Anomaly Detection in Host Signaling Pathways for the Early Prognosis of Acute Infection.
Clinical diagnosis of acute infectious diseases during the early stages of infection is critical to administering the appropriate treatment to improve the disease outcome. We present a data driven analysis of the human cellular response to respiratory viruses including influenza, respiratory syncytia virus, and human rhinovirus, and compared this with the response to the bacterial endotoxin, Lipopolysaccharides (LPS). Using an anomaly detection framework we identified pathways that clearly distinguish between asymptomatic and symptomatic patients infected with the four different respiratory viruses and that accurately diagnosed patients exposed to a bacterial infection. Connectivity pathway analysis comparing the viral and bacterial diagnostic signatures identified host cellular pathways that were unique to patients exposed to LPS endotoxin indicating this type of analysis could be used to identify host biomarkers that can differentiate clinical etiologies of acute infection. We applied the Multivariate State Estimation Technique (MSET) on two human influenza (H1N1 and H3N2) gene expression data sets to define host networks perturbed in the asymptomatic phase of infection. Our analysis identified pathways in the respiratory virus diagnostic signature as prognostic biomarkers that triggered prior to clinical presentation of acute symptoms. These early warning pathways correctly predicted that almost half of the subjects would become symptomatic in less than forty hours post-infection and that three of the 18 subjects would become symptomatic after only 8 hours. These results provide a proof-of-concept for utility of anomaly detection algorithms to classify host pathway signatures that can identify presymptomatic signatures of acute diseases and differentiate between etiologies of infection. On a global scale, acute respiratory infections cause a significant proportion of human co-morbidities and account for 4.25 million deaths annually. The development of clinical diagnostic tools to distinguish between acute viral and bacterial respiratory infections is critical to improve patient care and limit the overuse of antibiotics in the medical community. The identification of prognostic respiratory virus biomarkers provides an early warning system that is capable of predicting which subjects will become symptomatic to expand our medical diagnostic capabilities and treatment options for acute infectious diseases. The host response to acute infection may be viewed as a deterministic signaling network responsible for maintaining the health of the host organism. We identify pathway signatures that reflect the very earliest perturbations in the host response to acute infection. These pathways provide a monitor the health state of the host using anomaly detection to quantify and predict health outcomes to pathogens.


Risk and Protective Factors for Self-Harm in a Population-Based Sample of Transgender Youth.
This study sought to identify factors distinguishing transgender/gender non-conforming (GNC) adolescents across three groups: no self-harm, non-suicidal self-injury (NSSI) only, and NSSI and suicide attempt (NSSI + SA). Data were from the 2016 Minnesota Student Survey. The final analytic sample included 1,635 transgender/GNC students in grades 9 and 11. Logistic regression analyses determined factors that best distinguished transgender/GNC students who reported self-harm (NSSI only or NSSI + SA) from those who reported no self-harm, and transgender/GNC adolescents who reported NSSI + SA from those who reported NSSI only. Final models were developed over 3 stages of analysis that tested associations of variables within risk factor, protective factor, and health-risk behavior domains to self-harm. Over half (51.6%) of transgender/GNC adolescents reported past-year self-harm behavior. Factors that consistently distinguished transgender/GNC youth who reported self-harm from those who reported no self-harm included reports of a mental health problem, depression, running away from home, and substance use (alcohol or marijuana use). Factors that distinguished the NSSI + SA group from the NSSI only group were reports of a mental health problem, physical or sexual abuse, relationship violence, bullying victimization, less parent connectedness, lower grades, lower levels of perceived school safety, and running away from home. Clinicians and school personnel need to be prepared to address risk factors and enhance protective factors that may reduce the likelihood this population of vulnerable youth will engage in NSSI and/or attempt suicide.


Affinity and specificity of N-methyl- D-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats.
Phencyclidine (PCP) binds with high affinity to a site located within the ionophore of N-methyl- D-aspartate (NMDA) receptors. Previous studies have demonstrated that PCP and other high-affinity NMDA channel blockers reliably disrupt prepulse inhibition (PPI) of acoustic startle, an animal model of sensorimotor gating used to study attentional deficits associated with schizophrenia. Recently, a number of low-affinity NMDA channel blockers that exhibit minimal PCP-like effects in humans at therapeutic doses have been developed. The purpose of this study was to evaluate the effects on PPI of NMDA channel blockers with varying affinities for the channel site as well as different specificities for NMDA receptors. Sprague-Dawley rats were presented with multiple stimulus presentation trials, including pulse-alone and PPI trials. As expected, the high-affinity ligands dizocilpine and dextrorphan disrupted PPI at doses that did not affect the response during pulse-alone trials. Low-affinity drugs produced a mixed pattern of results. Whereas dextromethorphan and memantine disrupted PPI, orphenadrine, amantadine, desipramine, and alaproclate did not affect this response. Ibogaine also disrupted PPI, but only within a dose range that severely decreased the startle response during pulse-alone trials. These results suggest that not all NMDA channel blockers share PCP's effect of PPI disruption. In addition, they suggest caution in the use of supratherapeutic doses of these compounds and in their use in vulnerable populations (e.g., schizophrenic patients).


Evidence that the Great Pacific Garbage Patch is rapidly accumulating plastic.
Ocean plastic can persist in sea surface waters, eventually accumulating in remote areas of the world's oceans. Here we characterise and quantify a major ocean plastic accumulation zone formed in subtropical waters between California and Hawaii: The Great Pacific Garbage Patch (GPGP). Our model, calibrated with data from multi-vessel and aircraft surveys, predicted at least 79 (45-129) thousand tonnes of ocean plastic are floating inside an area of 1.6 million km2; a figure four to sixteen times higher than previously reported. We explain this difference through the use of more robust methods to quantify larger debris. Over three-quarters of the GPGP mass was carried by debris larger than 5 cm and at least 46% was comprised of fishing nets. Microplastics accounted for 8% of the total mass but 94% of the estimated 1.8 (1.1-3.6) trillion pieces floating in the area. Plastic collected during our study has specific characteristics such as small surface-to-volume ratio, indicating that only certain types of debris have the capacity to persist and accumulate at the surface of the GPGP. Finally, our results suggest that ocean plastic pollution within the GPGP is increasing exponentially and at a faster rate than in surrounding waters.


Clustering in surgical trials--database of intracluster correlations.
Randomised trials evaluation of surgical interventions are often designed and analysed as if the outcome of individual patients is independent of the surgeon providing the intervention. There is reason to expect outcomes for patients treated by the same surgeon tend to be more similar than those under the care of another surgeon due to previous experience, individual practice, training, and infrastructure. Such a phenomenon is referred to as the clustering effect and potentially impacts on the design and analysis adopted and thereby the required sample size. The aim of this work was to inform trial design by quantifying clustering effects (at both centre and surgeon level) for various outcomes using a database of surgical trials. Intracluster correlation coefficients (ICCs) were calculated for outcomes from a set of 10 multicentre surgical trials for a range of outcomes and different time points for clustering at both the centre and surgeon level. ICCs were calculated for 198 outcomes across the 10 trials at both centre and surgeon cluster levels. The number of cases varied from 138 to 1370 across the trials. The median (range) average cluster size was 32 (9 to 51) and 6 (3 to 30) for centre and surgeon levels respectively. ICC estimates varied substantially between outcome type though uncertainty around individual ICC estimates was substantial, which was reflected in generally wide confidence intervals. This database of surgical trials provides trialists with valuable information on how to design surgical trials. Our data suggests clustering of outcome is more of an issue than has been previously acknowledged. We anticipate that over time the addition of ICCs from further surgical trial datasets to our database will further inform the design of surgical trials.


Oropharyngeal Dysphagia and Cerebral Palsy.
To determine the progression of oropharyngeal dysphagia (OPD) in preschool-aged children with cerebral palsy (CP) according to gross motor function. It was hypothesized that fewer children would have OPD at 60 months compared with 18 to 24 months (predominately Gross Motor Function Classification System [GMFCS] I-II). Longitudinal population-based cohort of 179 children (confirmed CP diagnosis, born in Queensland in 2006-2009, aged 18-60 months at study entry [mean = 34.1 months ± 11.9; 111 boys; GMFCS I = 46.6%, II = 12.9%, III = 15.7%, IV = 10.1%, and V = 14.6%]). Children had a maximum of 3 assessments (median = 3, total n = 423 assessments). OPD was classified by using the Dysphagia Disorders Survey part 2 and rated from video by a certified pediatric speech pathologist. GMFCS was used to classify children's gross motor function. OPD prevalence reduced from 79.7% at 18 to 24 months to 43.5% at 60 months. There were decreasing odds of OPD with increasing age (odds ratio [OR] = 0.92 [95% confidence interval (CI) 0.90 to 0.95]; P < .001) and increasing odds with poorer gross motor function (OR = 6.2 [95% CI 3.6 to 10.6]; P < .001). This reduction was significant for children with ambulatory CP (GMFCS I-II, OR = 0.93 [95% CI 0.90 to 0.96]; P < .001) but not significant for children from GMFCS III to V (OR [III] = 1.0 [95% CI 0.9 to 1.1]; P = .897; OR [IV-V] = 1.0 [95% CI 1.0 to 1.1]; P = .366). Half of the OPD present in children with CP between 18 and 24 months resolved by 60 months, with improvement most common in GMFCS I to II. To more accurately detect and target intervention at children with persisting OPD at 60 months, we suggest using a more conservative cut point of 6 out of 22 on the Dysphagia Disorders Survey for assessments between 18 and 48 months.


Physical constraints on charge transport through bacterial nanowires.
Extracellular appendages of the dissimilatory metal-reducing bacterium Shewanella oneidensis MR-1 were recently shown to sustain currents of 10(10) electrons per second over distances of 0.5 microns [El-Naggar et al., Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 18127]. However, the identity of the charge localizing sites and their organization along the "nanowire" remain unknown. We use theory to predict redox cofactor separation distances that would permit charge flow at rates of 10(10) electrons per second over 0.5 microns for voltage biases of < or = IV, using a steady-state analysis governed by a non-adiabatic electron transport mechanism. We find the observed currents necessitate a multi-step hopping transport mechanism, with charge localizing sites separated by less than 1 nm and reorganization energies that rival the lowest known in biology.


High-Performance Polymers and Their Potential Application as Medical and Oral Implant Materials: A Review.
To review the literature on high-performance polymeric (HPP) materials used as medical and oral implants and make comparisons with the commonly used titanium. Original scientific articles published in English in MEDLINE (PubMed-NCBI) and Picarta literature databases between January 01, 1995 and June 01, 2013 were included in this review. Additional information was derived from scientific reports, medical and chemical textbooks, handbooks, product information, manufacturers' instructions, and Internet web sites of the manufacturers. Based on the 7 animal studies and 1 clinical study, HPP polyetheretherketone (PEEK) consisting of a single monomer and featuring a low Young modulus may be advantageous. PEEK seems to lead to less osteolyses and healing problems and no scattering in radiation was observed. Some animal studies showed direct contact between PEEK and the bone with high biocompatibility and no evidence for cytotoxicity, mutagenicity, carcinogenicity, and immunogenicity to the present day. The HPPs (ie, PEEK) may carry some potential to be an alternative material for titanium as medical and dental implants. Yet, clinical and animal studies are limited in the field of implantology with such materials.


Choosing the best method to estimate the energy density of a population using food purchase data.
Energy density (ED) is a measure of the energy content of a food component or diet relative to a standard unit of weight. Widespread variation in ED assessment methodologies exist. The present study aimed to explore the feasibility of calculating the ED of the Scottish diet using UK food purchase survey data and to identify the most appropriate method for calculating ED for use in the development of a Scottish Dietary Goal that captures any socioeconomic differences. Energy density was calculated using five different methods [food; food and milk; food, milk and energy containing (non-alcoholic) beverages; food, milk and all non-alcoholic beverages; and all food and beverages]. ED of the Scottish diet was estimated for each of the ED methods and data were examined by deprivation category. Mean ED varied from 409 to 847 kJ 100 g(-1) depending on the method used. ED values calculated from food (847 kJ 100 g(-1) ) and food and milk (718 kJ 100 g(-1) ) were most comparable to other published data, with the latter being a more accurate reflection of all food consumed. For these two methods, there was a significant gradient between the most and least deprived quintiles (892-807 and 737-696 kJ 100 g(-1) for food and food and milk, respectively). Because the World Cancer Research Fund recommendations are based on ED from food and milk, it was considered prudent to use this method for policy purposes and for future monitoring work of the Scottish Diet to ensure consistency of reporting and comparability with other published studies.


Using breast milk to assess breast cancer risk: the role of mass spectrometry-based proteomics.
Although mammography and treatment advances have led to declines in breast cancer mortality in the United States, breast cancer remains a major cause of morbidity and mortality. Breast cancer in young women is associated with increased mortality and current methods of detecting breast cancers in this group of women have known limitations. Tools for accurately assessing personal breast cancer risk in young women are needed to identify those women who would benefit the most from earlier intervention. Proteomic analysis of breast milk could identify biomarkers of breast cancer risk and provide a tool for identifying women at increased risk. A preliminary analysis of milk from four women provides a proof of concept for using breast milk to assess breast cancer risk.


Caring for mom and neglecting yourself? The health effects of caring for an elderly parent.
We examine the physical and mental health effects of providing care to an elderly mother on the adult child caregiver. We address the endogeneity of the selection in and out of caregiving using an instrumental variable approach, using the death of the care recipient and sibling characteristics. We also carefully control for baseline health and work status of the adult child. We explore flexible specifications, such as Arellano-Bond estimation techniques. Continued caregiving over time increases depressive symptoms and decreases self-rated health for married women and married men. In addition, the increase in depressive symptoms is persistent for married women. While depressive symptoms for single men and women are not affected by continued caregiving, there is evidence of increased incidence of heart conditions for single men, and that these effects are persistent. Robustness checks indicate that these health changes can be directly attributable to caregiving behavior, and not due to a direct effect of the death of the mother. The initial onset of caregiving has modest immediate negative effects on depressive symptoms for married women and no immediate effects on physical health. Negative physical health effects emerge 2 years later, however, suggesting that there are delayed effects on health that would be missed with a short recall period. Initial caregiving does not affect health of married men.


Bladder wall thickness on ultrasonographic cystourethrography: affecting factors and their implications.
To explore factors affecting bladder wall thickness on ultrasonographic cystourethrography in female patients with lower urinary tract symptoms. The records of 492 female patients with lower urinary tract symptoms who had undergone a urodynamic study and ultrasonography of the lower urinary tract and who had normal urinalysis findings, negative urine culture results, or both were identified from our urogynecologic database. These included 248 patients with urodynamic stress incontinence, 38 with detrusor overactivity, 39 with mixed incontinence, 35 with a hypersensitive bladder, 42 with voiding difficulty, and 90 with normal urodynamic findings. Age, resting bladder neck angle, urethral mobility, and maximum urethral closure pressure were significantly associated with bladder wall thickness at the trigone and dome. Bladder wall thickness at the trigone was correlated with that at the dome (P < .0001). Bladder wall thickness at the trigone was positively correlated with pressure transmission ratios in the first and second quarters of the urethra (P < .0001; P = .002, respectively), whereas that at the dome was positively correlated with intravesical pressure at maximum flow and with detrusor opening pressure (P = .027; P = .046, respectively). Age and intravesical pressure at maximum flow were independently associated with bladder wall thickness at the trigone and dome (P = .007; P = .028), respectively. A thickened bladder wall was a common finding in female lower urinary tract symptoms, except in the patients with a hypersensitive bladder. Demographic, anatomic, and urodynamic factors may affect the bladder wall thickness at the trigone, dome, or both.


Electron beam fabrication of a microfluidic device for studying submicron-scale bacteria.
Controlled restriction of cellular movement using microfluidics allows one to study individual cells to gain insight into aspects of their physiology and behaviour. For example, the use of micron-sized growth channels that confine individual Escherichia coli has yielded novel insights into cell growth and death. To extend this approach to other species of bacteria, many of whom have dimensions in the sub-micron range, or to a larger range of growth conditions, a readily-fabricated device containing sub-micron features is required. Here we detail the fabrication of a versatile device with growth channels whose widths range from 0.3 μm to 0.8 μm. The device is fabricated using electron beam lithography, which provides excellent control over the shape and size of different growth channels and facilitates the rapid-prototyping of new designs. Features are successfully transferred first into silicon, and subsequently into the polydimethylsiloxane that forms the basis of the working microfluidic device. We demonstrate that the growth of sub-micron scale bacteria such as Lactococcus lactis or Escherichia coli cultured in minimal medium can be followed in such a device over several generations. We have presented a detailed protocol based on electron beam fabrication together with specific dry etching procedures for the fabrication of a microfluidic device suited to study submicron-sized bacteria. We have demonstrated that both Gram-positive and Gram-negative bacteria can be successfully loaded and imaged over a number of generations in this device. Similar devices could potentially be used to study other submicron-sized organisms under conditions in which the height and shape of the growth channels are crucial to the experimental design.


Complete primary structures of two major murine serum amyloid A proteins deduced from cDNA sequences.
cDNA clones encoding two major mouse serum amyloid A proteins, SAA1 and SAA2, were isolated from a liver cDNA library of the lipopolysaccharide-stimulated BALB/c mouse, and their nucleotide sequences were determined. The insert of the SAA2 cDNA clone contained 607 nucleotides with a 5' untranslated region of 36 nucleotides, a signal peptide region corresponding to 19 amino acids, a mature protein region corresponding to 103 amino acids, and a 3' untranslated region of 202 nucleotides. The SAA1 cDNA insert contained 549 nucleotides specifying a part of a signal peptide region, a mature protein region, and a 3' untranslated region. A comparison of the nucleotide and deduced amino acid sequences of SAA1 cDNA with that of SAA2 cDNA showed a high degree of homology: 95% nucleotide sequence homology in the coding region (91% amino acid sequence homology) and 90% homology in the 3' untranslated region. One of nine amino acid differences between SAA1 and SAA2 predicted from the cDNA sequences was located in a putative proteolytic cleavage site for amyloid A protein formation: SAA2 had the Thr-Met sequence in this site, while SAA1 had the Thr-Ile sequence. This suggests that SAA1, which does not deposit as amyloid A protein, is also potentially susceptible to putative proteolytic enzymes. In addition, as compared with mouse SAA2, human SAA1, monkey and mink amyloid A protein, mouse SAA1 had two unique substitutions, which may play a role in differential deposition of mouse SAA isotypes in amyloid tissues.


Bax to the future - A novel, high-yielding approach for purification and expression of full-length Bax protein for structural studies.
Mitochondria-mediated apoptosis (programmed cell death) involves a sophisticated signaling and regulatory network that is regulated by the Bcl-2 protein family. Members of this family have either pro- or anti-apoptotic functions. An important pro-apoptotic member of this family is the cytosolic Bax. This protein is crucial for the onset of apoptosis by perforating the mitochondrial outer membrane (MOM). This process can be seen as point of no return, since disintegration of the MOM leads to the release of apotogenic factors such as cytochrome c into the cytosol triggering the activation of caspases and subsequent apoptotic steps. Bax is able to interact with the MOM with both its termini, making it inherently difficult to express in E. coli. In this study, we present a novel approach to express and purify full-length Bax with significantly increased yields, when compared to the commonly applied strategy. Using a double fusion approach with an N-terminal GST-tag and a C-terminal Intein-CBD-tag, we were able to render both Bax termini inactive and prevent disruptive interactions from occurring during gene expression. By deploying an Intein-CBD-tag at the C-terminus we were further able to avoid the introduction of any artificial residues, hence ensuring the native like activity of the membrane-penetrating C-terminus of Bax. Further, by engineering a His6-tag to the C-terminus of the CBD-tag we greatly improved the robustness of the purification procedure. We report yields for pure, full-length Bax protein that are increased by an order of magnitude, when compared to commonly used Bax expression protocols.


Preoperative predictors of nonorgan-confined disease in upper-tract urothelial carcinoma differ between China and the United States.
To compare preoperative predictors of nonorgan-confined (NOC) disease in patients with upper-tract urothelial carcinoma (UTUC) from the United States (US) and China. Clinicopathologic data of patients with UTUC treated surgically at tertiary care facilities in the US or China from 1998 to 2015 were, retrospectively, compiled. Patient characteristics, preoperative imaging, cytology, ureteroscopic findings, and serum markers (neutrophil-to-lymphocyte ratio, estimated glomerular filtration rate, hemoglobin, and albumin) were evaluated. After excluding patients who received neoadjuvant chemotherapy, rates of NOC disease at definitive surgery were tabulated. Logistic regression and receiver operating characteristic analyses were performed to determine predictors of NOC for each country using previously published nomograms, and the cohorts were compared. Totally, 753 patients with UTUC were included for analysis (451 Chinese and 302 US). NOC rates were similar between the 2 countries (31% vs. 29%, P = 0.568). On multivariable analysis, cT3 stage (P = 0.001) and high-grade pathology on ureteroscopy (P = 0.011) were significant predictors for NOC in the US, while male gender (P = 0.034), tumor location on imaging (P = 0.009), tumor size on imaging (P = 0.044), neutrophil-to-lymphocyte (P = 0.043), and preoperative estimated glomerular filtration rate (P = 0.028) were significant in China. Areas under the curve differed by nomogram used (Western model: 0.750 in US, vs. 0.670 in China; Chinese model: 0.763 in US, vs. 0.828 in China). Predictors for NOC in UTUC differ between the US and China. There may be unique population-based markers that more profoundly influence the accuracy of nomograms in certain populations. Our findings highlight the importance of considering population differences when clinically applying predictive tools in UTUC.


IL-2 production by virus- and tumor-specific human CD8 T cells is determined by their fine specificity.
Memory CD8 T cells mediate rapid and effective immune responses against previously encountered Ags. However, these cells display considerable phenotypic and functional heterogeneity. In an effort to identify parameters that correlate with immune protection, we compared cell surface markers, proliferation, and cytokine production of distinct virus- and tumor-specific human CD8 populations. Phenotypic analysis of epitope-specific CD8 T cells showed that Ag specificity is associated with distinct CCR7/CD45RA expression profiles, suggesting that Ag recognition drives the expression of these molecules on effector/memory T cells. Moreover, the majority of central memory T cells (CD45RAlowCCR7dull) secreting cytokines in response to an EBV epitope produces both IL-2 and IFN-gamma, whereas effector memory CD8 cells (CD45RAdullCCR7-) found in EBV, CMV, or Melan-A memory pools are mostly composed of cells secreting exclusively IFN-gamma. However, these various subsets, including Melan-A-specific effector memory cells differentiated in cancer patients, display similar Ag-driven proliferation in vitro. Our findings show for the first time that human epitope-specific CD8 memory pools differ in IL-2 production after antigenic stimulation, although they display similar intrinsic proliferation capacity. These results provide new insights in the characterization of human virus- and tumor-specific CD8 lymphocytes.


The BAX/BAK-like protein BOK is a prognostic marker in colorectal cancer.
The intrinsic or mitochondrial apoptosis pathway is controlled by the interaction of antiapoptotic and pro-apoptotic members of the BCL-2 protein family. Activation of this death pathway plays a crucial role in cancer progression and chemotherapy responses. The BCL-2-related ovarian killer (BOK) possesses three BCL-2 homology domains and has been proposed to act in a similar pro-apoptotic pathway as the pro-apoptotic proteins BAX and BAK. In this study, we showed that stage II and III colorectal cancer patients possessed decreased levels of BOK protein in their tumours compared to matched normal tissue. BOK protein levels in tumours were also prognostic of clinical outcome but increased BOK protein levels surprisingly associated with earlier disease recurrence and reduced overall survival. We found no significant association of BOK protein tumour levels with ER stress markers GRP78 or GRP94 or with cleaved caspase-3. In contrast, BOK protein levels correlated with Calreticulin. These data indicate BOK as a prognostic marker in colorectal cancer and suggest that different activities of BOK may contribute to cancer progression and prognosis.


Association of spironolactone use with all-cause mortality in heart failure: a propensity scored cohort study.
In 3 randomized controlled trials in heart failure (HF), mineralocorticoid receptor antagonists reduced mortality. The net benefit from randomized controlled trials may not be generalizable, and eplerenone was, but spironolactone was not, studied in mild HF. We tested the hypothesis that spironolactone is associated with reduced mortality also in a broad unselected contemporary population with HF and reduced ejection fraction, in particular New York Heart Association (NYHA) I-II. We prospectively studied 18 852 patients (age 71±12 years; 28% women) with NYHA I-IV and ejection fraction <40% who were registered in the Swedish Heart Failure Registry between 2000 and 2012 and who were (n=6551) or were not (n=12 301) treated with spironolactone. We derived propensity scores for spironolactone treatment based on 41 covariates. We assessed survival by Cox regression with adjustment for propensity scores and with matching based on propensity score. We performed sensitivity and residual confounding analyses and analyzed the NYHA I-II and III-IV subgroups separately. One-year survival was 83% versus 84% in treated versus untreated patients (log rank P<0.001). After adjustment for propensity scores, the hazard ratio for spironolactone was 1.05 (95% confidence interval, 1.00-1.11; P=0.054). Spironolactone interacted with NYHA (P<0.001). In the NYHA I-II subgroup, after adjustment for propensity scores, the hazard ratio for spironolactone was 1.11 (95% confidence interval, 1.02-1.21; P=0.019). In an unselected contemporary population of HF with reduced ejection fraction, spironolactone was not associated with reduced mortality. The net benefits of spironolactone may be lower outside the clinical trial setting and in milder HF.


Adsorption of lead (II) ions onto novel cassava starch 5-choloromethyl-8-hydroxyquinoline polymer from an aqueous medium.
Adsorption of lead (II) ions onto cassava starch 5-choloromethyl-8-hydroxyquinoline polymer (CSCMQ) was investigated with the variation in the parameters of pH, contact time, lead (II) ions concentration, temperature and the adsorbent dose. The Langmuir and Freundlich models have been applied. CSCMQ was characterized by Fourier transform infrared spectroscopy and scanning electron microscopy. Results showed that the adsorption process was better described by the Langmuir model. Adsorption kinetics data obtained for the metal ions sorption were investigated using pseudo-first-order, pseudo-second-order and intraparticle diffusion model. The maximum adsorption capacities (qm) were 46.512, 43.859 and 42.735 mg/g at 25, 35 and 45 °C, respectively. The dynamical data fit well with the second-order kinetics model. The results indicate that CSCMQ could be employed as low-cost material for the adsorption of Pb(II) ions from aqueous medium.


Highlights in the development of new antiviral agents.
The potential of a large variety of new compounds and new strategies for the treatment of virtually all major virus infections has been addressed. This includes, for the treatment of HIV infections, virus adsorption inhibitors (cosalane derivatives, cyanovirin-N), co-receptor antagonists (TAK-779, AMD3100), viral fusion inhibitors (pentafuside T-20, betulinic acid derivatives), viral uncoating inhibitors (azodicarbonamide), nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs: emtricitabine, amdoxovir, dOTC, d4TMP prodrugs, tenofovir disoproxil fumarate), non-nucleoside reverse transcriptase inhibitors (NNRTIs: thiocarboxanilide UC-781, capravirine, SJ-3366, DPC 083, TMC 125/R165335), integrase inhibitors (diketo acids), transcription inhibitors (temacrazine, flavopiridol), protease inhibitors (atazanavir, mozenavir, tipranavir); for the treatment of RSV and paramyxovirus infections, viral fusion inhibitors (R170591, VP-14637, NMS03); for the treatment of picornavirus infections, viral uncoating inhibitors (pleconaril); for the treatment of pesti- (hepaci-, flavi-) virus infections, RNA replicase inhibitors (VP-32947); for the treatment of herpesvirus (HSV, VZV, CMV) infections, DNA polymerase inhibitors (A-5021, L- and D-cyclohexenylguanine); for the treatment of VZV infections, bicyclic furopyrimidine analogues; for the treatment of CMV infections, fomivirsen; for the treatment of DNA virus infections at large (papilloma-, polyoma-, herpes-, adeno- and poxvirus infections), cidofovir; for the treatment of influenza, neuraminidase inhibitors (zanamivir, oseltamivir, RWJ-270201); for the treatment of HBV infections, adefovir dipivoxil; for the treatment of HBV and HCV infections, N-glycosylation inhibitors (N-nonyl-deoxynojirimycin); and, finally, IMP dehydrogenase inhibitors and S-adenosylhomocysteine hydrolase inhibitors, for the treatment of various virus infections, including hemorrhagic fever virus infections.


Dance movement therapy for dementia.
Dementia is a collective name for different degenerative brain syndromes which, according to Alzheimer's Disease International, affects approximately 35.6 million people worldwide. The latest NICE guideline for dementia highlights the value of diverse treatment options for the different stages and symptoms of dementia including non-pharmacological treatments. Relevant literature also argues for the value of interventions that acknowledge the complexity of the condition and address the person as a whole, including their physical, emotional, social and cognitive processes. At the same time, there is growing literature that highlights the capacity of the arts and embodied practices to address this complexity. Dance movement therapy is an embodied psychological intervention that can address complexity and thus, may be useful for people with dementia, but its effectiveness remains unclear. To assess the effects of dance movement therapy on behavioural, social, cognitive and emotional symptoms of people with dementia in comparison to no treatment, standard care or any other treatment. Also, to compare different forms of dance movement therapy (e.g. Laban-based dance movement therapy, Chacian dance movement therapy or Authentic Movement). Searches took place up to March 2016 through ALOIS, Cochrane Dementia and Cognitive Improvement's Specialized Register, which covers CENTRAL, a number of major healthcare databases and trial registers, and grey literature sources. We checked bibliographies of relevant studies and reviews, and contacted professional associations, educational programmes and experts from around the world. We considered randomised controlled trials (RCTs) in any language, including cross-over design and cluster-RCTs for inclusion. Studies considered had to include people with dementia, in any age group and in any setting, with interventions delivered by a dance movement therapy practitioner who (i) had received formal training (ii) was a dance movement therapist in training or (iii) was otherwise recognised as a dance movement therapist in the country in which the study was conducted. The two review authors independently reviewed studies on an abstract/title level and again after reading the full paper, and we independently evaluated methodological quality. Of the 102 studies identified through electronic searches and personal communication, after de-duplication we screened 80 at title/abstract level. We then reviewed 19 full papers, none of which met the inclusion criteria. Although three studies mentioned dance movement therapy as their intervention, they were excluded because they were not delivered by a qualified dance movement therapy practitioner. As a result, no studies were included in this review. Trials of high methodological quality, large sample sizes and clarity in the way the intervention is put together and delivered are needed to assess whether dance movement therapy is an effective intervention for dementia.


QMRA and water safety management: review of application in drinking water systems.
Quantitative microbial risk assessment (QMRA), the assessment of microbial risks when model inputs and estimated health impacts are explicitly quantified, is a valuable tool to support water safety plans (WSP). In this paper, research studies undertaken on the application of QMRA in drinking water systems were reviewed, highlighting their relevance for WSP. The important elements for practical implementation include: the data requirements to achieve sufficient certainty to support decision-making; level of expertise necessary to undertake the required analysis; and the accessibility of tools to support wider implementation, hence these aspects were the focus of the review. Recommendations to support the continued and growing application of QMRA to support risk management in the water sector are provided.


Survival of free and encapsulated human and rat islet xenografts transplanted into the mouse bone marrow.
Bone marrow was recently proposed as an alternative and potentially immune-privileged site for pancreatic islet transplantation. The aim of the present study was to assess the survival and rejection mechanisms of free and encapsulated xenogeneic islets transplanted into the medullary cavity of the femur, or under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. The median survival of free rat islets transplanted into the bone marrow or under the kidney capsule was 9 and 14 days, respectively, whereas that of free human islets was shorter, 7 days (bone marrow) and 10 days (kidney capsule). Infiltrating CD8+ T cells and redistributed CD4+ T cells, and macrophages were detected around the transplanted islets in bone sections. Recipient mouse splenocytes proliferated in response to donor rat stimulator cells. One month after transplantation under both kidney capsule or into bone marrow, encapsulated rat islets had induced a similar degree of fibrotic reaction and still contained insulin positive cells. In conclusion, we successfully established a small animal model for xenogeneic islet transplantation into the bone marrow. The rejection of xenogeneic islets was associated with local and systemic T cell responses and macrophage recruitment. Although there was no evidence for immune-privilege, the bone marrow may represent a feasible site for encapsulated xenogeneic islet transplantation.


Calcium imaging and selective computed tomography angiography in comparison to functional testing for suspected coronary artery disease: the multicentre, randomized CRESCENT trial.
To compare the effectiveness and safety of a cardiac computed tomography (CT) algorithm with functional testing in patients with symptoms suggestive of coronary artery disease (CAD). Between April 2011 and July 2013, 350 patients with stable angina, referred to the outpatient clinic of four Dutch hospitals, were prospectively randomized between cardiac CT and functional testing (2 : 1 ratio). The tiered cardiac CT protocol included a calcium scan followed by CT angiography if the Agatston calcium score was between 1 and 400. Patients with test-specific contraindications were not excluded from study participation. By 1 year, fewer patients randomized to cardiac CT reported anginal complaints (P = 0.012). The cumulative radiation dose was slightly higher in the CT group (6.6 ± 8.7 vs. 6.1 ± 9.3 mSv; P < 0.0001). After 1.2 years, event-free survival was 96.7% for patients randomized to CT and 89.8% for patients randomized to functional testing (P = 0.011). After CT, the final diagnosis was established sooner (P < 0.0001), and additional downstream testing was required less frequently (25 vs. 53%, P < 0.0001), resulting in lower cumulative diagnostic costs (€369 vs. €440; P < 0.0001). For patients with suspected stable CAD, a tiered cardiac CT protocol offers an effective and safe alternative to functional testing. Incorporating the calcium scan into the diagnostic workup was safe and lowered diagnostic expenses and radiation exposure.


Feasibility and analysis of CNN-based candidate beam generation for robotic radiosurgery.
Robotic radiosurgery offers the flexibility of a robotic arm to enable high conformity to the target and a steep dose gradient. However, treatment planning becomes a computationally challenging task as the search space for potential beam directions for dose delivery is arbitrarily large. We propose an approach based on deep learning to improve the search for treatment beams. In clinical practice, a set of candidate beams generated by a randomized heuristic forms the basis for treatment planning. We use a convolutional neural network to identify promising candidate beams. Using radiological features of the patient, we predict the influence of a candidate beam on the delivered dose individually and let this prediction guide the selection of candidate beams. Features are represented as projections of the organ structures which are relevant during planning. Solutions to the inverse planning problem are generated for random and CNN-predicted candidate beams. The coverage increases from 95.35% to 97.67% for 6000 heuristically and CNN-generated candidate beams, respectively. Conversely, a similar coverage can be achieved for treatment plans with half the number of candidate beams. This results in a patient-dependent reduced averaged computation time of 20.28%-45.69%. The number of active treatment beams can be reduced by 11.35% on average, which reduces treatment time. Constraining the maximum number of candidate beams per beam node can further improve the average coverage by 0.75 percentage points for 6000 candidate beams. We show that deep learning based on radiological features can substantially improve treatment plan quality, reduce computation runtime, and treatment time compared to the heuristic approach used in clinics.


Transcriptome Analysis of Orbital Adipose Tissue in Active Thyroid Eye Disease Using Next Generation RNA Sequencing Technology.
This study utilized Next Generation Sequencing (NGS) to identify differentially expressed transcripts in orbital adipose tissue from patients with active Thyroid Eye Disease (TED) versus healthy controls. This prospective, case-control study enrolled three patients with severe, active thyroid eye disease undergoing orbital decompression, and three healthy controls undergoing routine eyelid surgery with removal of orbital fat. RNA Sequencing (RNA-Seq) was performed on freshly obtained orbital adipose tissue from study patients to analyze the transcriptome. Bioinformatics analysis was performed to determine pathways and processes enriched for the differential expression profile. Quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR) was performed to validate the differential expression of selected genes identified by RNA-Seq. RNA-Seq identified 328 differentially expressed genes associated with active thyroid eye disease, many of which were responsible for mediating inflammation, cytokine signaling, adipogenesis, IGF-1 signaling, and glycosaminoglycan binding. The IL-5 and chemokine signaling pathways were highly enriched, and very-low-density-lipoprotein receptor activity and statin medications were implicated as having a potential role in TED. This study is the first to use RNA-Seq technology to elucidate differential gene expression associated with active, severe TED. This study suggests a transcriptional basis for the role of statins in modulating differentially expressed genes that mediate the pathogenesis of thyroid eye disease. Furthermore, the identification of genes with altered levels of expression in active, severe TED may inform the molecular pathways central to this clinical phenotype and guide the development of novel therapeutic agents.


Task-level value affects trial-level reward processing.
Despite disagreement about how anterior cingulate cortex (ACC) supports decision making, a recent hypothesis suggests that activity in this region is best understood in the context of a task or series of tasks. One important task-level variable is average reward because it is both a known driver of effortful behaviour and an important determiner of the tasks in which we choose to engage. Here we asked how average task value affects reward-related ACC activity. To answer this question, we measured a reward-related signal said to be generated in ACC called the reward positivity (RewP) while participants gambled in three tasks of differing average value. The RewP was reduced in the high-value task, an effect that was not explainable by either reward magnitude or outcome expectancy. This result suggests that ACC does not evaluate outcomes and cues in isolation, but in the context of the value of the current task.


Identification of a naturally processed HLA-A*02:01-restricted CTL epitope from the human tumor-associated antigen Nectin-4.
Nectin-4 is a tumor antigen present on the surface of breast, ovarian and lung carcinoma cells. It is rarely present in normal adult tissues and is therefore a candidate target for cancer immunotherapy. Here, we identified a Nectin-4 antigenic peptide that is naturally presented to T cells by HLA-A2 molecules. We first screened the 502 nonamer peptides of Nectin-4 (510 amino acids) for binding to and off-rate from eight different HLA class I molecules. We then combined biochemical, cellular and algorithmic assays to select 5 Nectin-4 peptides that bound to HLA-A*02:01 molecules. Cytolytic T lymphocytes were obtained from healthy donors, that specifically lyzed HLA-A2(+) cells pulsed with 2 out of the 5 peptides, indicating the presence of anti-Nectin-4 CD8(+) T lymphocytes in the human T cell repertoire. Finally, an HLA-A2-restricted cytolytic T cell clone derived from a breast cancer patient recognized peptide Nectin-4145-153 (VLVPPLPSL) and lyzed HLA-A2(+) Nectin-4(+) breast carcinoma cells. These results indicate that peptide Nectin-4145-153 is naturally processed for recognition by T cells on HLA-A2 molecules. It could be used to monitor antitumor T cell responses or to immunize breast cancer patients.


A detailed study of the magnetism of chiral {Cr₇M} rings: an investigation into parametrization and transferability of parameters.
Compounds of general formula [Cr7MF3(Etglu)(O2C(t)Bu)15(Phpy)] [H5Etglu = N-ethyl-d-glucamine; Phpy = 4-phenylpyridine; M = Zn (1), Mn (2), Ni (3)] have been prepared. The structures contain an irregular octagon of metal sites formed around the penta-deprotonated Etglu(5-) ligand; the chirality of N-ethyl-d-glucamine is retained in the final product. The seven Cr(III) sites have a range of coordination environments, and the divalent metal site is crystallographically identified and has a Phpy ligand attached to it. By using complementary experimental techniques, including magnetization and specific heat measurements, inelastic neutron scattering, and electron paramagnetic resonance spectroscopy, we have investigated the magnetic features of this family of {Cr7M} rings. Microscopic parameters of the spin Hamiltonian have been determined as a result of best fits of the different experimental data, allowing a direct comparison with corresponding parameters found in the parent compounds. We examine whether these parameters can be transferred between compounds and compare them with those of an earlier family of heterometallic rings.


Assessing the kaleidoscope of monocular deprivation effects.
Short-term monocular deprivation (∼150 min) temporarily shifts sensory eye balance in favor of the deprived eye (Lunghi, Burr, & Morrone, 2011; Zhou, Clavagnier, & Hess, 2013), opposite to classic deprivation studies (Hubel & Wiesel, 1970). Various types of deprivation-light-tight, diffuser lenses, image degradation-have been tested, and it seemed that a deprivation of contrast was necessary, and sufficient, for these shifts. This could be accommodated in a feedforward model of binocular combination (Meese, Georgeson, & Baker, 2006; Sperling & Ding, 2010), in which the shift reflects a (persistent) reweighting induced by an interocular gain control mechanism tasked with maintaining binocular balance (Zhou, Clavagnier, et al., 2013). Here, we used a novel "kaleidoscopic" monocular deprivation that, although it rendered images fractionated and uninformative, preserved gross luminance, color, spatial frequency, motion, and contrast information, effectively sneaking the image degradation past early, feedforward mechanisms, targeting higher levels. Kaleidoscopic deprivation produced effects indistinguishable from traditional light-tight patching. This rules out contrast imbalance as the sole factor driving these shifts in sensory eye balance. In addition, since the suppression of the kaleidoscopic image likely requires feedback from higher-level processes capable of determining the behavioral relevance of an eye's information (Foley & Miyanshi, 1969; Jiang, Costello, & He, 2007; Kovács, Papathomas, Yang, & Fehér, 1996; Wolf & Hochstein, 2011), feedforward-only models may need to be elaborated.


Coarticulation as an indicator of speech motor control development in children: an ultrasound study.
There are still crucial gaps in our knowledge about developmental paths taken by children to adult-like speech motor control. Mature control of articulators during speaking is manifested in the appropriate extent of coarticulation (the articulatory overlap of speech sounds). This study compared lingual coarticulatory properties of child and adult speech, using ultrasound tongue imaging. The participants were speakers of Standard Scottish English, ten adults and ten children aged 6-9 years. Consonant-vowel syllables were presented in a carrier phrase. Distances between tongue curves were used to quantify coarticulation. In both adults and children, vowel pairs /a/-/i/ and /a/-/u/ significantly affected the consonant, and the vowel pair /i/-/u/ did not. Extent of coarticulation was significantly greater in the children than in the adults, providing support for the notion that children's speech production operates with larger units than adults'. More within-speaker variability was found in the children than in the adults.


The Unknown microRNA Expression of Male Breast Cancer. Similarities and Differences with Female Ductal Carcinoma. Their Role as Tumor Biomarker.
Mature microRNAs (miRNAs) are small non-protein coding RNAs that modulate gene expression after transcription. Few studies have shown that male breast cancer (MBC) shows distinctive miRNAs pattern, suggesting its relevance in this pathology. To study this, we performed a profile of 800 miRNAs in 9 MBC samples and in normal epithelial cells of 3 MBC cases. Of FFPE tissues, miRNA was extracted for profiles using the NanoString method. miRNAs were obtained by comparing tumor samples versus normal epithelium. Quantitative real-time PCR analyzes were performed by the TaqMan approach for specific miRNAs. The profile of 800 miRNAs showed a different microRNA expression pattern between MBC and its normal counterpart, suggesting a specific microRNA cancer expression profile for MBC. Forty-nine miRNAs showed greater expression, while 26 were found to be down-regulated in MBC, compared to normal tissue. The lower expression of miR-125b correlated significantly with tumors> 2 cm, suggesting that its down-regulation may be implicated in mechanisms to more aggressive tumors. These results suggest that MBC has a unique expression profile compared to normal breast tissue and expression profile of female breast cancer. Differentially expressed miRNAs provide insights of this uncommon but highly aggressive pathology.


Olfactory identification in LRRK2 G2019S mutation carriers: a relevant marker?
Olfactory impairment is a potential marker for impending phenoconversion to Parkinson disease (PD) that may precede the development of disease by several years. Because of low specificity, it may be of greater predictive value in those with genetic mutations and its potential as a marker for developing LRRK2 PD should be evaluated. We examined olfactory identification in 126 LRRK2 G2019S mutation carriers with PD, 125 mutation carriers not manifesting PD, 126 noncarriers with idiopathic PD, 106 noncarrier family members without PD, and 35 unrelated controls. We compared olfactory performance and performed mixture modeling to identify possible subgroups of olfactory performance in LRRK2 PD and nonmanifesting carriers. Adjusting for sex, age, cognitive score, site, and smoking history, LRRK2 PD had better olfactory scores compared to idiopathic PD (mean olfaction difference: -3.7, P < 0.001), and both LRRK2 PD and idiopathic PD had worse olfaction than controls (-12.8, -9.1, both P < 0.001). LRRK2 PD were less likely to be hyposmic than idiopathic PD (54.8% vs. 80.2%, P < 0.001). Nonmanifesting carriers and noncarrier family members did not differ. Mixture model analysis identified three classes in the LRRK2 PD and nonmanifesting carriers, suggesting that there are subgroups with poor olfactory identification in both LRRK2 PD and nonmanifesting carriers. Therefore, olfactory identification deficit is less likely to be an obligate feature in LRRK2 PD than idiopathic PD, and while a relevant marker in some, a subset of carriers who eventually phenoconvert may proceed directly to PD without prior impaired olfaction.


Motor abnormalities and basal ganglia in first-episode psychosis (FEP).
Motor abnormalities (MAs) are the primary manifestations of schizophrenia. However, the extent to which MAs are related to alterations of subcortical structures remains understudied. We aimed to investigate the associations of MAs and basal ganglia abnormalities in first-episode psychosis (FEP) and healthy controls. Magnetic resonance imaging was performed on 48 right-handed FEP and 23 age-, gender-, handedness-, and educational attainment-matched controls, to obtain basal ganglia shape analysis, diffusion tensor imaging techniques (fractional anisotropy and mean diffusivity), and relaxometry (R2*) to estimate iron load. A comprehensive motor battery was applied including the assessment of parkinsonism, catatonic signs, and neurological soft signs (NSS). A fully automated model-based segmentation algorithm on 1.5T MRI anatomical images and accurate corregistration of diffusion and T2* volumes and R2* was used. FEP patients showed significant local atrophic changes in left globus pallidus nucleus regarding controls. Hypertrophic changes in left-side caudate were associated with higher scores in sensory integration, and in right accumbens with tremor subscale. FEP patients showed lower fractional anisotropy measures than controls but no significant differences regarding mean diffusivity and iron load of basal ganglia. However, iron load in left basal ganglia and right accumbens correlated significantly with higher extrapyramidal and motor coordination signs in FEP patients. Taken together, iron load in left basal ganglia may have a role in the emergence of extrapyramidal signs and NSS of FEP patients and in consequence in the pathophysiology of psychosis.


Molecular changes during TGFβ-mediated lung fibroblast-myofibroblast differentiation: implication for glucocorticoid resistance.
Airway remodeling is an important process in response to repetitive inflammatory-mediated airway wall injuries. This is characterized by profound changes and reorganizations at the cellular and molecular levels of the lung tissue. It is of particular importance to understand the mechanisms involved in airway remodeling, as this is strongly associated with severe asthma leading to devastating airway dysfunction. In this study, we have investigated the transforming growth factor-β (TGFβ, a proinflammatory mediator)-activated fibroblast to myofibroblast transdifferentiation pathway, which plays a key role in asthma-related airway remodeling. We show that TGFβ induces fibroblast to myofibroblast transdifferentiation by the expression of αSMA, a specific myofibroblast marker. Furthermore, Smad2/Smad3 gene and protein expression patterns are different between fibroblasts and myofibroblasts. Such a change in expression patterns reveals an important role of these proteins in the cellular phenotype as well as their regulation by TGFβ during cellular transdifferentiation. Interestingly, our data show a myofibroblastic TGFβ-mediated increase in glucocorticoid receptor (GR) expression and a preferential localization of GR in the nucleus, compared to in fibroblasts. Furthermore, the GRβ (nonfunctional GR isoform) is increased relative to GRα (functional isoform) in myofibroblasts. These results are interesting as they support the idea of a GRβ-mediated glucocorticoid resistance observed in the severe asthmatic population. All together, we provide evidence that key players are involved in the TGFβ-mediated fibroblast to myofibroblast transdifferentiation pathway in a human lung fibroblast cell line. These players could be the targets of new treatments to limit airway remodeling and reverse glucocorticoid resistance in severe asthma.


Snacking increased among U.S. adults between 1977 and 2006.
This study built on limited knowledge about patterns and trends of adult snacking in the US. We selected adults aged 19 y and older (n = 44,754) between 1977-1978 and 2003-2006 with results weighted and adjusted for sample design effects. Differences testing, by a Student's t test, used STATA 10 (P < or = 0.01). We defined a snacking event as intake of foods over a 15-min period and excluded food defined as snacks but eaten at a meal. Dietary data were obtained from the first 2 d for the 1977-1978 Nationwide Food Consumption Survey (NFCS 77) and the 1989-1991 Continuing Survey of Food Intake by Individuals (CSFII 89); and 2-d dietary data from the 1994-1996 CSFII (CSFII 96) and the NHANES from 2 consecutive surveys: NHANES 2003-2004 and NHANES 2005-2006 (NHANES 03-06). Results showed that snacking prevalence increased significantly from 71 to 97% in 2003-2006 with increases in both the 1989-1994 and the 1994-2006 periods. In all adults, snacking occasions increased 0.97 events over this time period (P < 0.01) and the contribution of snacks to total energy intake increased from 18 to 24% (P < 0.01). The energy density of snacks (food plus beverages) also increased progressively over the time period studied. Important changes in snacking food sources were found among desserts, salty snacks, candies, and sweetened beverages. More research is needed to gain a better understanding of the implications for overall energy intake and energy imbalance.


Effect of colloidal bismuth subcitrate on symptoms and gastric histology in non-ulcer dyspepsia. A double blind placebo controlled study.
The aim of this study was to determine the effect of colloidal bismuth subcitrate (De Nol) on symptoms and gastric histology in patients with non-ulcer dyspepsia. In a single centre trial, patients with food related upper abdominal pain not caused by ulcer disease were randomised to receive one tablet of colloidal bismuth subcitrate or matching placebo four times daily for eight weeks. Seventy three patients were entered and 51 completed the trial: 28 patients in the colloidal bismuth subcitrate group and 23 in the placebo group. Overall there was no difference between the two groups in terms of symptom relief. Among patients with histological gastritis (n = 23), however, those who took colloidal bismuth subcitrate used fewer antacid tablets (for three of four fortnightly periods) and were more likely to become asymptomatic (eight of 11 v three of 12, p less than 0.05); their gastritis was more likely to resolve (five of 10 v 0 of 12, p less than 0.025) and their gastric biopsies more likely to become negative for Helicobacter like organisms (eight of nine v 0 of 12, p less than 0.001) when compared with patients taking placebo. In contrast, patients who did not have gastritis in their index biopsies (n = 28) fared similarly whether they received colloidal bismuth subcitrate or placebo. Our results indicate that the administration of colloidal bismuth subcitrate benefited non-ulcer dyspepsia patients with gastritis but had no effect on those without.


The homeopathic preparation Vertigoheel versus Ginkgo biloba in the treatment of vertigo in an elderly population: a double-blinded, randomized, controlled clinical trial.
Alternative medical practices are common in the treatment of vertigo. This study compared the effects of Ginkgo biloba treatment with the homeopathic remedy Vertigoheel (Biologische Heilmittel Heel GmbH, Baden-Baden, Germany). Randomized, double-blinded, parallel group study. One hundred and seventy (170) patients, ages 60-80 years, with atherosclerosis-related vertigo. Patients were randomly allocated to receive treatment with either Vertigoheel (n = 87) or G. biloba (n = 83). The results were analyzed for the non-inferiority of Vertigoheel to G. biloba on the combined endpoint of changes from baseline to week 6 in dizziness score (assessed by questionnaire), frequency, duration, and intensity of vertigo episodes (recorded in patient diaries). Both treatments improved vertigo status. From a baseline mean value of 26.1 +/- 5.2 (on a 50-point scale) in the Vertigoheel group, the dizziness questionnaire score improved by -10.6 +/- 10.0, and by -10.7 +/- 9.0 from 25.8 - 4.7 in the G. biloba group. Statistical analysis of this endpoint showed that Vertigoheel was not inferior to G. biloba. The 95% confidence interval for the difference between treatment did not reach the inferiority threshold of 0.36 at any of the time points tested. The results were supported by the results of a line walking test, Unterberger's stepping test, and patient and physician global assessments of therapeutic effect. Both treatments were well tolerated. Vertigoheel is an appealing alternative to established G. biloba therapy for atherosclerosis-related vertigo.


Evaluation of mechanism of change in transdiagnostic cognitive behaviour therapy using single case experimental design.
Transdiagnostic mechanisms of change (txMOC) specific to cognitive behaviour therapy are poorly understood. Salkovskis (1996) proposed one such mechanism in terms of the shift towards an alternative, less negative view of their problems or cognitive flexibility. This hypothesis has been described as involving a shift in beliefs, from "theory A″ to "theory B". The objective of this research was to evaluate this hypothesis. Effectiveness of a novel txCBT and temporal changes in process and symptom measures were evaluated using a non-concurrent multiple baseline design and Tau-U calculations with thirteen participants (five with obsessive-compulsive disorder, two with panic disorder with agoraphobia and six with major depressive disorder). As a secondary analysis authors calculated Kendall's - Tau correlation between process and symptom measures, performed the Wilcoxon signed-rank test to assess treatment modules effect on negative thought and calculated Reliable change index (RCI). The txCBT was clearly effective for eight participants. The results varied dependent on the stimuli evaluated as negative or threatening. Level and trend of the ratings of belief in theory A followed the level and trend of symptom measures to a greater extent than the (inverse) level and trend of belief in theory B. Only thirteen participants were recruited and evaluated. The results are consistent with the view that effective treatment may involve a txMOC characterized by the ability to shift from a relatively fixed negative view of their experience to a less negative psychologically focused alternative.


Fourier phase in Fourier-domain optical coherence tomography.
Phase of an electromagnetic wave propagating through a sample-of-interest is well understood in the context of quantitative phase imaging in transmission-mode microscopy. In the past decade, Fourier-domain optical coherence tomography has been used to extend quantitative phase imaging to the reflection-mode. Unlike transmission-mode electromagnetic phase, however, the origin and characteristics of reflection-mode Fourier phase are poorly understood, especially in samples with a slowly varying refractive index. In this paper, the general theory of Fourier phase from first principles is presented, and it is shown that Fourier phase is a joint estimate of subresolution offset and mean spatial frequency of the coherence-gated sample refractive index. It is also shown that both spectral-domain phase microscopy and depth-resolved spatial-domain low-coherence quantitative phase microscopy are special cases of this general theory. Analytical expressions are provided for both, and simulations are presented to explain and support the theoretical results. These results are further used to show how Fourier phase allows the estimation of an axial mean spatial frequency profile of the sample, along with depth-resolved characterization of localized optical density change and sample heterogeneity. Finally, a Fourier phase-based explanation of Doppler optical coherence tomography is also provided.


Sexually transmitted diseases treatment guidelines, 2015.
These guidelines for the treatment of persons who have or are at risk for sexually transmitted diseases (STDs) were updated by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on April 30-May 2, 2013. The information in this report updates the Sexually Transmitted Diseases Treatment Guidelines, 2010 (MMWR Recomm Rep 2010;59 [No. RR-12]). These updated guidelines discuss 1) alternative treatment regimens for Neisseria gonorrhoeae; 2) the use of nucleic acid amplification tests for the diagnosis of trichomoniasis; 3) alternative treatment options for genital warts; 4) the role of Mycoplasma genitalium in urethritis/cervicitis and treatment-related implications; 5) updated HPV vaccine recommendations and counseling messages; 6) the management of persons who are transgender; 7) annual testing for hepatitis C in persons with HIV infection; 8) updated recommendations for diagnostic evaluation of urethritis; and 9) retesting to detect repeat infection. Physicians and other health-care providers can use these guidelines to assist in the prevention and treatment of STDs.


Bronchus- and nasal-associated lymphoid tissues.
The bronchus-associated lymphoid tissue (BALT) and the nasal-associated lymphoid tissue (NALT) constitute organized lymphoid aggregates that are capable of T- and B-cell responses to inhaled antigens. BALT, located mostly at bifurcations of the bronchus in animals and humans, is present in the fetus and develops rapidly following birth, especially in the presence of antigens. Humoral immune responses elicited by BALT are primarily immunoglobulin A secretion both locally and by BALT-derived B cells that have trafficked to distant mucosal sites. Similarly located T-cell responses have been noted. On the basis of these findings, the BALT can be thought of as functionally analogous to mucosal lymphoid aggregates in the intestine and is deemed a member of the common mucosal immunologic system. NALT has been described principally in the rodent nasal passage as two separate lymphoid aggregates. It develops after birth, likely in response to antigen, and B- and T-cell responses parallel those that occur in BALT. It is not known whether NALT cells traffic to distant mucosal sites, although mucosal responses have been detected after nasal immunization. NALT appears from many studies to be a functionally distinct lymphoid aggregate when compared with BALT and Peyer's patches. It may exist, however, in humans as a diffuse collection of isolated lymphoid follicles.


Evanescent-wave infrared spectroscopy of solid materials using deformable silver-halide optical fibers.
Silver-halide crystalline infrared optical fibers are used for infrared evanescent-wave spectroscopy of solid materials. The fiber is pressed onto the material to be studied and good contact is achieved either by elastic or plastic deformation of the ductile fiber. The absorption-signal level is determined by the length and pressure of contact. This method allows convenient measurement of the absorption signals in large samples that cannot be introduced into an IR spectrometer and in materials that are practically opaque so that their spectra cannot be obtained by conventional transmission measurements. Examples of measurements of hard polymers are given, and the evanescent-wave spectra of polyethylene are compared with conventional transmission measurements.


Reduction of 2-methoxy-1,4-naphtoquinone by mitochondrially-localized Nqo1 yielding NAD+ supports substrate-level phosphorylation during respiratory inhibition.
Provision of NAD+ for oxidative decarboxylation of alpha-ketoglutarate to succinyl-CoA by the ketoglutarate dehydrogenase complex (KGDHC) is critical for maintained operation of succinyl-CoA ligase yielding high-energy phosphates, a process known as mitochondrial substrate-level phosphorylation (mSLP). We have shown previously that when NADH oxidation by complex I is inhibited by rotenone or anoxia, mitochondrial diaphorases yield NAD+, provided that suitable quinones are present (Kiss G et al., FASEB J 2014, 28:1682). This allows for KGDHC reaction to proceed and as an extension of this, mSLP. NAD(P)H quinone oxidoreductase 1 (NQO1) is an enzyme exhibiting diaphorase activity. Here, by using Nqo1-/- and WT littermate mice we show that in rotenone-treated, isolated liver mitochondria 2-methoxy-1,4-naphtoquinone (MNQ) is preferentially reduced by matrix Nqo1 yielding NAD+ to KGDHC, supporting mSLP. This process was sensitive to inhibition by specific diaphorase inhibitors. Reduction of idebenone and its analogues MRQ-20 and MRQ-56, menadione, mitoquinone and duroquinone were unaffected by genetic disruption of the Nqo1 gene. The results allow for the conclusions that i) MNQ is a Nqo1-preferred substrate, and ii) in the presence of suitable quinones, mitochondrially-localized diaphorases other than Nqo1 support NADH oxidation when complex I is inhibited. Our work confirms that complex I bypass can occur by quinones reduced by intramitochondrial diaphorases oxidizing NADH, ultimately supporting mSLP. Finally, it may help to elucidate structure-activity relationships of redox-active quinones with diaphorase enzymes.


Linking Intertidal and Subtidal Food Webs: Consumer-Mediated Transport of Intertidal Benthic Microalgal Carbon.
We examined stable carbon and nitrogen isotope ratios for a large variety of consumers in intertidal and subtidal habitats, and their potential primary food sources [i.e., microphytobenthos (MPB), phytoplankton, and Phragmites australis] in a coastal bay system, Yeoja Bay of Korea, to test the hypothesis that the transfer of intertidal MPB-derived organic carbon to the subtidal food web can be mediated by motile consumers. Compared to a narrow δ13C range (-18 to -16‰) of offshore consumers, a broad δ13C range (-18 to -12‰) of both intertidal and subtidal consumers indicated that 13C-enriched sources of organic matter are an important trophic source to coastal consumers. In the intertidal areas, δ13C of most consumers overlapped with or was 13C-enriched relative to MPB. Despite the scarcity of MPB in the subtidal, highly motile consumers in subtidal habitat had nearly identical δ13C range with many intertidal foragers (including crustaceans and fish), overlapping with the range of MPB. In contrast, δ13C values of many sedentary benthic invertebrates in the subtidal areas were similar to those of offshore consumers and more 13C-depleted than motile foragers, indicating high dependence on phytoplankton-derived carbon. The isotopic mixing model calculation confirms that the majority of motile consumers and also some of subtidal sedentary ones depend on intertidal MPB for more than a half of their tissue carbon. Finally, although further quantitative estimates are needed, these results suggest that direct foraging by motile consumers on intertidal areas, and thereby biological transport of MPB-derived organic carbon to the subtidal areas, may provide important trophic connection between intertidal production and the nearshore shallow subtidal food webs.


Orofacial pain as the sole manifestation of syringobulbia-syringomyelia associated with Arnold-Chiari malformation.
This is a case report of a male patient who presented with orofacial pain for a year as the only manifestation of syringobulbia-syringomyelia associated with Arnold-Chiari malformation. This article places emphasis on the clinical presentation and possible differential diagnoses. The pain was continuous and affected the left side of the face. It was exacerbated by coughing and physical effort, possibly as a consequence of an increase in intracranial pressure. Paroxysmal pain crises developed over this background of continuous pain, compatible with neurogenic trigeminal pain of the left second branch, together with pain episodes similar to cluster headache on the same side. The symptoms were resolved following neurosurgical management with amplification of the foramen magnum.


The effect on memory of chronic prednisone treatment in patients with systemic disease.
There have been no systematic investigations of the effects of glucocorticoid treatment on memory in a clinical population despite experimental and clinical evidence that such treatment could cause memory disturbance. We conducted both cross-sectional and longitudinal studies. In Study 1, we administered tests of both hippocampal-dependent explicit memory and hippocampal-independent implicit memory to twenty-five prednisone-treated patients with systemic disease without CNS involvement and 25 matched clinical controls. All treated patients were taking doses of 5 to 40 mg of prednisone daily for at least 1 year. The glucocorticoid-treated group performed worse than the controls on tests of explicit memory, but the groups did not differ on the implicit memory task. Multiple regression analyses suggested that elderly patients are more susceptible to memory impairment with less protracted treatment. The results of Study 2, a prospective, longitudinal study of the effects of prednisone on memory across 3 months of therapy, suggest that even acute treatment can adversely affect memory. The observed alteration in memory was not secondary to inattention, affective disturbance, generalized global cognitive decline, or severity of disease. Results reported here, combined with previous clinical and experimental reports, indicate that the risk of memory impairment should be carefully considered before initiating treatment with glucocorticoids. Conversely, use of glucocorticoids should be considered in the differential diagnosis of memory loss. Finally, the potential benefit of anti-inflammatory treatment in Alzheimer's disease might be counterbalanced by possible iatrogenic memory impairment, at least when synthetic glucocorticoids are considered.


Prevention of central venous catheter-associated bloodstream infections in pediatric intensive care units: a performance improvement collaborative.
The goal of this effort was to reduce central venous catheter (CVC)-associated bloodstream infections (BSIs) in pediatric intensive care unit (ICU) patients by means of a multicenter evidence-based intervention. An observational study was conducted in 26 freestanding children's hospitals with pediatric or cardiac ICUs that joined a Child Health Corporation of America collaborative. CVC-associated BSI protocols were implemented using a collaborative process that included catheter insertion and maintenance bundles, daily review of CVC necessity, and daily goals. The primary goal was either a 50% reduction in the CVC-associated BSI rate or a rate of 1.5 CVC-associated BSIs per 1,000 CVC-days in each ICU at the end of a 9-month improvement period. A 12-month sustain period followed the initial improvement period, with the primary goal of maintaining the improvements achieved. The collaborative median CVC-associated BSI rate decreased from 6.3 CVC-associated BSIs per 1,000 CVC-days at the start of the collaborative to 4.3 CVC-associated BSIs per 1,000 CVC-days at the end of the collaborative. Sixty-five percent of all participants documented a decrease in their CVC-associated BSI rate. Sixty-nine CVC-associated BSIs were prevented across all teams, with an estimated cost avoidance of $2.9 million. Hospitals were able to sustain their improvements during a 12-month sustain period and prevent another 198 infections. We conclude that our collaborative quality improvement project demonstrated that significant reduction in CVC-associated BSI rates and related costs can be realized by means of evidence-based prevention interventions, enhanced communication among caregivers, standardization of CVC insertion and maintenance processes, enhanced measurement, and empowerment of team members to enforce adherence to best practices.


Vocal warm-up and breathing training for teachers: randomized clinical trial.
OBJECTIVE To compare the effectiveness of two speech therapy interventions, vocal warm-up and breathing training, focusing on teachers' voice quality.METHODS A single-blind, randomized, parallel clinical trial was conducted. The research included 31 20 to 60-year old teachers from a public school in Salvador, BA, Northeasatern Brazil, with minimum workloads of 20 hours a week, who have or have not reported having vocal alterations. The exclusion criteria were the following: being a smoker, excessive alcohol consumption, receiving additional speech therapy assistance while taking part in the study, being affected by upper respiratory tract infections, professional use of the voice in another activity, neurological disorders, and history of cardiopulmonary pathologies. The subjects were distributed through simple randomization in groups vocal warm-up (n = 14) and breathing training (n = 17). The teachers' voice quality was subjectively evaluated through the Voice Handicap Index (Índice de Desvantagem Vocal, in the Brazilian version) and computerized voice analysis (average fundamental frequency, jitter, shimmer, noise, and glottal-to-noise excitation ratio) by speech therapists.RESULTS Before the interventions, the groups were similar regarding sociodemographic characteristics, teaching activities, and vocal quality. The variations before and after the intervention in self-assessment and acoustic voice indicators have not significantly differed between the groups. In the comparison between groups before and after the six-week interventions, significant reductions in the Voice Handicap Index of subjects in both groups were observed, as wells as reduced average fundamental frequencies in the vocal warm-up group and increased shimmer in the breathing training group. Subjects from the vocal warm-up group reported speaking more easily and having their voices more improved in a general way as compared to the breathing training group.CONCLUSIONS Both interventions were similar regarding their effects on the teachers' voice quality. However, each contribution has individually contributed to improve the teachers' voice quality, especially the vocal warm-up.TRIAL RECORD NCT02102399, "Vocal Warm-up and Respiratory Muscle Training in Teachers".


Testicular Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.
Testicular cancer is relatively uncommon and accounts for <1% of all male tumors. However, it is the most common solid tumor in men between the ages of 20 and 34 years, and the global incidence has been steadily rising over the past several decades. Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism. Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes and are categorized into 2 main histologic subtypes: seminoma and nonseminoma. Although nonseminoma is the more clinically aggressive tumor subtype, 5-year survival rates exceed 70% with current treatment options, even in patients with advanced or metastatic disease. Radical inguinal orchiectomy is the primary treatment for most patients with testicular GCTs. Postorchiectomy management is dictated by stage, histology, and risk classification; treatment options for nonseminoma include surveillance, systemic therapy, and nerve-sparing retroperitoneal lymph node dissection. Although rarely occurring, prognosis for patients with brain metastases remains poor, with >50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.


Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial.
Artefenomel (OZ439) is a novel synthetic trioxolane with improved pharmacokinetic properties compared with other antimalarial drugs with the artemisinin pharmacophore. Artefenomel has been generally well tolerated in volunteers at doses up to 1600 mg and is being developed as a partner drug in an antimalarial combination treatment. We investigated the efficacy, tolerability, and pharmacokinetics of artefenomel at different doses in patients with Plasmodium falciparum or Plasmodium vivax malaria. This phase 2a exploratory, open-label trial was done at the Hospital for Tropical Diseases, Bangkok, and the Shoklo Malaria Research Unit in Thailand. Adult patients with acute, uncomplicated P falciparum or P vivax malaria received artefenomel in a single oral dose (200 mg, 400 mg, 800 mg, or 1200 mg). The first cohort received 800 mg. Testing of a new dose of artefenomel in a patient cohort was decided on after safety and efficacy assessment of the preceding cohort. The primary endpoint was the natural log parasite reduction per 24 h. Definitive oral treatment was given at 36 h. This trial is registered with ClinicalTrials.gov, number NCT01213966. Between Oct 24, 2010, and May 25, 2012, 82 patients were enrolled (20 in each of the 200 mg, 400 mg, and 800 mg cohorts, and 21 in the 1200 mg cohort). One patient withdrew consent (before the administration of artefenomel) but there were no further dropouts. The parasite reduction rates per 24 h ranged from 0·90 to 1·88 for P falciparum, and 2·09 to 2·53 for P vivax. All doses were equally effective in both P falciparum and P vivax malaria, with median parasite clearance half-lives of 4·1 h (range 1·3-6·7) to 5·6 h (2·0-8·5) for P falciparum and 2·3 h (1·2-3·9) to 3·2 h (0·9-15·0) for P vivax. Maximum plasma concentrations, dose-proportional to 800 mg, occurred at 4 h (median). The estimated elimination half-life was 46-62 h. No serious drug-related adverse effects were reported; other adverse effects were generally mild and reversible, with the highest number in the 1200 mg cohort (17 [81%] patients with at least one adverse event). The most frequently reported adverse effect was an asymptomatic increase in plasma creatine phosphokinase concentration (200 mg, n=5; 400 mg, n=3; 800 mg, n=1; 1200 mg, n=3). Artefenomel is a new synthetic antimalarial peroxide with a good safety profile that clears parasitaemia rapidly in both P falciparum and P vivax malaria. Its long half-life suggests a possible use in a single-dose treatment in combination with other drugs. Bill & Melinda Gates Foundation, Wellcome Trust, and UK Department for International Development.


Mercury toxicokinetics--dependency on strain and gender.
Mercury (Hg) exposure from dental amalgam fillings and thimerosal in vaccines is not a major health hazard, but adverse health effects cannot be ruled out in a small and more susceptible part of the exposed population. Individual differences in toxicokinetics may explain susceptibility to mercury. Inbred, H-2-congenic A.SW and B10.S mice and their F1- and F2-hybrids were given HgCl2 with 2.0 mg Hg/L drinking water and traces of (203)Hg. Whole-body retention (WBR) was monitored until steady state after 5 weeks, when the organ Hg content was assessed. Despite similar Hg intake, A.SW males attained a 20-30% significantly higher WBR and 2- to 5-fold higher total renal Hg retention/concentration than A.SW females and B10.S mice. A selective renal Hg accumulation but of lower magnitude was seen also in B10.S males compared with females. Differences in WBR and organ Hg accumulation are therefore regulated by non-H-2 genes and gender. Lymph nodes lacked the strain- and gender-dependent Hg accumulation profile of kidney, liver and spleen. After 15 days without Hg A.SW mice showed a 4-fold higher WBR and liver Hg concentration, but 11-fold higher renal Hg concentration, showing the key role for the kidneys in explaining the slower Hg elimination in A.SW mice. The trait causing higher mercury accumulation was not dominantly inherited in the F1 hybrids. F2 mice showed a large inter-individual variation in Hg accumulation, showing that multiple genetic factors influence the Hg toxicokinetics in the mouse. The genetically heterogeneous human population may therefore show a large variation in mercury toxicokinetics.


Human papillomavirus infection and associated factors for cervical intraepithelial neoplasia in women living with HIV in China: a cross-sectional study.
Women living with HIV (WLHIV) face disproportionately higher risks of acquiring human papillomavirus (HPV) compared with HIV negative counterparts. We aimed to investigate the prevalence of HPV in WLHIV in Chinese hospital setting and identify associated factors to the progression of late-stage cervical intraepithelial neoplasia (CIN2+) in this population. This retrospective study collected data from 183 WLHIV on antiretroviral treatment (ART), based on reproductive health questionnaires. Gynaecological examination results including serum (for HIV viral load, CD4 T-cell count, hepatitis B infections, syphilis) and vaginal swabs for common bacterial sexually transmitted infections (STIs). Multivariate-logistic regression was applied to analyze the contributing factors to CIN2+. HIV coinfection with other Sexually Transmitted Infections (STIs) were observed in 99 participants (54.1%, (99/183)). HPV (43.7% (80/183)) was the most prevalent STI. The three most prevalent HPV subtypes were all high-risk HPV (HR-HPV), including HPV52 (33.8% (27/80)), HPV58 (21.3% (17/80)) and HPV33 (13.75% (11/80)). About a third (37.5%, 30/80) of women with HPV had HR-HPV. Multiple HPV coinfections were common in HIV-HPV coinfected women (41.3%, 33/80). Cytological examinations revealed that 77.5% (62/80) HPV+ women had detectable cervical lesions. In comparison, only 4.9% (5/103) HPV negative womenwith Atypia and 1.0% (1/103) with CIN1 were diagnosed. Multivariate logistic regression revealed that HPV16 (OR=19.04, 2.53 to 122.92; p=0.004) and HPV18 (OR=11.54, 1.45 to 91.64; p=0.021) infections were significantly associated with CIN2+ in HIV-HPV coinfected women. A high prevalence of HPV was found in women on ART. HPV16/18 infection are strong associated factors to CIN2+ in HIV-HPV coinfected women.


Bispecific antibodies overcome the opsonin-receptor mismatch of cystic fibrosis in vitro: restoration of neutrophil-mediated phagocytosis and killing of Pseudomonas aeruginosa.
Inflammation and infection associated with bacterial pathogens, primarily Pseudomonas aeruginosa (Pa), are the primary causes of morbidity and mortality for cystic fibrosis (CF) patients. CF patients may be predisposed to these bacterial infections by a defect in phagocytosis due to "opsonin-receptor mismatch," in which a complement receptor (CR1) and an important opsonin (iC3b) are destroyed by proteolytic enzymes. We show that opsonin-receptor mismatch can be mitigated in vitro using a bispecific Ab (bsAb) to cross-link neutrophils via the beta-chain of leukocyte integrins (CD18) to bacterial epitopes or C3d on opsonized Pa. Two chemically cross-linked bsAb were constructed with mAb specific for C3d (or the O-specific side chain of Fisher Devlin Immunotype 1 Pa) and CD18. Using an in vitro model of elastase-mediated opsonin-receptor mismatch, these bsAb specifically enhanced Pa phagocytosis and killing, with the anti-C3d-containing bsAb restoring the levels of phagocytosis to approximately those for the non-elastase-treated opsonic control. These results encourage the further investigation of bsAb as therapeutic agents for bacterial infection in the lungs of CF patients.


High quality draft genome sequence and analysis of Pontibacter roseus type strain SRC-1(T) (DSM 17521(T)) isolated from muddy waters of a drainage system in Chandigarh, India.
Pontibacter roseus is a member of genus Pontibacter family Cytophagaceae, class Cytophagia. While the type species of the genus Pontibacter actiniarum was isolated in 2005 from a marine environment, subsequent species of the same genus have been found in different types of habitats ranging from seawater, sediment, desert soil, rhizosphere, contaminated sites, solar saltern and muddy water. Here we describe the features of Pontibacter roseus strain SRC-1(T) along with its complete genome sequence and annotation from a culture of DSM 17521(T). The 4,581,480 bp long draft genome consists of 12 scaffolds with 4,003 protein-coding and 50 RNA genes and is a part of Genomic Encyclopedia of Type Strains: KMG-I project.


PHENOS: a high-throughput and flexible tool for microorganism growth phenotyping on solid media.
Microbial arrays, with a large number of different strains on a single plate printed with robotic precision, underpin an increasing number of genetic and genomic approaches. These include Synthetic Genetic Array analysis, high-throughput Quantitative Trait Loci (QTL) analysis and 2-hybrid techniques. Measuring the growth of individual colonies within these arrays is an essential part of many of these techniques but is useful for any work with arrays. Measurement is typically done using intermittent imagery fed into complex image analysis software, which is not especially accurate and is challenging to use effectively. We have developed a simple and fast alternative technique that uses a pinning robot and a commonplace microplate reader to continuously measure the thickness of colonies growing on solid agar, complemented by a technique for normalizing the amount of cells initially printed to each spot of the array in the first place. We have developed software to automate the process of combining multiple sets of readings, subtracting agar absorbance, and visualizing colony thickness changes in a number of informative ways. The "PHENOS" pipeline (PHENotyping On Solid media), optimized for Saccharomyces yeasts, produces highly reproducible growth curves and is particularly sensitive to low-level growth. We have empirically determined a formula to estimate colony cell count from an absorbance measurement, and shown this to be comparable with estimates from measurements in liquid. We have also validated the technique by reproducing the results of an earlier QTL study done with conventional liquid phenotyping, and found PHENOS to be considerably more sensitive. "PHENOS" is a cost effective and reliable high-throughput technique for quantifying growth of yeast arrays, and is likely to be equally very useful for a range of other types of microbial arrays. A detailed guide to the pipeline and software is provided with the installation files at https://github.com/gact/phenos .


Modelling co-infection of the cystic fibrosis lung by Pseudomonas aeruginosa and Burkholderia cenocepacia reveals influences on biofilm formation and host response.
The Gram-negative bacteria Pseudomonas aeruginosa and Burkholderia cenocepacia are opportunistic human pathogens that are responsible for severe nosocomial infections in immunocompromised patients and those suffering from cystic fibrosis (CF). These two bacteria have been shown to form biofilms in the airways of CF patients that make such infections more difficult to treat. Only recently have scientists begun to appreciate the complicated interplay between microorganisms during polymicrobial infection of the CF airway and the implications they may have for disease prognosis and response to therapy.To gain insight into the possible role that interaction between strains of P. aeruginosa and B. cenocepacia may play during infection, we characterised co-inoculations of in vivo and in vitro infection models. Co-inoculations were examined in an in vitro biofilm model and in a murine model of chronic infection. Assessment of biofilm formation showed that B. cenocepacia positively influenced P. aeruginosa biofilm development by increasing biomass. Interestingly, co-infection experiments in the mouse model revealed that P. aeruginosa did not change its ability to establish chronic infection in the presence of B. cenocepacia but co-infection did appear to increase host inflammatory response.Taken together, these results indicate that the co-infection of P. aeruginosa and B. cenocepacia leads to increased biofilm formation and increased host inflammatory response in the mouse model of chronic infection. These observations suggest that alteration of bacterial behavior due to interspecies interactions may be important for disease progression and persistent infection.


No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects.
Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.


Chinese expert brief consensus on newborn screening of inherited metabolic disorders during the novel coronavirus infection epidemic.
Novel coronavirus (2019-nCov) infection (COVID-19) rapidly spread across China and 25 countries in the worldwide, which infected not only adults but also children, even neonates. Each year, about 15 million newborns are delivered in China. Newborn screening (NBS) helps effectively prevent some mental retardation, premature death, and adverse outcomes in the early stage of baby, which could detect some inherited metabolic disorders (IMDs). During this COVID-19 epidemic, how to balance the risk of infected 2019-nCov and the risk of disability and teratogenesis of IMDs. Expert members of NBS extra quality assessment in National Clinical Center of Laboratory (NCCL) give a brief consensus for NBS of IMDs in the COVID-2019 epidemic, hoping that the brief consensus could be reference for NBS of IMDs in the other epidemic areas or periods all over the world.


Rationale for targeting the Ras/MAPK pathway in triple-negative breast cancer.
"Triple negative" breast cancer (TNBC) is the most aggressive and least common clinical subtype of breast cancer. As its nomenclature implies, TNBC lacks specific biomarker expression marking response to an effective targeted therapy. The incidence of TNBC is higher in young minority women who suffer from high rates of early recurrence and death from their disease. Mounting preclinical evidence supports targeting the Ras/MAPK cell signaling pathway in the TNBC subtype, despite large genomic surveys such as The Cancer Genome Atlas demonstrating infrequent canonical mutations in this pathway. Due to the early spread of TNBC, targeted treatment in the neoadjuvant setting may offer the effective therapeutic punch needed to eliminate micro-metastatic disease and reduce mortality. Herein, we will review the evidence supporting clinical trials of targeted inhibitors of the Ras/MAPK pathway in TNBC, and discuss the obstacles and opportunities of this approach.