analysis in high-content screening.
The field of High Content Screening (HCS) has evolved from a technology used exclusively by the pharmaceutical industry for secondary drug screening, to a technology used for primary drug screening and basic research in academia. The size and the complexity of the screens have been steadily increasing. This is reflected in the fact that the major challenges facing the field at the present are data mining and data storage due to the large amount of data generated during HCS. On the one hand, technological progress of fully automated image acquisition platforms, and on the other hand advances in the field of automated image analysis have made this technology more powerful and more accessible to less specialized users. Image analysis solutions for many biological problems exist and more are being developed to increase both the quality and the quantity of data extracted from the images acquired during the screens. We highlight in this review some of the major challenges facing automatic high throughput image analysis and present some of the software solutions available on the market or from academic open source solutions.


Genetic evidence of a coupling role for the TraG protein family in bacterial conjugation.
The ability of conjugative plasmids from six different incompatibility groups to mobilize a set of mobilizable plasmids was examined. The mobilization frequencies of plasmids RSF1010, ColE1, ColE3, and CloDF13 varied over seven orders of magnitude, depending on the helper conjugative plasmid used. Mobilization of CloDF13 was unique in that it did not require TrwB, TraG or TraD (all members of the TraG family) for mobilization by R388, RP4 or F, respectively. CloDF13 itself codes for an essential mobilization protein (MobB) which is also a TraG homolog, only requiring a source of the genes for pilus formation. Besides, CloDF13 was mobilized efficiently by all conjugative plasmids, suggesting that TraG homologs are the primary determinants of the mobilization efficiency of a plasmid, interacting differentially with the various relaxosomes. Previous results indicated that TraG and TrwB were interchangeable for mobilization of RSF1010 and ColE1 by PILw (the pilus system of IncW plasmids) but TraG could not complement conjugation of trwB mutants, suggesting that additional interactions were taking place between TrwB and oriT(R388) that were not essential for mobilization. To further test this hypothesis, we analyzed the mobilization frequencies of ColE1 and RSF1010 by the P, W, and F pili in the presence of alternative TraG homologs. The results obtained indicated that the frequency of mobilization was determined both by the particular TraG-like protein used and by the pilus system. Thus, TraG-like proteins are not generally interchangeable for mobilization. Therefore we suggest that the factors that determine the frequencies of transfer of different MOB regions are the differential interactions of TrwB with pilus and relaxosome.


Visual hallucinations in photographs in Parkinson's disease.
Visual hallucinations are reported in 16-37% of drug-treated patients with Parkinson's disease (PD) and are the most common hallucinations in PD. We report two patients with PD with symptoms that uniquely integrate visual hallucinations and delusions. We report two cases of patients with PD with visual hallucinations who saw the persistence of these hallucinations in photographs. These pictures were taken to prove the absence of these hallucinations. We believe this is the first description of this peculiar phenomenon, in which hallucinations or illusions could be replicated in photographs. Both patients had delusions associated with the images and we speculate that the images they saw in the photographs represent a further delusion, hence a 'delusional hallucination' or 'delusional illusion.' We believe that delusions fostering hallucinations are rare.


Peripheral blood cytotoxic gammadelta T lymphocytes from patients with human immunodeficiency virus type 1 infection and AIDS lyse uninfected CD4+ T cells, and their cytocidal potential correlates with viral load.
Progression of human immunodeficiency virus type 1 (HIV-1) infection in humans is marked by declining CD4+-T-cell counts and increasing virus load (VL). Cytotoxic T lymphocytes (CTL) play an important role in the lysis of HIV-infected cells, especially during the early phase of asymptomatic infection. CTL responses in the later phase of disease progression may not be as effective since progressors with lower CD4+-T-cell counts have consistently higher VL despite having elevated CTL counts. We hypothesized that, apart from antiviral effects, some CTL might also contribute to AIDS pathogenesis by depleting CD4+ T cells and that this CTL activity may correlate with the VL in AIDS patients. Therefore, a cross-sectional study of 31 HIV-1-infected patients at various clinical stages was carried out. Purified CTL from these donors as well as HIV-seronegative controls were used as effectors against different human cell targets by using standard 51Cr release cytolytic assays. A direct correlation between VL and CTL-mediated, major histocompatibility complex (MHC)-unrestricted lysis of primary CD4+-T-cell, CEM.NKR, and K562 targets was observed. CD4+-T-cell counts and duration of infection also correlated with MHC-unrestricted cytolytic activity. Our data clearly show that gammadelta CTL are abnormally expanded in the peripheral blood of HIV-infected patients and that the Vdelta1 subset of gammadelta T cells is the main effector population responsible for this type of cytolysis. The present data suggest that gammadelta CTL can contribute to the depletion of bystander CD4+ T cells in HIV-infected patients as a parallel mechanism to HIV-associated immunopathogenesis and hence expedite AIDS progression.


Characteristics of Beverage Consumption Habits among a Large Sample of French Adults: Associations with Total Water and Energy Intakes.
Adequate hydration is a key factor for correct functioning of both cognitive and physical processes. In France, public health recommendations about adequate total water intake (TWI) only state that fluid intake should be sufficient, with particular attention paid to hydration for seniors, especially during heatwave periods. The objective of this study was to calculate the total amount of water coming from food and beverages and to analyse characteristics of consumption in participants from a large French national cohort. TWI, as well as contribution of food and beverages to TWI was assessed among 94,939 adult participants in the Nutrinet-Santé cohort (78% women, mean age 42.9 (SE 0.04)) using three 24-h dietary records at baseline. Statistical differences in water intakes across age groups, seasons and day of the week were assessed. The mean TWI was 2.3 L (Standard Error SE 4.7) for men and 2.1 L (SE 2.4) for women. A majority of the sample did comply with the European Food Safety Authority (EFSA) adequate intake recommendation, especially women. Mean total energy intake (EI) was 1884 kcal/day (SE 1.5) (2250 kcal/day (SE 3.6) for men and 1783 kcal/day (SE 1.5) for women). The contribution to the total EI from beverages was 8.3%. Water was the most consumed beverage, followed by hot beverages. The variety score, defined as the number of different categories of beverages consumed during the three 24-h records out of a maximum of 8, was positively correlated with TWI (r = 0.4); and with EI (r = 0.2), suggesting that beverage variety is an indicator of higher consumption of food and drinks. We found differences in beverage consumptions and water intakes according to age and seasonality. The present study gives an overview of the water intake characteristics in a large population of French adults. TWI was found to be globally in line with public health recommendations.


Comparative analyses of parasites with a comprehensive database of genome-scale metabolic models.
Protozoan parasites cause diverse diseases with large global impacts. Research on the pathogenesis and biology of these organisms is limited by economic and experimental constraints. Accordingly, studies of one parasite are frequently extrapolated to infer knowledge about another parasite, across and within genera. Model in vitro or in vivo systems are frequently used to enhance experimental manipulability, but these systems generally use species related to, yet distinct from, the clinically relevant causal pathogen. Characterization of functional differences among parasite species is confined to post hoc or single target studies, limiting the utility of this extrapolation approach. To address this challenge and to accelerate parasitology research broadly, we present a functional comparative analysis of 192 genomes, representing every high-quality, publicly-available protozoan parasite genome including Plasmodium, Toxoplasma, Cryptosporidium, Entamoeba, Trypanosoma, Leishmania, Giardia, and other species. We generated an automated metabolic network reconstruction pipeline optimized for eukaryotic organisms. These metabolic network reconstructions serve as biochemical knowledgebases for each parasite, enabling qualitative and quantitative comparisons of metabolic behavior across parasites. We identified putative differences in gene essentiality and pathway utilization to facilitate the comparison of experimental findings and discovered that phylogeny is not the sole predictor of metabolic similarity. This knowledgebase represents the largest collection of genome-scale metabolic models for both pathogens and eukaryotes; with this resource, we can predict species-specific functions, contextualize experimental results, and optimize selection of experimental systems for fastidious species.


Evaluating multimedia/multipathway model intake fraction estimates using POP emission and monitoring data.
This paper presents a structured evaluation of a novel multimedia chemical fate and multi-pathway human exposure model for Western Europe, IMPACT 2002, using data for PCDD/F congeners. PCDD/F congeners provide an illustration of the potential use of POPs (Persistent Organic Pollutant) data for the evaluation of such models. Based on available emission estimates, model predictions with and without spatial resolution are evaluated at three different stages against monitored data: at environmental contamination levels, food exposure concentration, and in terms of human intake fractions (iF): the fraction of an emission that is taken in by the population. The iF is approximately 3.5.10(-3) for emissions of dioxin in Western Europe. This iF compares well to the traditional non-spatial multi-media/-pathway model predictions of 3.9.10(-3) for the same region and to 2.10(-3) for the USA. Approximately 95% of the intake from Western European emissions occurs within the same region, 5% being transferred out of the region in terms of food contaminants and atmospheric advective transport.


The appropriate and justified use of medical radiation in cardiovascular imaging: a position document of the ESC Associations of Cardiovascular Imaging, Percutaneous Cardiovascular Interventions and Electrophysiology.
The benefits of cardiac imaging are immense, and modern medicine requires the extensive and versatile use of a variety of cardiac imaging techniques. Cardiologists are responsible for a large part of the radiation exposures every person gets per year from all medical sources. Therefore, they have a particular responsibility to avoid unjustified and non-optimized use of radiation, but sometimes are imperfectly aware of the radiological dose of the examination they prescribe or practice. This position paper aims to summarize the current knowledge on radiation effective doses (and risks) related to cardiac imaging procedures. We have reviewed the literature on radiation doses, which can range from the equivalent of 1-60 milliSievert (mSv) around a reference dose average of 15 mSv (corresponding to 750 chest X-rays) for a percutaneous coronary intervention, a cardiac radiofrequency ablation, a multidetector coronary angiography, or a myocardial perfusion imaging scintigraphy. We provide a European perspective on the best way to play an active role in implementing into clinical practice the key principle of radiation protection that: 'each patient should get the right imaging exam, at the right time, with the right radiation dose'.


Enhancement in Site-Specific Delivery of Carvacrol against Methicillin Resistant Staphylococcus aureus Induced Skin Infections Using Enzyme Responsive Nanoparticles: A Proof of Concept Study.
Methicillin resistant Staphylococcus aureus (MRSA) induced skin infections have become a challenging problem due to the escalating antibiotic resistance. Carvacrol (CAR) has been reported to be effective against MRSA. However, due to its characteristics, CAR exhibits low skin retention. In this study, CAR was formulated into site-specific nanoparticle (NPs) delivery system using poly(ε-caprolactone) (PCL), following incorporation into a hydrogel matrix to facilitate dermal delivery. The release study exhibited significantly higher release of CAR from PCL NPs in the presence of bacterial lipase, highlighting its potential for differential delivery. Moreover, encapsulation of CAR in PCL NPs resulted in a two-fold increase in its anti-MRSA activity. Dermatokinetic studies revealed that the NPs loaded hydrogel was able to enhance skin retention of CAR after 24 h (83.29 ± 3.15%), compared to free CAR-loaded hydrogel (0.85 ± 0.14%). Importantly, this novel approach exhibited effective antimicrobial activity in an ex-vivo skin infection model. Hence, these findings have proven the concept that the loading of CAR into a responsive NPs system can lead to sustained antimicrobial effect at the desired site, and may provide a novel effective approach for treatment of MRSA induced skin infections. However, further studies must be conducted to investigate in-vivo efficacy of the developed system in an appropriate infection model.


Ethnicity and drug therapy for hypertension.
Physiological and pharmacological responses may be influenced by ethnicity as a result of genetic factors, environmental factors and/or their interaction. This review is divided into 2 parts. Firstly, there will be overview of ethnicity as a determinant of drug metabolism and response with reference to antihypertensive agents. The concept of ethnicity has been applied extensively to the study of hypertension especially in American blacks in whom the hypertension is more common and more aggressive. Thus, the second part of this review will then focus on examining the black-white differences in physiological responses to pharmacological challenge that may provide a link between these models and known ethnic differences in drug responses. We will discuss the hypertension studies that have examined the relative effectiveness of different classes of antihypertensive agents including several recent cardiovascular outcome trials that either have a high proportion of blacks or were conducted entirely in black subjects.


The quorum-sensing molecules farnesol/homoserine lactone and dodecanol operate via distinct modes of action in Candida albicans.
Living as a commensal, Candida albicans must adapt and respond to environmental cues generated by the mammalian host and by microbes comprising the natural flora. These signals have opposing effects on C. albicans, with host cues promoting the yeast-to-hyphal transition and bacteria-derived quorum-sensing molecules inhibiting hyphal development. Hyphal development is regulated through modulation of the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway, and it has been postulated that quorum-sensing molecules can affect filamentation by inhibiting the cAMP pathway. Here, we show that both farnesol and 3-oxo-C(12)-homoserine lactone, a quorum-sensing molecule secreted by Pseudomonas aeruginosa, block hyphal development by affecting cAMP signaling; they both directly inhibited the activity of the Candida adenylyl cyclase, Cyr1p. In contrast, the 12-carbon alcohol dodecanol appeared to modulate hyphal development and the cAMP signaling pathway without directly affecting the activity of Cyr1p. Instead, we show that dodecanol exerted its effects through a mechanism involving the C. albicans hyphal repressor, Sfl1p. Deletion of SFL1 did not affect the response to farnesol but did interfere with the response to dodecanol. Therefore, quorum sensing in C. albicans is mediated via multiple mechanisms of action. Interestingly, our experiments raise the possibility that the Burkholderia cenocepacia diffusible signal factor, BDSF, also mediates its effects via Sfl1p, suggesting that dodecanol's mode of action, but not farnesol or 3-oxo-C(12)-homoserine lactone, may be used by other quorum-sensing molecules.