Socioeconomic position and the risk of gastric and oesophageal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).
To evaluate the association of socioeconomic position with adenocarcinoma of the oesophagus and stomach. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort comprises about 520 000 participants mostly aged 35-70 years. Information on diet and lifestyle was collected at recruitment. After an average follow-up of 6.5 years, 268 cases with adenocarcinoma of the stomach and 56 of the oesophagus were confirmed. We examined the effect of socioeconomic position on cancer risk by means of educational data and a computed Relative Index of Inequality (RII). In a nested case-control study, adjustment for Helicobacter pylori (H. pylori) infection was performed. Higher education was significantly associated with a reduced risk of gastric cancer [vs lowest level of education, hazard ratio (HR): 0.64, 95% Confidence intervals (CI): 0.43-0.98]. This effect was more pronounced for cancer of the cardia (HR: 0.42, 95% CI: 0.20-0.89) as compared to non-cardia gastric cancer (HR: 0.66, 95% CI: 0.36-1.22). Additionally, the inverse association of educational level and gastric cancer was stronger for cases with intestinal (extreme categories, HR: 0.13, 95% CI: 0.04-0.44) rather than diffuse histological subtype (extreme categories, HR: 0.71 95% CI: 0.37-1.40). In the nested case-control study, inverse but statistically non-significant associations were found after additional adjustment for H. pylori infection [highest vs lowest level of education: Odds ratio (OR) 0.53, 95% CI: 0.24-1.18]. Educational level was non-significantly, inversely associated with carcinoma of the oesophagus. A higher socioeconomic position was associated with a reduced risk of gastric adenocarcinoma, which was strongest for cardia cancer or intestinal histological subtype, suggesting different risk profiles according to educational level. These effects appear to be explained only partially by established risk factors.


Relationships between abdominal and diaphragmatic volume displacements.
We investigated the relationship between the volumes displaced by the diaphragm and the abdominal wall during spontaneous breathing in supine anesthetized dogs. Diaphragmatic volume displacement (Vdi) was calculated from measurements taken from anteroposterior fluoroscopic images employing a previously described geometric model. The volume displacement of the abdominal wall (Vabd) was measured with a calibrated Respitrace. Shortening of single diaphragm muscle bundles in costal and crural regions was measured as the distance between radiopaque beads sutured to the peritoneal surface of the muscle. We found that Vdi always exceeded Vabd, but Vabd/Vdi was larger in animals in which the abdominal wall was more compliant. In this preparation, Vdi is better correlated with costal than with crural shortening. Vabd did not correlate with either costal or crural shortening. We infer that the difference between Vdi and Vabd reflects the volume displacement of the lower rib cage caused by diaphragm contraction. This volume difference was tightly correlated with costal shortening. We conclude from these data that coupling between Vdi and Vabd is influenced by the relative compliances of the chest wall and abdomen. Shortening of regions of the diaphragm may have variable relationships to the measured volume displacement, but costal shortening is intimately related to expansion of the lower rib cage.


Quinones as dienophiles in the Diels-Alder reaction: history and applications in total synthesis.
In the canon of reactions available to the organic chemist engaged in total synthesis, the Diels-Alder reaction is among the most powerful and well understood. Its ability to rapidly generate molecular complexity through the simultaneous formation of two carbon-carbon bonds is almost unrivalled, and this is reflected in the great number of reported applications of this reaction. Historically, the use of quinones as dienophiles is highly significant, being the very first example investigated by Diels and Alder. Herein, we review the application of the Diels-Alder reaction of quinones in the total synthesis of natural products. The highlighted examples span some 60 years from the landmark syntheses of morphine (1952) and reserpine (1956) by Gates and Woodward, respectively, through to the present day examples, such as the tetracyclines.


Magnetic nanoparticles for "smart liposomes".
Liposomal drug delivery systems (LDDSs) are promising tools used for the treatment of diseases where highly toxic pharmacological agents are administered. Currently, destabilising LDDSs by a specific stimulus at a target site remains a major challenge. The bacterial mechanosensitive channel of large conductance (MscL) presents an excellent candidate biomolecule that could be employed as a remotely controlled pore-forming nanovalve for triggered drug release from LDDSs. In this study, we developed superparamagnetic nanoparticles for activation of the MscL nanovalves by magnetic field. Synthesised CoFe2O4 nanoparticles with the radius less than 10 nm were labelled by SH groups for attachment to MscL. Activation of MscL by magnetic field with the nanoparticles attached was examined by the patch clamp technique showing that the number of activated channels under ramp pressure increased upon application of the magnetic field. In addition, we have not observed any cytotoxicity of the nanoparticles in human cultured cells. Our study suggests the possibility of using magnetic nanoparticles as a specific trigger for activation of MscL nanovalves for drug release in LDDSs.


A microbial symbiosis factor prevents intestinal inflammatory disease.
Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles.


Bright and dark polar deposits on Mercury: evidence for surface volatiles.
Measurements of surface reflectance of permanently shadowed areas near Mercury's north pole reveal regions of anomalously dark and bright deposits at 1064-nanometer wavelength. These reflectance anomalies are concentrated on poleward-facing slopes and are spatially collocated with areas of high radar backscatter postulated to be the result of near-surface water ice. Correlation of observed reflectance with modeled temperatures indicates that the optically bright regions are consistent with surface water ice, whereas dark regions are consistent with a surface layer of complex organic material that likely overlies buried ice and provides thermal insulation. Impacts of comets or volatile-rich asteroids could have provided both dark and bright deposits.


Implementing a patient safety culture survey to identify and target process improvements in academic ambulatory urology practices: a multi-institutional collaborative.
A shared professional culture focused on patient safety is critical to delivering high-quality care. There is a need for objective metrics to help identify target areas for improvement in patient safety culture. The Medical Office Survey on Patient Safety Culture (SOPS) was developed and validated by the United States Agency for Healthcare Research and Quality to measure patient safety culture in the ambulatory setting. In this study we report on safety culture and practices in six academic urology clinics utilizing this validated questionnaire. The SOPS was administered to all staff in ambulatory urology practices affiliated with participating centers. Percent positive responses were calculated for each of 10 validated composite domains and were compared between sites and respondent roles. Nonparametric statistical analyses were performed to identify differences between groups. The survey was administered to 185 staff members, with an overall response rate of 66%. Within each domain there was substantial variability between sites, with significant differences observed in staff training (p = 0.034), office processes/standardization (p = 0.008), patient care tracking (p = 0.047), communication about errors (p = 0.001), and organizational learning (p = 0.015). Similar variation was seen between respondent roles with significant differences for patient care tracking (p = 0.002) and communication about errors (p = 0.014). The SOPS is a clinically useful tool to identify issues impacting a practice's safety culture. Substantial variability was observed within each composite domain at the levels of practice site and respondent role. Comparing composite domain results between clinics will allow leadership to identify gaps and evaluate policies and resources of higher performing peer sites.


Impaired neurite development and mitochondrial dysfunction associated with calcium accumulation in dopaminergic neurons differentiated from the dental pulp stem cells of a patient with metatropic dysplasia.
Transient receptor potential vanilloid member 4 (TRPV4) is a Ca2+ permeable nonselective cation channel, and mutations in the TRPV4 gene cause congenital skeletal dysplasias and peripheral neuropathies. Although TRPV4 is widely expressed in the brain, few studies have assessed the pathogenesis of TRPV4 mutations in the brain. We aimed to elucidate the pathological associations between a specific TRPV4 mutation and neurodevelopmental defects using dopaminergic neurons (DNs) differentiated from dental pulp stem cells (DPSCs). DPSCs were isolated from a patient with metatropic dysplasia and multiple neuropsychiatric symptoms caused by a gain-of-function TRPV4 mutation, c.1855C>T (p.L619F). The mutation was corrected by CRISPR/Cas9 to obtain isogenic control DPSCs. Mutant DPSCs differentiated into DNs without undergoing apoptosis; however, neurite development was significantly impaired in mutant vs. control DNs. Mutant DNs also showed accumulation of mitochondrial Ca2+ and reactive oxygen species, low adenosine triphosphate levels despite a high mitochondrial membrane potential, and lower peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression and mitochondrial content. These results suggested that the persistent Ca2+ entry through the constitutively activated TRPV4 might perturb the adaptive coordination of multiple mitochondrial functions, including oxidative phosphorylation, redox control, and biogenesis, required for dopaminergic circuit development in the brain. Thus, certain mutations in TRPV4 that are associated with skeletal dysplasia might have pathogenic effects on brain development, and mitochondria might be a potential therapeutic target to alleviate the neuropsychiatric symptoms of TRPV4-related diseases.


Molecular cloning of the cDNA and gene for an elastinolytic aspartic proteinase from Aspergillus fumigatus and evidence of its secretion by the fungus during invasion of the host lung.
Hydrolysis of structural proteins in the lung by extracellular proteinases secreted by Aspergillus fumigatus is thought to play a significant role in invasive aspergillosis. This fungus was found previously to secrete an elastinolytic serine proteinase and a metalloproteinase. We report that A. fumigatus also secretes an aspartic proteinase (aspergillopepsin F) that can catalyze hydrolysis of the major structural proteins of basement membrane, elastin, collagen, and laminin. The pH optimum for the enzymatic activity was 5.0 with elastin-Congo red as the substrate, and the activity was not significantly inhibited by pepstatin A, diazoacetyl norleucine methylester, and 1,2-epoxy-3-(p-nitrophenoxy) propane. The cDNA and gene encoding this aspartic proteinase were cloned and sequenced. The open reading frame, interrupted by three introns, would encode a protein of 393 amino acids composed of a putative 21-amino-acid signal peptide and a 49-amino-acid propeptide preceding the 323-amino-acid mature protein. The amino acid sequence of A. fumigatus aspartic proteinase has 70, 66, and 67% homology to the sequences of those from Aspergillus oryzae, Aspergillus awamori, and Aspergillus saitoi, respectively. The active-site motif (DTG) and the catalytic aspartic residues characteristic of aspartic proteinases are found in the presently described enzyme, indicating that it belongs to a family of aspartic proteinases. Polyclonal antibodies were produced in rabbits against both the mature and precursor forms of the aspartic proteinase expressed in Escherichia coli. Immunoblotting with both antibodies detected a 39-kDa mature enzyme in the culture supernatant of A. fumigatus. The aspartic proteinase activity was inhibited by the antibodies, suggesting that the aspartic proteinase in the culture supernatant corresponds to the product of the cloned gene. Immunogold electron microscopy showed that the aspartic proteinase was secreted by A. fumigatus invading neutropenic mouse lung and its secretion was directed toward the germ tubes of penetrating hyphae.


The need for a behavioural science focus in research on mental health and mental disorders.
Psychology as a science offers an enormous diversity of theories, principles, and methodological approaches to understand mental health, abnormal functions and behaviours and mental disorders. A selected overview of the scope, current topics as well as strength and gaps in Psychological Science may help to depict the advances needed to inform future research agendas specifically on mental health and mental disorders. From an integrative psychological perspective, most maladaptive health behaviours and mental disorders can be conceptualized as the result of developmental dysfunctions of psychological functions and processes as well as neurobiological and genetic processes that interact with the environment. The paper presents and discusses an integrative translational model, linking basic and experimental research with clinical research as well as population-based prospective-longitudinal studies. This model provides a conceptual framework to identify how individual vulnerabilities interact with environment over time, and promote critical behaviours that might act as proximal risk factors for ill-health and mental disorders. Within the models framework, such improved knowledge is also expected to better delineate targeted preventive and therapeutic interventions that prevent further escalation in early stages before the full disorder and further complications thereof develop. In contrast to conventional "personalized medicine" that typically targets individual (genetic) variation of patients who already have developed a disease to improve medical treatment, the proposed framework model, linked to a concerted funding programme of the "Science of Behaviour Change", carries the promise of improved diagnosis, treatment and prevention of health-risk behaviour constellations as well as mental disorders.


Optimal therapy for desmoid tumors: current options and challenges for the future.
Desmoid tumors, or aggressive fibromatosis, are rare, locally infiltrative neoplasms caused by mutations that activate β-catenin. Although these tumors do not metastasize, they are difficult to manage due to variability in tumor presentation and behavior. A variety of treatment options exist, including surgery, radiotherapy, chemotherapy, hormone therapy, isolated limb perfusion, cryoablation and tyrosine kinase inhibitors. Treatment-induced morbidity and poor local control rates, combined with spontaneous stabilization of some desmoid tumors, have allowed watchful waiting to recently emerge as a front-line management option. This has emphasized the need to better understand tumor behavior in order to differentiate between tumors that may stabilize and those that may progress. Here, we review the most recent findings in desmoid tumor biology and treatment options for this enigmatic disease.


Advances in supportive care of patients with cancer and bone metastases: nursing implications of zoledronic acid.
The knowledge and training of nursing staff is essential for the safety and comfort of patients receiving i.v. therapies. The use of i.v. bisphosphonates as an adjunct to standard antineoplastic therapies in patients with advanced cancer is becoming widespread. Zoledronic acid and pamidronate (Zometa and Aredia, Novartis Pharmaceuticals Corporation, East Hanover, NJ) are nitrogen-containing bisphosphonates. Pamidronate has been the standard of care for patients with osteolytic bone lesions from breast cancer or multiple myeloma. However, zoledronic acid, which has demonstrated increased potency and a broad clinical utility, is emerging as the new standard of care. In addition to treating hypercalcemia of malignancy, zoledronic acid is approved for treating patients with bone metastases (osteolytic or osteoblastic) from a wide range of solid tumors, including breast, prostate, and lung cancers, or osteolytic bone lesions from multiple myeloma. Zoledronic acid (4 mg via a 15-minute infusion) has a safety profile comparable with pamidronate (90 mg via a two-hour infusion) and has demonstrated comparable or superior efficacy to that of pamidronate in every patient population tested. The shorter infusion time of zoledronic acid compared with that of pamidronate may provide added convenience, but safety guidelines should be followed for all i.v. bisphosphonate therapies. These guidelines and nursing care of patients receiving i.v. bisphosphonates are reviewed.


Multi-Phase US Spread and Habitat Switching of a Post-Columbian Invasive, Sorghum halepense.
Johnsongrass (Sorghum halepense) is a striking example of a post-Columbian founder event. This natural experiment within ecological time-scales provides a unique opportunity for understanding patterns of continent-wide genetic diversity following range expansion. Microsatellite markers were used for population genetic analyses including leaf-optimized Neighbor-Joining tree, pairwise FST, mismatch analysis, principle coordinate analysis, Tajima's D, Fu's F and Bayesian clusterings of population structure. Evidence indicates two geographically distant introductions of divergent genotypes, which spread across much of the US in <200 years. Based on geophylogeny, gene flow patterns can be inferred to have involved five phases. Centers of genetic diversity have shifted from two introduction sites separated by ~2000 miles toward the middle of the range, consistent with admixture between genotypes from the respective introductions. Genotyping provides evidence for a 'habitat switch' from agricultural to non-agricultural systems and may contribute to both Johnsongrass ubiquity and aggressiveness. Despite lower and more structured diversity at the invasion front, Johnsongrass continues to advance northward into cooler and drier habitats. Association genetic approaches may permit identification of alleles contributing to the habitat switch or other traits important to weed/invasive management and/or crop improvement.


On Bootstrap Tests of Symmetry About an Unknown Median.
It is important to examine the symmetry of an underlying distribution before applying some statistical procedures to a data set. For example, in the Zuni School District case, a formula originally developed by the Department of Education trimmed 5% of the data symmetrically from each end. The validity of this procedure was questioned at the hearing by Chief Justice Roberts. Most tests of symmetry (even nonparametric ones) are not distribution free in finite sample sizes. Hence, using asymptotic distribution may not yield an accurate type I error rate or/and loss of power in small samples. Bootstrap resampling from a symmetric empirical distribution function fitted to the data is proposed to improve the accuracy of the calculated p-value of several tests of symmetry. The results show that the bootstrap method is superior to previously used approaches relying on the asymptotic distribution of the tests that assumed the data come from a normal distribution. Incorporating the bootstrap estimate in a recently proposed test due to Miao, Gel and Gastwirth (2006) preserved its level and shows it has reasonable power properties on the family of distribution evaluated.


Revitalization of clinical skills training at the University of the Western Cape.
Most educational institutions that offer health related qualifications make use of clinical skills laboratories. These spaces are generally used for the demonstration and assessment of clinical skills. The purpose of this paper is to share our experiences related to the revitalization of skills training by introducing the skills lab method at the School of Nursing (SoN), University of the Western Cape (UWC). To accommodate the contextual changes as a result of the restructuring of the higher education landscape in 2003, the clinical skills training programme at UWC had to be reviewed. With a dramatic increase in the student numbers and a reduction in hospital beds, the skills lab method provided students with an opportunity to develop clinical skills prior to their placement in real service settings. The design phase centred on adopting a skills training methodology that articulates with the case-based approach used by the SoN. Kolb's, experiential learning cycle provided the theoretical underpinning for the methodology. The planning phase was spent on the development of resources. Eight staff members were trained by our international higher education collaborators who also facilitated the training of clinical supervisors and simulated patients. The physical space had to be redesigned to accommodate audio visual and information technology to support the phases of the skills lab method. The implementation of the skills lab method was phased in from the first-year level. An interactive seminar held after the first year of implementation provided feedback from all the role players and was mostly positive. The results of introducing the skills lab method include: a move by students towards self-directed clinical skills development, clinical supervisors adopting the role of facilitators of learning and experiential clinical learning being based on, amongst others, the students' engagement with simulated patients. Finally, the recommendations relate to tailor-making clinical skills training by using various aspects of teaching and learning principles, i.e. case-based teaching, experiential learning and the skills lab method.


Specific inhibition of DNA polymerase beta by its 14 kDa domain: role of single- and double-stranded DNA binding and 5'-phosphate recognition.
DNA polymerase beta (beta-polymerase) has been implicated in short-patch DNA synthesis in the DNA repair pathway known as base excision repair. The native 39 kDa enzyme is organized into four structurally and functionally distinct domains. In an effort to examine this enzyme as a potential therapeutic target, we analyzed the effect of various beta-polymerase domains on the activity of the enzyme in vitro. We show that the 14 kDa N-terminal segment of beta-polymerase, which binds to both single- and double-stranded DNA, but lacks DNA polymerase activity, inhibits beta-polymerase activity in vitro. Most importantly, the 8, 27 and 31 kDa domains of beta-polymerase do not inhibit beta-polymerase activity, demonstrating that the inhibition by the 14 kDa domain is specific. The inhibition of beta-polymerase activity in vitro is abolished by increasing the concentrations of both of the substrates (template-primer and deoxynucleoside triphosphate). In contrast, an in vitro base excision repair assay is inhibited in a domain specific manner by the 14 kDa domain even in the presence of saturating substrates. The inhibition of beta-polymerase activity by the 14 kDa domain appears specific to beta-polymerase as this domain does not inhibit either mammalian DNA polymerase alpha or Escherichia coli polymerase I (Klenow fragment). These data suggest that the 14 kDa domain could be used as a potential inhibitor of intracellular beta-polymerase and that it may provide a means for sensitizing cells to therapeutically relevant DNA damaging agents.


The good and the bad of vitamin D inactivation.
While disorders of impaired vitamin D activation and action have long been appreciated, the consequences of abnormalities in pathways leading to the inactivation of vitamin D metabolites have only recently been identified. Two recent articles have shed new light on this area of vitamin D biology. The report by Martineau et al., published in the JCI, describes a pathway in which binding of the vitamin D metabolite 24R,25(OH)2D3 to its effector molecule FAM57B2 plays an important role in endochondral ossification during bone repair. This work follows, and adds to, another recent JCI publication by Roizen et al., showing that rapid inactivation of vitamin D metabolites causes vitamin D deficiency, leading to vitamin D-dependent rickets.


Macroorchidism in FMR1 knockout mice is caused by increased Sertoli cell proliferation during testicular development.
The fragile X syndrome is the most frequent hereditary form of mental retardation. This X-linked disorder is, in most cases, caused by an unstable and expanding trinucleotide CGG repeat located in the 5'-untranslated region of the gene involved, the fragile X mental retardation 1 (FMR1) gene. Expansion of the CGG repeat to a length of more than 200 trinucleotides results in silencing of the FMR1 gene promoter and, thus, in an inactive gene. The clinical features of male fragile X patients include mental retardation, autistiform behavior, and characteristic facial features. In addition, macroorchidism is observed. To study the role of Sertoli cell proliferation and FSH signal transduction in the occurrence of macroorchidism in fragile X males, we made use of an animal model for the fragile X syndrome, an Fmr1 knockout mouse. The results indicate that in male Fmr1 knockout mice, the rate of Sertoli cell proliferation is increased from embryonic day 12 to 15 days postnatally. The onset and length of the period of Sertoli cell proliferation were not changed compared with those in the control males. Serum levels of FSH, FSH receptor messenger RNA expression, and short term effects of FSH on Sertoli cell function, as measured by down-regulation of FSH receptor messenger RNA, were not changed. We conclude that macroorchidism in Fmr1 knockout male mice is caused by an increased rate of Sertoli cell proliferation. This increase does not appear to be the result of a major change in FSH signal transduction in Fmr1 knockout mice.


Gastroesophageal reflux in relation to adenocarcinomas of the esophagus: a pooled analysis from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON).
Previous studies have evidenced an association between gastroesophageal reflux and esophageal adenocarcinoma (EA). It is unknown to what extent these associations vary by population, age, sex, body mass index, and cigarette smoking, or whether duration and frequency of symptoms interact in predicting risk. The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) allowed an in-depth assessment of these issues. Detailed information on heartburn and regurgitation symptoms and covariates were available from five BEACON case-control studies of EA and esophagogastric junction adenocarcinoma (EGJA). We conducted single-study multivariable logistic regressions followed by random-effects meta-analysis. Stratified analyses, meta-regressions, and sensitivity analyses were also conducted. Five studies provided 1,128 EA cases, 1,229 EGJA cases, and 4,057 controls for analysis. All summary estimates indicated positive, significant associations between heartburn/regurgitation symptoms and EA. Increasing heartburn duration was associated with increasing EA risk; odds ratios were 2.80, 3.85, and 6.24 for symptom durations of <10 years, 10 to <20 years, and ≥20 years. Associations with EGJA were slighter weaker, but still statistically significant for those with the highest exposure. Both frequency and duration of heartburn/regurgitation symptoms were independently associated with higher risk. We observed similar strengths of associations when stratified by age, sex, cigarette smoking, and body mass index. This analysis indicates that the association between heartburn/regurgitation symptoms and EA is strong, increases with increased duration and/or frequency, and is consistent across major risk factors. Weaker associations for EGJA suggest that this cancer site has a dissimilar pathogenesis or represents a mixed population of patients.


Favourable impact of low-calorie cranberry juice consumption on plasma HDL-cholesterol concentrations in men.
A low HDL-cholesterol concentration is an independent risk factor for CVD. Studies have suggested that flavonoid consumption may be cardioprotective, and a favourable impact on circulating HDL-cholesterol concentrations has been suggested to partially explain this association. The aim of the present study was to determine the effect of consuming increasing daily doses of low-calorie cranberry juice cocktail (CJC) on the plasma lipid profile of abdominally obese men. For that purpose, thirty men (mean age 51 (SD 10) years) consumed increasing doses of CJC during three successive periods of 4 weeks (125 ml/d, 250 ml/d, 500 ml/d). Before the study and after each phase, we measured changes in physical and metabolic variables. We noted a significant increase in plasma HDL-cholesterol concentration after the consumption of 250 ml CJC/d (+8.6+/-14.0% v. 0 ml CJC/d; P<0.01), an effect that plateaued during the last phase of the study (500 ml CJC/d: +8.1+/-10.0% v. 0 ml CJC/d; P<0.0001). Multivariate analyses revealed that changes in plasma apo A-I (R(2)=48%, P<0.0001) and triacylglycerol (R(2)=16%, P<0.005) concentrations were the only variables significantly contributing to the variation in plasma HDL-cholesterol concentration noted in response to the intervention. No variation was observed in total as well as in LDL and VLDL cholesterol. The present results show that daily CJC consumption is associated with an increase in plasma HDL-cholesterol concentrations in abdominally obese men. We hypothesise that polyphenolic compounds from cranberries may be responsible for this effect, supporting the notion that the consumption of flavonoid-rich foods can be cardioprotective.


A point mutation in a cadherin gene, Cdh23, causes deafness in a novel mutant, Waltzer mouse niigata.
A novel mouse model for human nonsyndromic hearing loss, Waltzer niigata (v(ngt)), is found and subjected to positional cloning analysis. Genome-wide scan of 1648 backcross mice maps v(ngt) to the D10Mit258 locus near Waltzer (v). Recombination breakpoints are positioned on a physical map consisting of 13 BACs relative to the flanking markers in the vicinity of v(ngt). Allelism test done in parallel shows that v(ngt) and v are allelic. Sequence analysis reveals one-base deletion in the cDNA encoding a cadherin-related protein, Cdh23, mutation of which is recently reported in v mutants. The frame-shift change, producing a truncated protein of 51 amino acids, is ascribed to a base-substitution of G to A in the acceptor site of splicing junction which is predicted to cause one-base shift of the splicing position.


The entorhinal cortex regulates blood glucose level in response to microinjection of neostigmine into the hippocampus.
Microinjectin of neostigmine, an inhibitor of acetylcholine esterase, into the rat hippocampus elicited stress-like responses reflected by the release of adrenocorticotropic hormone (ACTH) and blood glucose elevations. The entorhinal cortex is regarded as an interface between the hippocampus and neocortex. The current study was designed to examine the role of the entorhinal cortex in regulation of blood glucose elevation induced by hippocampal neostigmine injection. We produced the entorhinal cortex lesions in 9 week-old male Wistar rats by the bilateral injections of the cell-selective neurotoxin, ibotenic acid (15microg/microl). Two weeks after the injections, neostigmine methylsulfate (sigma, 5x10(-8) mol) was microinjected into the rat hippocampus in a volume of 1microl for 1min using a CMA/100 microinjection pump. Plasma ACTH levels were measured by radioimmunoassay. Plasma glucose concentrations were determined by the immobilized enzyme membrane/H2O2 method with a compact glucose analyzer Antsense II (Bayer Medical Co.Ltd,Tokyo, Japan). Compared with sham-operated control rats, the entorhinal lesions produced by ibotenic acid significantly attenuated the elevations of blood glucose evoked by the microinjection of neostigmine into the hippocampus. However, no significant difference of plasma ACTH in response to the injection was observed between the entorhinal-lesioned rats and controls. The results of the present study indicate that the entorhinal cortex plays a role in the central nervous systems regulation of blood glucose and may be involved in a stress response presumably via an alternative pathway.


Targeting Polycomb systems to regulate gene expression: modifications to a complex story.
Polycomb group proteins are transcriptional repressors that are essential for normal gene regulation during development. Recent studies suggest that Polycomb repressive complexes (PRCs) recognize and are recruited to their genomic target sites through a range of different mechanisms, which involve transcription factors, CpG island elements and non-coding RNAs. Together with the realization that the interplay between PRC1 and PRC2 is more intricate than was previously appreciated, this has increased our understanding of the vertebrate Polycomb system at the molecular level.


Mechanics of stimulated neutrophils: cell stiffening induces retention in capillaries.
The effect of peptide chemoattractants on neutrophil mechanical properties was studied to test the hypothesis that stimulated neutrophils (diameter, 8 micrometers) are retained in pulmonary capillaries (5.5 micrometers) as a result of a decreased ability of the cell to deform within the capillary in response to the hydrodynamic forces of the bloodstream. Increased neutrophil stiffness, actin assembly, and retention in both 5-micrometer pores and the pulmonary vasculature were seen in response to N-formyl-methionyl-leucyl-phenylalanine. These changes were abolished in cells that had been incubated with 2 micromolar cytochalasin D, an agent that disrupts cellular actin organization. A monoclonal antibody directed at the CD11-CD18 adhesive glycoprotein complex did not inhibit the increase in stiffness or retention in pores. These data suggest that neutrophil stiffening may be both necessary and sufficient for the retention that is observed. Hence, neutrophil sequestration in lung and other capillaries in the acute inflammatory process may be the result of increased stiffness stimulated by chemoattractants.


Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children's Oncology Group.
Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096G>A) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors. One hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques. A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m(2): reference; 1 to 100 mg/m(2): odds ratio [OR], 1.65; 101 to 150 mg/m(2): OR, 3.85; 151 to 200 mg/m(2): OR, 3.69; 201 to 250 mg/m(2): OR, 7.23; 251 to 300 mg/m(2): OR, 23.47; > 300 mg/m(2): OR, 27.59; P(trend) < .001). Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m(2)) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m(2)) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status. This study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m(2). Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.


The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication.
Despite growing interest in adult attention deficit hyperactivity disorder (ADHD), little is known about its prevalence or correlates. A screen for adult ADHD was included in a probability subsample (N=3,199) of 18-44-year-old respondents in the National Comorbidity Survey Replication, a nationally representative household survey that used a lay-administered diagnostic interview to assess a wide range of DSM-IV disorders. Blinded clinical follow-up interviews of adult ADHD were carried out with 154 respondents, oversampling those with positive screen results. Multiple imputation was used to estimate prevalence and correlates of clinician-assessed adult ADHD. The estimated prevalence of current adult ADHD was 4.4%. Significant correlates included being male, previously married, unemployed, and non-Hispanic white. Adult ADHD was highly comorbid with many other DSM-IV disorders assessed in the survey and was associated with substantial role impairment. The majority of cases were untreated, although many individuals had obtained treatment for other comorbid mental and substance-related disorders. Efforts are needed to increase the detection and treatment of adult ADHD. Research is needed to determine whether effective treatment would reduce the onset, persistence, and severity of disorders that co-occur with adult ADHD.


Perioperative management with antiplatelet and statin medication is associated with reduced mortality following vascular surgery.
Many patients undergoing vascular surgical procedures are not on appropriate medical therapy. This study sought to examine the variation and impact of antiplatelet (AP) and statin therapy on early and late mortality in patients undergoing vascular surgery in our region. We studied all patients (n = 14,489) undergoing elective carotid endarterectomy (n = 6978), carotid stenting (n = 524), and suprainguinal (n = 763) and infrainguinal bypass (n = 3053), as well as patients with known coronary risk factors undergoing open (n = 1044) and endovascular (n = 2127) abdominal aortic aneurysm repair from 2005 to 2012 in the Vascular Study Group of New England. Optimal medical management was defined as treatment with both AP and statin agents, preoperatively and at discharge. We analyzed temporal, procedural, and center variation of medication use. Multivariable analyses were used to determine the adjusted impact of AP and statin therapy on 30-day mortality and 5-year survival. Optimal medical management improved over the study interval (55% in 2005 to 68% in 2012; P trend < .01) with carotid interventions having the highest rates of optimal medications use (carotid artery stenting, 78%; carotid endarterectomy, 74%) and abdominal aortic aneurysm repair in patients with known cardiac risk factors having the lowest (open, 57%; endovascular aneurysm repair, 56%). Optimal medication use varied by center as well (range, 40%-86%). Preoperative AP and statin use was associated with reduced 30-day mortality (odds ratio, 0.76; 95% confidence interval [CI], 0.5-1.05; P = .09). AP and statin prescription at discharge was additive in survival benefit with improved 5-year survival (hazard ratio, 0.5; 95% CI, 0.4-0.7; P < .01) that was consistent across procedure types. Patients prescribed AP and statin at discharge had 5-year survival of 79% (95% CI, 77%-81%) compared with only 61% (95% CI, 52%-68%; P < .001) for patients on neither medication. AP and statin therapy preoperatively and at discharge was associated with reduced 30-day mortality and an absolute 18% improved 5-year survival after vascular surgery. However, one-third of patients are suboptimally managed in real world practice. This demonstrates an opportunity for quality improvement that can substantially improve survival after vascular surgery.


Is preeclampsia itself a risk factor for the development of metabolic syndrome after delivery?
This study aimed to determine the association between preeclampsia and the postpartum development of metabolic syndrome based on the pre-pregnancy status. Korean women who delivered their first child between January 1, 2011, and December 31, 2012, were enrolled. All subjects underwent a national health screening examination conducted by the National Health Insurance Corporation 1 or 2 years prior to their first delivery and within 2 years after their first delivery. Among the 49,065 participants, preeclampsia developed in 3,391 participants (6.9%). The prevalence of metabolic syndrome was higher postpartum in women with preeclampsia than in those without preeclampsia (4.9% vs. 2.7%, respectively, P<0.001). Through the pre-pregnancy to postpartum period, women with preeclampsia had a greater increase in gestational weight retention, body mass index, waist circumference, systolic blood pressure, and triglyceride levels and a greater decrease in high-density lipoprotein cholesterol levels than women without preeclampsia. Preeclampsia was associated with an increased risk of the postpartum development of metabolic syndrome in women without pre-pregnancy metabolic syndrome (odds ratio, 1.28; 95% confidence interval, 1.05-1.56). However, preeclampsia was not associated with postpartum metabolic syndrome in women with pre-pregnancy metabolic syndrome or 2 components of metabolic syndrome. In this study, preeclampsia was associated with the postpartum development of metabolic syndrome in women without pre-pregnancy metabolic syndrome. However, the effects were attenuated by predisposing risk factors in the pre-pregnancy period.


Structure-activity correlations for psychotomimetics. 1. Phenylalkylamines: electronic, volume, and hydrophobicity parameters.
CNDO/2 calculations have been performed on a series of alkyl, alkoxy, and alkylthio derivatives of phenethylamine and phenylisopropylamine. The results of these, of van der Waals volume calculations, and of Hansch type hydrophobicity calculations were correlated with psychotomimetic activity by chemometric methods. Eight parameters, involving seven chemical descriptors, were found to be highly significant. Directional hydrophobicity and volume effects were found, which suggests that steric and hydrophobic interactions in the neighborhood of the receptor site are important. A puzzling but strong interaction effect between meta and para substituents was noted. Electronic terms may be explicable in terms of formation of charge-transfer complexes by accepting, rather than by donating, charge, as has been believed in the past. A charge effect indicates that a charge or dipole is influential at the binding site, or alternatively, a specific reactivity at the meta position is involved.


Canine toxocariasis and the associated environmental contamination of urban areas in eastern Nigeria.
The prevalence of canine toxocariasis in pet dogs in two urban towns in eastern Nigeria and the associated environmental contamination were studied through examination of 262 faecal and 400 soil samples. Infection rates in dogs varied from 6.67% to 42.35%, the prevalence rate being inversely related to the age of dogs. Sex and breed of dogs had no significant influence (P greater than 0.05) on the prevalence of infection. There was no evidence of widespread contamination of public places, as Toxocara ova were recovered only from some private premises, namely, those of a dog owner and the kennel of a veterinary hospital.


Metabolic rates of ATP transfer through creatine kinase (CK Flux) predict clinical heart failure events and death.
Morbidity and mortality from heart failure (HF) are high, and current risk stratification approaches for predicting HF progression are imperfect. Adenosine triphosphate (ATP) is required for normal cardiac contraction, and abnormalities in creatine kinase (CK) energy metabolism, the primary myocardial energy reserve reaction, have been observed in experimental and clinical HF. However, the prognostic value of abnormalities in ATP production rates through CK in human HF has not been investigated. Fifty-eight HF patients with nonischemic cardiomyopathy underwent ³¹P magnetic resonance spectroscopy (MRS) to quantify cardiac high-energy phosphates and the rate of ATP synthesis through CK (CK flux) and were prospectively followed for a median of 4.7 years. Multiple-event analysis (MEA) was performed for HF-related events including all-cause and cardiac death, HF hospitalization, cardiac transplantation, and ventricular-assist device placement. Among baseline demographic, clinical, and metabolic parameters, MEA identified four independent predictors of HF events: New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), African-American race, and CK flux. Reduced myocardial CK flux was a significant predictor of HF outcomes, even after correction for NYHA class, LVEF, and race. For each increase in CK flux of 1 μmol g⁻¹ s⁻¹, risk of HF-related composite outcomes decreased by 32 to 39%. These findings suggest that reduced CK flux may be a potential HF treatment target. Newer imaging strategies, including noninvasive ³¹P MRS that detect altered ATP kinetics, could thus complement risk stratification in HF and add value in conditions involving other tissues with high energy demands, including skeletal muscle and brain.


Carbon dioxide effects on stomatal responses to the environment and water use by crops under field conditions.
Reductions in leaf stomatal conductance with rising atmospheric carbon dioxide concentration ([CO2]) could reduce water use by vegetation and potentially alter climate. Crop plants have among the largest reductions in stomatal conductance at elevated [CO2]. The relative reduction in stomatal conductance caused by a given increase in [CO2] is often not constant within a day nor between days, but may vary considerably with light, temperature and humidity. Species also differ in response, with a doubling of [CO2] reducing mean midday conductances by <15% in some crop species to >50% in others. Elevated [CO2] increases leaf area index throughout the growing season in some species. Simulations, and measurements in free air carbon dioxide enrichment systems both indicate that the relatively large reductions in stomatal conductance in crops would translate into reductions of <10% in evapotranspiration, partly because of increases in temperature and decreases in humidity in the air around crop leaves. The reduction in evapotranspiration in crops is similar to that in other types of vegetation which have smaller relative reductions in stomatal conductance, because of the poorer aerodynamic coupling of the canopy to the atmosphere in crops. The small decreases in evapotranspiration at elevated [CO2] may themselves be important to crop production in dry environments, but changes in climate and microclimate caused by reduced stomatal conductance could also be important to crop production.


Patient experience and preferences toward colon cancer screening: a comparison of virtual colonoscopy and conventional colonoscopy.
Virtual colonoscopy has excellent sensitivity for the detection of cancer and polyps greater than 1 cm in diameter. For virtual colonoscopy to succeed as a screening test for colorectal neoplasia, it must be well tolerated and accepted by patients. Patients' experiences with virtual colonoscopy and conventional colonoscopy were assessed and compared. Patients referred to the GI clinic for colonoscopy for any indication were recruited to undergo virtual colonoscopy before conventional colonoscopy. Patients were asked to complete a questionnaire twice: after virtual colonoscopy and after completing both tests. Three variables, overall pain, discomfort, and lack of respect, were assessed by using a 7-point Liken scale with higher scores denoting a worse experience. Patients' preferences for virtual colonoscopy versus conventional colonoscopy were determined with a time tradeoff technique. To verify response stability, patients were asked to return an additional questionnaire by mail at 24 hours. Two hundred ninety-five patients completed the questionnaire immediately after the procedures, and 83 patients completed the questionnaire at 24 hours. At both 0 and 24 hours, patients reported more pain, discomfort, and less respect after virtual colonoscopy than conventional colonoscopy (p < 0.01). The overall agreement (Kappa statistic) between times 0 and 24 hours was fair. Patients reported that they preferred conventional colonoscopy and would wait longer for conventional colonoscopy (mean = 4.9 weeks) than undergo a virtual colonoscopy (p < 0.01). Patients tolerate both virtual colonoscopy and conventional colonoscopy, although they report more pain, discomfort, and less respect undergoing virtual colonoscopy. Efforts to improve patient experience during virtual colonoscopy need to be investigated.


Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene corresponds with desirability of "unhealthy" foods.
The role of dopamine is extensively documented in weight regulation and food intake in both animal models and humans. Yet the role of dopamine has not been well studied in individual differences for food desirability. Genotype status of the dopamine-related catechol-O-methyltransferase (COMT) gene has been shown to influence dopamine levels, with greater COMT enzymatic activity in val/val individuals corresponding to greater degradation of dopamine. Decreased dopamine has been associated with poorer cognitive control and diminished goal-directed behavior in various behavioral paradigms. Additionally, dopaminergic-rich regions such as the frontal cortex and dorsal striatum have been shown to be important for supporting food-related decision-making. However, the role of dopamine, as assessed by COMT genotype status, in food desirability has not been fully explored. Therefore, we utilized an individual's COMT genotype status (n = 61) and investigated food desirability based on self-rated "healthy" and "unhealthy" food perceptions. Here we found val/val individuals (n = 19) have greater desirability for self-rated "unhealthy" food items, but not self-rated "healthy" food items, as compared to val/met (n = 24) and met/met (n = 18) individuals (p < 0.005). Utilizing an objective health measure for the food items, we also found val/val and val/met individuals have greater desirability for objectively defined "unhealthy" food items, as compared to met/met individuals (p < 0.01). This work further substantiates the role of dopamine in food-related behaviors and more specifically in relationship to food desirability for "unhealthy" food items.


Comprehensive evaluation of antibiotics emission and fate in the river basins of China: source analysis, multimedia modeling, and linkage to bacterial resistance.
Antibiotics are widely used in humans and animals, but there is a big concern about their negative impacts on ecosystem and human health after use. So far there is a lack of information on emission inventory and environmental fate of antibiotics in China. We studied national consumption, emissions, and multimedia fate of 36 frequently detected antibiotics in China by market survey, data analysis, and level III fugacity modeling tools. Based on our survey, the total usage for the 36 chemicals was 92700 tons in 2013, an estimated 54000 tons of the antibiotics was excreted by human and animals, and eventually 53800 tons of them entered into the receiving environment following various wastewater treatments. The fugacity model successfully predicted environmental concentrations (PECs) in all 58 river basins of China, which are comparable to the reported measured environmental concentrations (MECs) available in some basins. The bacterial resistance rates in the hospitals and aquatic environments were found to be related to the PECs and antibiotic usages, especially for those antibiotics used in the most recent period. This is the first comprehensive study which demonstrates an alarming usage and emission of various antibiotics in China.


Northern European Salmo trutta (L.) populations are genetically divergent across geographical regions and environmental gradients.
The salmonid fish Brown trout is iconic as a model for the application of conservation genetics to understand and manage local interspecific variation. However, there is still scant information about relationships between local and large-scale population structure, and to what extent geographical and environmental variables are associated with barriers to gene flow. We used information from 3,782 mapped SNPs developed for the present study and conducted outlier tests and gene-environment association (GEA) analyses in order to examine drivers of population structure. Analyses comprised >2,600 fish from 72 riverine populations spanning a central part of the species' distribution in northern Europe. We report hitherto unidentified genetic breaks in population structure, indicating strong barriers to gene flow. GEA loci were widely spread across genomic regions and showed correlations with climatic, abiotic and geographical parameters. In some cases, individual loci showed consistent GEA across the geographical regions Britain, Europe and Scandinavia. In other cases, correlations were observed only within a sub-set of regions, suggesting that locus-specific variation was associated with local processes. A paired-population sampling design allowed us to evaluate sampling effects on detection of outlier loci and GEA. Two widely applied methods for outlier detection (pcadapt and bayescan) showed low overlap in loci identified as statistical outliers across sub-sets of data. Two GEA analytical approaches (LFMM and RDA) showed good correspondence concerning loci associated with specific variables, but LFMM identified five times more statistically significant associations than RDA. Our results emphasize the importance of carefully considering the statistical methods applied for the hypotheses being tested in outlier analysis. Sampling design may have lower impact on results if the objective is to identify GEA loci and their population distribution. Our study provides new insights into trout populations, and results have direct management implications in serving as a tool for identification of conservation units.


Experimentally reduced insulin/IGF-1 signaling in adulthood extends lifespan of parents and improves Darwinian fitness of their offspring.
Classical theory maintains that ageing evolves via energy trade-offs between reproduction and survival leading to accumulation of unrepaired cellular damage with age. In contrast, the emerging new theory postulates that ageing evolves because of deleterious late-life hyper-function of reproduction-promoting genes leading to excessive biosynthesis in late-life. The hyper-function theory uniquely predicts that optimizing nutrient-sensing molecular signaling in adulthood can simultaneously postpone ageing and increase Darwinian fitness. Here, we show that reducing evolutionarily conserved insulin/IGF-1 nutrient-sensing signaling via daf-2 RNA interference (RNAi) fulfils this prediction in Caenorhabditis elegans nematodes. Long-lived daf-2 RNAi parents showed normal fecundity as self-fertilizing hermaphrodites and improved late-life reproduction when mated to males. Remarkably, the offspring of daf-2 RNAi parents had higher Darwinian fitness across three different genotypes. Thus, reduced nutrient-sensing signaling in adulthood improves both parental longevity and offspring fitness supporting the emerging view that suboptimal gene expression in late-life lies at the heart of ageing.


Anemia in the elderly.
There have been several large-scale epidemiologic studies, including the National Health and Nutrition Examination Survey III (NHANES III), which have described the prevalence and impact of anemia in the elderly. The information derived has been critically important. However, given the large number of patients surveyed, these reports necessarily relied substantially on the laboratory-based screening evaluations. There are now two recent reports describing the cause of anemia in elderly outpatients, and although the numbers are smaller than the large scale surveys, they constitute comprehensive hematologic evaluations with therapeutic interventions and clinical follow-up. The purpose of this review is to compare these different analyses. There are distinct differences and similarities in the two types of studies, which are derived from patients seen in hematology clinics. Despite comprehensive hematologic evaluation, the puzzling entity of unexplained anemia of the elderly is confirmed and found to account for 30-46% of patients. NHANES III classified iron-deficiency anemia with other nutritional anemias, a classification that might be correct in the developing third world, but in North America and Western Europe, iron deficiency is more often caused by blood loss and the cause must be sought and dealt with. The myelodysplastic syndromes are an important cause of anemia in the elderly, with a prevalence of at least 4%. Large-scale screening studies of anemia in the elderly are of great importance, and when complemented by comprehensive hematologic evaluations, provide a more accurate picture of the clinical situation.


The influence of cleansing shampoos on ethyl glucuronide concentration in hair analyzed with an optimized and validated LC-MS/MS method.
Ethyl glucuronide (EtG) is widely used as a marker for assessment of alcohol consumption behavior. In this study the influence of special cleansing shampoos on ethyl glucuronide concentrations in hair was investigated. For that purpose an optimized LC-MS/MS method was developed using a Hypercarb™ porous graphitic carbon (PGC) column and validated according to the guidelines of the German Society of Toxicological and Forensic Chemistry (GTFCh). Twenty-five hair samples of persons with known alcohol consumption behavior were investigated (21 positive samples and 4 blank samples). The hair samples were divided into two strands of hair and were analyzed after treatment with one out of four cleansing shampoos and without shampoo treatment. EtG concentrations in hair did not show any significant differences after a single application of the different cleansing shampoos. EtG was still detectable in all the positive hair samples without significant concentration change. These results clearly demonstrated that a single application of the tested cleansing shampoos did not remove EtG from hair and therefore had no influence on EtG concentration in analytical hair analysis.


Regional brain atrophy development is related to specific aspects of clinical dysfunction in multiple sclerosis.
Brain atrophy in multiple sclerosis (MS) is thought to reflect irreversible tissue damage leading to persistent clinical deficit. Little is known about the rate of atrophy in specific brain regions in relation to specific clinical deficits. We determined the displacement of the brain surface between two T1-weighted MRI images obtained at baseline and after a median follow-up time of 2.2 years for 79 recently diagnosed, mildly disabled MS patients. Voxel- and cluster-wise permutation-based statistics were used to identify brain regions in which atrophy development was significantly related to Expanded Disability Status Scale (EDSS), Timed Walk Test (TWT), Paced Auditory Serial Addition Test (PASAT) and 9-Hole Peg Test (HPT). Clusters were considered significant at a corrected cluster-wise p-value of 0.05. Worse EDSS change-score and worse follow-up EDSS were related to atrophy development of periventricular and brainstem regions and right-sided parietal, occipital and temporal regions. Worse PASAT at follow-up was significantly related to atrophy of the ventricles. A worse TWT change-score and worse follow-up TWT were exclusively related to atrophy around the ventricles and of the brainstem. Worse HPT change-score and worse follow-up HPT of either arm were significantly related to the atrophy of widely distributed peripheral regions, as well as atrophy of periventricular and brainstem regions. Our findings suggest that decline in ambulatory function is related to atrophy of central brain regions exclusively, whereas decline in neurologically more complex tasks for coordinated hand function is related to atrophy of both central and peripheral brain regions.


Confident predictability: identifying reliable gene expression patterns for individualized tumor classification using a local minimax kernel algorithm.
Molecular classification of tumors can be achieved by global gene expression profiling. Most machine learning classification algorithms furnish global error rates for the entire population. A few algorithms provide an estimate of probability of malignancy for each queried patient but the degree of accuracy of these estimates is unknown. On the other hand local minimax learning provides such probability estimates with best finite sample bounds on expected mean squared error on an individual basis for each queried patient. This allows a significant percentage of the patients to be identified as confidently predictable, a condition that ensures that the machine learning algorithm possesses an error rate below the tolerable level when applied to the confidently predictable patients. We devise a new learning method that implements: (i) feature selection using the k-TSP algorithm and (ii) classifier construction by local minimax kernel learning. We test our method on three publicly available gene expression datasets and achieve significantly lower error rate for a substantial identifiable subset of patients. Our final classifiers are simple to interpret and they can make prediction on an individual basis with an individualized confidence level. Patients that were predicted confidently by the classifiers as cancer can receive immediate and appropriate treatment whilst patients that were predicted confidently as healthy will be spared from unnecessary treatment. We believe that our method can be a useful tool to translate the gene expression signatures into clinical practice for personalized medicine.


Biocompatibility of nanostructured boron doped diamond for the attachment and proliferation of human neural stem cells.
We quantitatively investigate the biocompatibility of chemical vapour deposited (CVD) nanocrystalline diamond (NCD) after the inclusion of boron, with and without nanostructuring. The nanostructuring method involves a novel approach of growing NCD over carbon nanotubes (CNTs) that act as a 3D scaffold. This nanostructuring of BNCD leads to a material with increased capacitance, and this along with wide electrochemical window makes BNCD an ideal material for neural interface applications, and thus it is essential that their biocompatibility is investigated. Biocompatibility was assessed by observing the interaction of human neural stem cells (hNSCs) with a variety of NCD substrates including un-doped ones, and NCD doped with boron, which are both planar, and nanostructured. hNSCs were chosen due to their sensitivity, and various methods including cell population and confluency were used to quantify biocompatibility. Boron inclusion into NCD film was shown to have no observable effect on hNSC attachment, proliferation and viability. Furthermore, the biocompatibility of nanostructured boron-doped NCD is increased upon nanostructuring, potentially due to the increased surface area. Diamond is an attractive material for supporting the attachment and development of cells as it can show exceptional biocompatibility. When boron is used as a dopant within diamond it becomes a p-type semiconductor, and at high concentrations the diamond becomes quasi-metallic, offering the prospect of a direct electrical device-cell interfacing system.


Smoothing strategies combined with ARIMA and neural networks to improve the forecasting of traffic accidents.
Two smoothing strategies combined with autoregressive integrated moving average (ARIMA) and autoregressive neural networks (ANNs) models to improve the forecasting of time series are presented. The strategy of forecasting is implemented using two stages. In the first stage the time series is smoothed using either, 3-point moving average smoothing, or singular value Decomposition of the Hankel matrix (HSVD). In the second stage, an ARIMA model and two ANNs for one-step-ahead time series forecasting are used. The coefficients of the first ANN are estimated through the particle swarm optimization (PSO) learning algorithm, while the coefficients of the second ANN are estimated with the resilient backpropagation (RPROP) learning algorithm. The proposed models are evaluated using a weekly time series of traffic accidents of Valparaíso, Chilean region, from 2003 to 2012. The best result is given by the combination HSVD-ARIMA, with a MAPE of 0:26%, followed by MA-ARIMA with a MAPE of 1:12%; the worst result is given by the MA-ANN based on PSO with a MAPE of 15:51%.


Mutation Processes in 293-Based Clones Overexpressing the DNA Cytosine Deaminase APOBEC3B.
Molecular, cellular, and clinical studies have combined to demonstrate a contribution from the DNA cytosine deaminase APOBEC3B (A3B) to the overall mutation load in breast, head/neck, lung, bladder, cervical, ovarian, and other cancer types. However, the complete landscape of mutations attributable to this enzyme has yet to be determined in a controlled human cell system. We report a conditional and isogenic system for A3B induction, genomic DNA deamination, and mutagenesis. Human 293-derived cells were engineered to express doxycycline-inducible A3B-eGFP or eGFP constructs. Cells were subjected to 10 rounds of A3B-eGFP exposure that each caused 80-90% cell death. Control pools were subjected to parallel rounds of non-toxic eGFP exposure, and dilutions were done each round to mimic A3B-eGFP induced population fluctuations. Targeted sequencing of portions of TP53 and MYC demonstrated greater mutation accumulation in the A3B-eGFP exposed pools. Clones were generated and microarray analyses were used to identify those with the greatest number of SNP alterations for whole genome sequencing. A3B-eGFP exposed clones showed global increases in C-to-T transition mutations, enrichments for cytosine mutations within A3B-preferred trinucleotide motifs, and more copy number aberrations. Surprisingly, both control and A3B-eGFP clones also elicited strong mutator phenotypes characteristic of defective mismatch repair. Despite this additional mutational process, the 293-based system characterized here still yielded a genome-wide view of A3B-catalyzed mutagenesis in human cells and a system for additional studies on the compounded effects of simultaneous mutation mechanisms in cancer cells.


Targeting rehabilitation to improve outcomes after total knee arthroplasty in patients at risk of poor outcomes: randomised controlled trial.
To evaluate whether a progressive course of outpatient physiotherapy offers superior outcomes to a single physiotherapy review and home exercise based intervention when targeted at patients with a predicted poor outcome after total knee arthroplasty. Parallel group randomised controlled trial. 13 secondary and tertiary care centres in the UK providing postoperative physiotherapy. 334 participants with knee osteoarthritis who were defined as at risk of a poor outcome after total knee arthroplasty, based on the Oxford knee score, at six weeks postoperatively. 163 were allocated to therapist led outpatient rehabilitation and 171 to a home exercise based protocol. All participants were reviewed by a physiotherapist and commenced 18 sessions of rehabilitation over six weeks, either as therapist led outpatient rehabilitation (progressive goal oriented functional rehabilitation protocol, modified weekly in one-one contact sessions) or as physiotherapy review followed by a home exercise based regimen (without progressive input from a physiotherapist). Primary outcome was Oxford knee score at 52 weeks, with a 4 point difference between groups considered to be clinically meaningful. Secondary outcomes included additional patient reported outcome measures of pain and function at 14, 26, and 52 weeks post-surgery. 334 patients were randomised. Eight were lost to follow-up. Intervention compliance was more than 85%. The between group difference in Oxford knee score at 52 weeks was 1.91 (95% confidence interval -0.18 to 3.99) points, favouring the outpatient rehabilitation arm (P=0.07). When all time point data were analysed, the between group difference in Oxford knee score was a non-clinically meaningful 2.25 points (0.61 to 3.90, P=0.01). No between group differences were found for secondary outcomes of average pain (0.25 points, -0.78 to 0.28, P=0.36) or worst pain (0.22 points, -0.71 to 0.41, P=0.50) at 52 weeks or earlier time points, or of satisfaction with outcome (odds ratio 1.07, 95% confidence interval 0.71 to 1.62, P=0.75) or post-intervention function (4.64 seconds, 95% confidence interval -14.25 to 4.96, P=0.34). Outpatient therapist led rehabilitation was not superior to a single physiotherapist review and home exercise based regimen in patients at risk of poor outcomes after total knee arthroplasty. No clinically relevant differences were observed across primary or secondary outcome measures. Current Controlled Trials ISRCTN23357609 and ClinicalTrials.gov NCT01849445.


Measuring patient activation in The Netherlands: translation and validation of the American short form Patient Activation Measure (PAM13).
The American short form Patient Activation Measure (PAM) is a 13-item instrument which assesses patient (or consumer) self-reported knowledge, skills and confidence for self-management of one's health or chronic condition. In this study the PAM was translated into a Dutch version; psychometric properties of the Dutch version were established and the instrument was validated in a panel of chronically ill patients. The translation was done according to WHO guidelines. The PAM 13-Dutch was sent to 4178 members of the Dutch National Panel of people with Chronic illness or Disability (NPCD) in April 2010 (study A) and again to a sub sample of this group (N = 973) in June 2010 (study B). Internal consistency, test-retest reliability and cross-validation with the SBSQ-D (a measure for Health literacy) were computed. The Dutch results were compared to similar Danish and American data. The psychometric properties of the PAM 13-Dutch were generally good. The level of internal consistency is good (α = 0.88) and item-rest correlations are moderate to strong. The Dutch mean PAM score (61.3) is comparable to the American (61.9) and lower than the Danish (64.2). The test-retest reliability was moderate. The association with Health literacy was weak to moderate. The PAM-13 Dutch is a reliable instrument to measure patient activation. More research is needed into the validity of the Patient Activation Measure, especially with respect to a more comprehensive measure of Health literacy.


Comparison of the activity of short stay independent hospitals in England and Wales, 1981 and 1986.
From a sample of 19,000 treatment episodes at 183 of the 193 independent hospitals with operating facilities in England and Wales that were open during 1986 it is estimated that 404,000 inpatients were treated in 1986 (an increase of 48% since 1981) and 99,000 day cases (an increase of 112%). It was found that the procedure most commonly performed was abortion, though this made up only 19% of the total caseload in 1986 compared with 30% in 1981, otherwise the case mix in 1986 was similar to that in 1981. Fewer patients came from overseas in 1986 than in 1981, but the distribution by age and sex remained the same, with three quarters of the patients aged between 15 and 65. The estimated bed occupancy in the independent hospitals in 1986 was less than 60% nationally and only 52% in the Thames regions. It is concluded that in these five years the nature of the independent hospital sector changed little, and in 1986 the activity still consisted largely of routine cold elective surgery for people of working age, and the regional differences in admission rates to independent hospitals were nearly as great as in 1981.


Age-Related Accumulation of Somatic Mitochondrial DNA Mutations in Adult-Derived Human iPSCs.
The genetic integrity of iPSCs is an important consideration for therapeutic application. In this study, we examine the accumulation of somatic mitochondrial genome (mtDNA) mutations in skin fibroblasts, blood, and iPSCs derived from young and elderly subjects (24-72 years). We found that pooled skin and blood mtDNA contained low heteroplasmic point mutations, but a panel of ten individual iPSC lines from each tissue or clonally expanded fibroblasts carried an elevated load of heteroplasmic or homoplasmic mutations, suggesting that somatic mutations randomly arise within individual cells but are not detectable in whole tissues. The frequency of mtDNA defects in iPSCs increased with age, and many mutations were non-synonymous or resided in RNA coding genes and thus can lead to respiratory defects. Our results highlight a need to monitor mtDNA mutations in iPSCs, especially those generated from older patients, and to examine the metabolic status of iPSCs destined for clinical applications.


Long-term performance of ceramic and metal femoral heads on conventional polyethylene in young and active patients: a matched-pair analysis.
Ceramic femoral heads produce less wear of the opposing polyethylene than do metal femoral heads in wear simulation studies. This is a matched-pair analysis of the wear of ceramic and metal femoral heads on conventional polyethylene in uncemented total hip replacements in young, active patients at a minimum of fifteen years of follow-up. From June 1989 to May 1992, thirty-one matched pairs of alumina ceramic or cobalt-chromium metal femoral heads were identified. Patients were matched on the basis of age, sex, body weight, diagnosis, and activity level. The mean age was 55 ± 9 years (range, twenty-three to sixty-five years) at the time of surgery. All procedures were performed with a posterolateral surgical approach by a single surgeon using press-fit Ranawat-Bernstein femoral stems, Harris-Galante-II acetabular cups, GUR 4150 conventional polyethylene (sterilized in argon), and 28-mm-diameter femoral heads. Wear measurements were performed by two independent observers using the computer-assisted Roman software. The average duration of follow-up was 17 ± 1.7 years (range, fifteen to twenty years). The mean Hospital for Special Surgery hip scores (and standard deviation) in the ceramic and metal groups were 39 ± 4 and 40 ± 3 at the time of final follow-up. The University of California Los Angeles activity score at the time of the final follow-up was 6 ± 2 for both groups. The mean wear rates for the ceramic group and the metal group were 0.086 ± 0.05 mm/yr and 0.137 ± 0.05 mm/yr, respectively (p = 0.0015). There was one reoperation in the ceramic group because of distal femoral osteolysis. There were three failures in the metal group, requiring isolated liner exchange in two hips and revision of the acetabular component in one hip because of wear-induced osteolysis and/or loosening that caused symptoms. Five hips in the ceramic group and six hips in the metal group had radiographic evidence of acetabular or femoral osteolysis, but none were symptomatic. Ceramic femoral heads produced significantly less wear on conventional polyethylene liners at the time of long-term follow-up than did metal heads in this matched-pair analysis of young and active patients with uncemented fixation.


Diverse polyubiquitin interaction properties of ubiquitin-associated domains.
The ubiquitin-associated (UBA) domain occurs frequently in proteins involved in ubiquitin-dependent signaling pathways. Although polyubiquitin chain binding is considered to be a defining feature of the UBA domain family, the generality of this property has not been established. Here we have surveyed the polyubiquitin interaction properties of 30 UBA domains, including 16 of 17 occurrences in budding yeast. The UBA domains sort into four classes that include linkage-selective polyubiquitin binders and domains that bind different chains (and monoubiquitin) in a nondiscriminatory manner; one notable class ( approximately 30%) did not bind any ubiquitin ligand surveyed. The properties of a given UBA domain are conserved from yeast to mammals. Their functional relevance is further suggested by the ability of an ectopic UBA domain to alter the specificity of a deubiquitylating enzyme in a predictable manner. Conversely, non-UBA sequences can modulate the interaction properties of a UBA domain.


Cricket fast bowling workload patterns as risk factors for tendon, muscle, bone and joint injuries.
To assess workload-related risk factors for injuries to particular tissue types in cricket fast bowlers. 235 fast bowlers who bowled in 14600 player innings over a period of 15 years were followed in a prospective cohort risk factor study to compare overs bowled in each match (including preceding workload patterns) and injury risk in the 3-4 weeks subsequent to the match. Injuries were categorised according to the affected tissue type as either: bone stress, tendon injuries, muscle strain or joint injuries. Workload risk factors were examined using binomial logistic regression multivariate analysis, with a forward stepwise procedure requiring a significance of <0.05. High acute match workload and high previous season workload were risk factors for tendon injuries, but high medium term (3-month workload) was protective. For bone stress injuries, high medium term workload and low career workload were risk factors. For joint injuries, high previous season and career workload were risk factors. There was little relationship between muscle injury and workload although high previous season workload was slightly protective. The level of injury risk for some tissue types varies in response to preceding fast bowling workload, with tendon injuries most affected by workload patterns. Workload planning may need to be individualised, depending on individual susceptibility to various injury types. This study supports the theory that tendons are at lowest risk with consistent workloads and susceptible to injury with sudden upgrades in workload. Gradual upgrades are recommended, particularly at the start of a bowler's career to reduce the risk of bone stress injury.


Climate Change Should Be on Every Nursing Research Agenda.
Human-caused climate change is a global emergency, and its harms are predicted to increase exponentially in the coming years, particularly if unsustainable practices continue unmitigated. Adverse effects of climate change on communities affected by or at risk for cancer, such as frail older adults, are already measurable and deadly. If nurse scientists continue to ignore these realities, more people are likely to suffer and die as a result. The purpose of this critical reflection is to discuss the vital necessity of including climate change in the research agenda of the Oncology Nursing Society and all nursing science. Using an approach grounded in critical theory and design justice, the authors provide specific suggestions for the incorporation of scientific considerations and nursing measures related to climate change into oncology nursing science.


Clinical results with the Resolute zotarolimus-eluting stent in total coronary occlusions.
We conducted a pooled post hoc analysis (RESOLUTE All Comers and RESOLUTE International) of patients who had the Resolute® zotarolimus-eluting stent (R-ZES) implanted in revascularised total occlusions (TO) compared with patients treated with R-ZES for non-occluded lesions. Patients were divided into three groups: chronic TO (CTO; n=256), non-chronic TO (n=292), and no occlusion (n=2,941). Clinical and safety outcomes assessed through two years included target lesion failure (TLF: cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularisation) and Academic Research Consortium definite or probable stent thrombosis. The rate of TLF at two years was not significantly different among patients in the CTO (9.1%), TO (9.8%), and no occlusion (10.4%) groups (log-rank p=0.800); neither were the components of TLF. Definite or probable stent thrombosis occurred more frequently in the TO group (2.8% vs. 1.2% in the CTO and 1.1% in the group with no occlusion, p=0.027). There were 10 late and six very late stent thrombosis events. Apart from a higher rate of stent thrombosis in patients with TO, patients with totally occluded coronary arteries who receive revascularisation with an R-ZES have clinical outcomes comparable to those who receive a similar stent in non-occluded lesions.


Malingering in the Psychiatric Emergency Department: Prevalence, Predictors, and Outcomes.
Malingering is commonly encountered in the psychiatric emergency department, yet little is known about its prevalence, objectives, or effect on patient management. This study analyzed characteristics of malingering and patient disposition in a 24/7-staffed comprehensive psychiatric emergency program (CPEP) and created predictive models to understand malingering and its effect on physician decision making. Attending psychiatrists completed questionnaires after comprehensive assessments of 405 patients presenting to the CPEP during the 1-month study, recording suspicion of malingering, symptoms malingered, associated secondary gains, demographic characteristics, and initial disposition decision. Analyses examined characteristics associated with degree of malingering suspicion and disposition. Malingering was suspected among one-third of patients, and 20% were strongly or definitely suspected of malingering. High suspicion was associated with malingering of multiple symptoms and was likely to result in immediate discharge. Lower suspicion was associated with being held for further observation. Among patients for whom suspicion of malingering was high, malingering was most frequent for suicidal ideation (58%) and depression (39%); malingering was often used to seek hospital admission (54%) and to stay in the CPEP (35%); malingering was sometimes used to seek multiple secondary gains (25%); and malingering often involved multiple symptoms (44%). Patients for whom suspicion was high had an admission rate of 4%. Among patients suspected of malingering, three variables each independently increased the likelihood of hospital admission: seeking social work or housing services, seeking admission, and malingering of suicidal ideation. Malingering was prevalent in the psychiatric emergency department, and suspicion of malingering was associated with disposition differences. Disposition was significantly influenced by both suspicion of malingering and the gains sought by patients.


Structural basis for antibody recognition in the receptor-binding domains of toxins A and B from Clostridium difficile.
Clostridium difficile infection is a serious and highly prevalent nosocomial disease in which the two large, Rho-glucosylating toxins TcdA and TcdB are the main virulence factors. We report for the first time crystal structures revealing how neutralizing and non-neutralizing single-domain antibodies (sdAbs) recognize the receptor-binding domains (RBDs) of TcdA and TcdB. Surprisingly, the complexes formed by two neutralizing antibodies recognizing TcdA do not show direct interference with the previously identified carbohydrate-binding sites, suggesting that neutralization of toxin activity may be mediated by mechanisms distinct from steric blockage of receptor binding. A camelid sdAb complex also reveals the molecular structure of the TcdB RBD for the first time, facilitating the crystallization of a strongly negatively charged protein fragment that has resisted previous attempts at crystallization and structure determination. Electrospray ionization mass spectrometry measurements confirm the stoichiometries of sdAbs observed in the crystal structures. These studies indicate how key epitopes in the RBDs from TcdA and TcdB are recognized by sdAbs, providing molecular insights into toxin structure and function and providing for the first time a basis for the design of highly specific toxin-specific therapeutic and diagnostic agents.


Evaluation of functional impairment in psoriasis.
Psoriasis is a chronic disease, the course of which is punctuated by exacerbations and remissions. The impact of a chronic, relapsing, and disfiguring disease such as psoriasis on occupational, social, and other areas of functioning is substantial and needs attention. The purpose of this study was to assess the level and nature of functional impairment in psoriasis. Forty-three consecutive patients attending the dermatology clinic of a rural hospital were studied for psychiatric comorbidity and the level of functioning, using a semistructured questionnaire. Psoriasis affected social functioning of 48% patients, led to decreased work efficiency in 51.1% and to subjective distress at work in 62.8% of patients. Stress in home environment and interpersonal relationships was reported by 69.8%. Social and occupational functioning worsened with increasing severity of psoriasis after 1-year duration of illness. Patients complaining of pruritus frequently had anxiety disorders. Psychiatric comorbidity was detected in 67.4% cases. Substantial proportion of patients suffered deterioration of functioning, especially with increasing duration of illness. Thus, timely attention by dermatologists is needed in order to limit the disability caused by psoriasis. To achieve this, liaison with psychiatrist would be crucial along with illness education and emotional support.


Nudging people with Type 2 diabetes towards better self-management through personalized risk communication: A pilot randomized controlled trial in primary care.
To assess the feasibility in routine primary care consultation and investigate the effect on risk recall and self-management of a new type of risk communication intervention based on behavioural economics ("nudge-based") for people with Type 2 diabetes mellitus (T2DM). Forty adults with poorly controlled T2DM (HbA1c > 7.5%) were randomized to receive a personalized, nudge-based risk communication intervention (n = 20) or standard care (n = 20). Risk recall and self-management were evaluated at baseline and 12 weeks after the intervention. Both in terms of feasibility and acceptability, this new risk communication intervention was very satisfactory. Study retention rate after 12 weeks was very high (90%) and participants were highly satisfied with the intervention (4.4 out of 5 on the COMRADE scale). Although not powered to identify significant between-group effects, the intervention significantly improved risk recall after 12 weeks and intentions to make lifestyle changes (dietary behaviour) compared to standard care. This pilot study provides the first evidence of the feasibility of implementing in primary care a nudge-based risk communication intervention for people with T2DM. Based on the promising results observed, an adequately powered trial to determine the effectiveness of the intervention on long-term self-management is judged feasible. As a result of this feasibility study, some minor adaptations to the intervention and study methods that would help to facilitate a definitive trial are also reported.


Transcutaneous bilirubinometry. Interinstrumental variability of TcB instruments.
We studied the interinstrumental variability of the transcutaneous bilirubin meter (TcB) in 35 high risk neonates, using eight commercially available TcB instruments. Our study showed that commercially available TcB instruments were stable and had little interinstrumental variability for repeated TcB measurements at the forehead, chest, and sternum.


HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope.
HIV-1 envelope (Env) mimetics are candidate components of prophylactic vaccines and potential therapeutics. Here we use a synthetic V3-glycopeptide ("Man9-V3") for structural studies of an HIV Env third variable loop (V3)-glycan directed, broadly neutralizing antibody (bnAb) lineage ("DH270"), to visualize the epitope on Env and to study how affinity maturation of the lineage proceeded. Unlike many previous V3 mimetics, Man9-V3 encompasses two key features of the V3 region recognized by V3-glycan bnAbs-the conserved GDIR motif and the N332 glycan. In our structure of an antibody fragment of a lineage member, DH270.6, in complex with the V3 glycopeptide, the conformation of the antibody-bound glycopeptide conforms closely to that of the corresponding segment in an intact HIV-1 Env trimer. An additional structure identifies roles for two critical mutations in the development of breadth. The results suggest a strategy for use of a V3 glycopeptide as a vaccine immunogen.


Neural network analysis of clinical variables predicts escalated care in COVID-19 patients: a retrospective study.
This study sought to identify the most important clinical variables that can be used to determine which COVID-19 patients hospitalized in the general floor will need escalated care early on using neural networks (NNs). Analysis was performed on hospitalized COVID-19 patients between 7 February 2020 and 4 May 2020 in Stony Brook Hospital. Demographics, comorbidities, laboratory tests, vital signs and blood gases were collected. We compared those data obtained at the time in emergency department and the time of intensive care unit (ICU) upgrade of: (i) COVID-19 patients admitted to the general floor (N = 1203) vs. those directly admitted to ICU (N = 104), and (ii) patients not upgraded to ICU (N = 979) vs. those upgraded to the ICU (N = 224) from the general floor. A NN algorithm was used to predict ICU admission, with 80% training and 20% testing. Prediction performance used area under the curve (AUC) of the receiver operating characteristic analysis (ROC). We found that C-reactive protein, lactate dehydrogenase, creatinine, white-blood cell count, D-dimer and lymphocyte count showed temporal divergence between COVID-19 patients hospitalized in the general floor that were upgraded to ICU compared to those that were not. The NN predictive model essentially ranked the same laboratory variables to be important predictors of needing ICU care. The AUC for predicting ICU admission was 0.782 ± 0.013 for the test dataset. Adding vital sign and blood-gas data improved AUC (0.822 ± 0.018). This work could help frontline physicians to anticipate downstream ICU need to more effectively allocate healthcare resources.


Biocompatible reverse thermal gel sustains the release of intravitreal bevacizumab in vivo.
We assessed the in vivo release profile of bevacizumab from and biocompatibility of poly(ethylene glycol)-poly-(serinol hexamethylene urethane), or ESHU, a thermoresponsive hydrogel administered intravitreally for drug delivery. The technical feasibility of injection was assessed quantitatively via mechanical testing. For in vivo studies, New Zealand White rabbit eyes were injected intravitreally with 0.05 mL of either: ESHU dissolved in 25 mg/mL bevacizumab, ESHU dissolved in PBS, or 25 mg/mL bevacizumab. Clinical examination included IOP measurements and examination with indirect ophthalmoscopy for signs of inflammation. Additionally, eyes were examined histologically following euthanasia. To quantify bevacizumab release, aqueous humor samples were obtained via anterior chamber paracentesis and ELISA was used to determine the concentration of drug weekly. In vitro cytotoxicity testing also was performed using bovine corneal endothelial cells. The ESHU was injected easily through a 31-gauge needle, was well tolerated in vivo, and caused minimal cell death in vitro when compared to other common materials, such as silicone oil. The long-term presence of the gel did not affect IOP, and there was no evidence of inflammation histologically or through indirect observation. The ESHU sustained the release of bevacizumab for over 9 weeks and maintained a drug concentration that averaged 4.7 times higher than eyes receiving bolus bevacizumab injections. To our knowledge, this is the first report demonstrating sustained bevacizumab release in vivo from an intravitreally injected hydrogel formulation, suggesting that this delivery system may be a promising candidate for ocular drug delivery.


Impaired insulin action in rats with non-insulin-dependent diabetes.
Studies were performed to test the hypothesis that impaired insulin action occurs as an acquired phenomenon in the streptozocin (STZ)-treated, non-insulin-dependent (NIDDM) diabetic rat model. A number of methods were used to evaluate impaired carbohydrate tolerance in these animals. Plasma glucose and insulin levels were measured at 6 and 14 wk of age, and insulin glucose tolerance tests were performed at 4 and 5 wk of age (before overt hyperglycemia ensues), and at 8 and 14 wk of age (after the animals manifest overt diabetes). The STZ-treated rats had higher plasma glucose levels than those of control animals (P less than 0.001) at 6 and 14 wk of age, while their plasma insulin values were decreased to levels 73% of the controls (1.7 ng/ml versus 2.3 ng/ml, P less than 0.04). Glucose disappearance rates after high (0.35 U/kg) and low (0.175 U/kg) insulin challenge were reduced in the experimental diabetic animals at all ages with both insulin doses. The data suggest that these animals have an early and progressive acquired impairment in insulin action, most compatible with a defect in cellular biologic response to insulin. The possibility that this abnormality is secondary to insulin deficiency is raised.


CT IVC venogram: normalized quantitative criteria for patency and thrombosis.
Establish normal attenuation ratios for vein to artery on CT IVC venogram and determine a vascular attenuation ratio diagnostic of thrombus. This retrospective, HIPAA-compliant study included 56 CT IVC venograms. Images were reviewed for the presence of femoral vein or IVC thrombus. Attenuation ratios for each vein and its corresponding artery were calculated by two observers and averaged in four venous stations (right and left femoral veins, and IVC at the confluence of the iliac veins and at the left renal vein). The reference standard for the absence of thrombus was clinical follow-up and for the presence of thrombus it was thrombectomy or catheter venogram. Receiver operating characteristic (ROC) analysis was performed using ratios from one venous station and threshold for thrombus was determined using the Youden's index. 36 of 56 CTs demonstrated no thrombus. 20 CTs demonstrated thrombus, confirmed in eight patients. For CTs with no thrombus, median ratios among the venous stations ranged from 0.89 (IQR 0.83-0.93) to 0.91 (IQR 0.86-0.94). ROC analysis of ratios from a single representative station (left femoral vein, n = 4 confirmed clots) demonstrated an area under the curve (AUC) of 0.994 (p = 0.001) and a threshold of 0.67 for diagnosing thrombus [sensitivity 100% (95% CI 39.76-100%), specificity 97.5% (86.84-99.94%)]. The normal attenuation ratio of vein to artery in the absence of venous thrombus on a 3-min delay CT IVC venogram is approximately 0.91. A ratio less than 0.67 is highly suggestive of thrombus.


Iatrogenic nerve injuries in shoulder surgery.
The range of open and arthroscopic shoulder procedures continues to evolve and expand. Despite advances in instrumentation and technology, complications still exist and neurologic injury remains an inherent part of these procedures. Iatrogenic nerve injuries are among the more commonly cited complications associated with shoulder surgery. Various surgical procedures about the shoulder are known to place the brachial plexus and peripheral motor nerves at risk. Peripheral nerve monitoring has been helpful in identifying specific surgical steps and key anatomic regions that are susceptible to iatrogenic nerve injury.