Effect of immediate dentine sealing on the fracture strength of lithium disilicate and multiphase resin composite inlay restorations.
Limited information is available on the effect of Immediate Dentin Sealing (IDS) on the fracture strength of indirect partial posterior restorations. This study evaluated the effect of IDS on the fracture strength and failure types of two indirect restorative materials. Standard MOD inlay preparations were made on sound molars (N=40, n=10 per group) and randomly divided into four groups to receive the inlay materials with and without the application of IDS: Group L-IDS-: Li2Si2O5 (Lithium disilicate, IPS e.max) without IDS; Group L-IDS+: Li2Si2O5 with IDS; Group MR-IDS-: Multiphase resin composite (MR, Lava Ultimate) without IDS; MR-IDS+: MR with IDS. Inlays made of L were etched with 5% hydrofluoric acid, and MR inlays were silica coated. After silanization, they were cemented using adhesive resin cement (Variolink Esthetic DC). The specimens were thermo-mechanically aged (1.2×106 cycles, 1.7Hz, 8000 cycles, 5-55°C) and then subjected to load to failure (1 mm/min). Failure types and locations of debondings were classified. Data were statistically analyzed using ANOVA, Mann Whitney U-test and Chi-square tests (α=0.05). Two-parameter Weibull distribution values including the Weibull modulus, scale (m) and shape (0), values were calculated. After aging conditions, no apparent changes were observed in marginal integrity but occlusal wear facets were more common with MR than with L (p<0.001). Material type and the application of IDS significantly affected the results (p=0.013). While group L-IDS- showed the lowest mean fracture strength (1358±506N) among all groups (p<0.05), application of IDS significantly increased the results significantly (L-IDS+: 2035±403N) (p=0.006). MR groups with and without IDS, did not show significant difference (MR-IDS-: 1861±423, MR-IDS+: 1702±596 N) (p=0.498). When materials without IDS are compared, L showed significantly lower results than that of MR (p=0.035). With the application of IDS, no significant difference was noted between L and MR materials (p=0.160). Weibull distribution presented the highest shape (0) for L-IDS+ (5.66) compared to those of other groups (3.01-4.76). Neither the material type (p=0.830), nor the application of IDS (p=0.54) affected the severity of the failure types. In 95% of the cases, the IDS layer left adhered on the tooth surface after fracture tests. In groups where no IDS was used, resin cement remained on the tooth surface in 44% of the cases (p=0.001). No significant differences were observed between the materials with respect to cement remnants or IDS after fracture (p=0.880). The incidence of repairable failure types (83%) was more common with L than with MR (75%) material (p>0.05). Immediate dentin sealing improves adhesion, and thereby the fracture strength of inlays made of lithium disilicate but not that multiphase resin composite.


Genetic Marker Discovery in Complex Traits: A Field Example on Fat Content and Composition in Pigs.
Among the large number of attributes that define pork quality, fat content and composition have attracted the attention of breeders in the recent years due to their interaction with human health and technological and sensorial properties of meat. In livestock species, fat accumulates in different depots following a temporal pattern that is also recognized in humans. Intramuscular fat deposition rate and fatty acid composition change with life. Despite indication that it might be possible to select for intramuscular fat without affecting other fat depots, to date only one depot-specific genetic marker (PCK1 c.2456C>A) has been reported. In contrast, identification of polymorphisms related to fat composition has been more successful. For instance, our group has described a variant in the stearoyl-coA desaturase (SCD) gene that improves the desaturation index of fat without affecting overall fatness or growth. Identification of mutations in candidate genes can be a tedious and costly process. Genome-wide association studies can help in narrowing down the number of candidate genes by highlighting those which contribute most to the genetic variation of the trait. Results from our group and others indicate that fat content and composition are highly polygenic and that very few genes explain more than 5% of the variance of the trait. Moreover, as the complexity of the genome emerges, the role of non-coding genes and regulatory elements cannot be disregarded. Prediction of breeding values from genomic data is discussed in comparison with conventional best linear predictors of breeding values. An example based on real data is given, and the implications in phenotype prediction are discussed in detail. The benefits and limitations of using large SNP sets versus a few very informative markers as predictors of genetic merit of breeding candidates are evaluated using field data as an example.


Direction discovery: A science enrichment program for high school students.
Launch into education about pharmacology (LEAP) is an inquiry-based science enrichment program designed to enhance competence in biology and chemistry and foster interest in science careers especially among under-represented minorities. The study of how drugs work, how they enter cells, alter body chemistry, and exit the body engages students to conceptualize fundamental precepts in biology, chemistry, and math. Students complete an intensive three-week course in the fundamentals of pharmacology during the summer followed by a mentored research component during the school year. Following a 5E learning paradigm, the summer course captures student interest by introducing controversial topics in pharmacology and provides a framework that guides them to explore topics in greater detail. The 5E learning cycle is recapitulated as students extend their knowledge to design and to test an original research question in pharmacology. LEAP students demonstrated significant gains in biology and chemistry knowledge and interests in pursuing science. Several students earned honors for the presentation of their research in regional and state science fairs. Success of the LEAP model in its initial 2 years argues that coupling college-level coursework of interest to teens with an authentic research experience enhances high school student success in and enthusiasm for science.


Biogas production in an anaerobic sequencing batch reactor by using tequila vinasses: effect of pH and temperature.
In recent years, anaerobic digestion has been recognized as a suitable alternative for tequila vinasses treatment due to its high energy recovery and chemical oxygen demand (COD) removal efficiency. However, key factors such as the lack of suitable monitoring schemes and the presence of load disturbances, which may induce unstable operating conditions in continuous systems, have limited its application at full scale. Therefore, the aim of this work was to evaluate the anaerobic sequencing batch reactor (AnSBR) configuration in order to provide a low cost and easy operation alternative for the treatment of these complex effluents. In particular, the AnSBR was evaluated under different pH-temperature combinations: 7 and 32 °C; 7 and 38 °C; 8 and 32 °C and 8 and 38 °C. Results showed that the AnSBR configuration was able to achieve high COD removal efficiencies (around 85%) for all the tested conditions, while the highest methane yield was obtained at pH 7 and 38 °C (0.29 L/g COD added). Furthermore, high robustness was found in all the AnSBR experiments. Therefore, the full-scale application of the AnSBR technology for the treatment of tequila vinasses is quite encouraging, in particular for small and medium size tequila industries that operate under seasonal conditions.


Is Preoperative Quantitative Sensory Testing Related to Persistent Postsurgical Pain? A Systematic Literature Review.
Persistent postsurgical pain (PPSP) is a common complication of surgery that significantly affects quality of life. A better understanding of which patients are likely to develop PPSP would help to identify when perioperative and postoperative pain management may require specific attention. Quantitative sensory testing (QST) of a patient's preoperative pain perception is associated with acute postoperative pain, and acute postoperative pain is a risk factor for PPSP. The direct association between preoperative QST and PPSP has not been reviewed to date. In this systematic review, we assessed the relationship of preoperative QST to PPSP. We searched databases with components related to (1) preoperative QST; (2) association testing; and (3) PPSP. Two authors reviewed all titles and abstracts for inclusion. Inclusion criteria were as follows: (1) QST performed before surgery; (2) PPSP assessed ≥3 months postoperatively; and (3) the association between QST measures and PPSP is investigated. The search retrieved 905 articles; 24 studies with 2732 subjects met inclusion criteria. Most studies (22/24) had moderate to high risk of bias in multiple quality domains. Fourteen (58%) studies reported a significant association between preoperative QST and PPSP. Preoperative temporal summation of pain (4 studies), conditioned pain modulation (3 studies), and pressure pain threshold (3 studies) showed the most frequent association with PPSP. The strength of the association between preoperative QST and PPSP varied from weak to strong. Preoperative QST is variably associated with PPSP. Measurements related to central processing of pain may be most consistently associated with PPSP.


Interrogation of allelic chromatin states in human cells by high-density ChIP-genotyping.
Allele-specific (AS) assessment of chromatin has the potential to elucidate specific cis-regulatory mechanisms, which are predicted to underlie the majority of the known genetic associations to complex disease. However, development of chromatin landscapes at allelic resolution has been challenging since sites of variable signal strength require substantial read depths not commonly applied in sequencing based approaches. In this study, we addressed this by performing parallel analyses of input DNA and chromatin immunoprecipitates (ChIP) on high-density Illumina genotyping arrays. Allele-specificity for the histone modifications H3K4me1, H3K4me3, H3K27ac, H3K27me3, and H3K36me3 was assessed using ChIP samples generated from 14 lymphoblast and 6 fibroblast cell lines. AS-ChIP SNPs were combined into domains and validated using high-confidence ChIP-seq sites. We observed characteristic patterns of allelic-imbalance for each histone-modification around allele-specifically expressed transcripts. Notably, we found H3K4me1 to be significantly anti-correlated with allelic expression (AE) at transcription start sites, indicating H3K4me1 allelic imbalance as a marker of AE. We also found that allelic chromatin domains exhibit population and cell-type specificity as well as heritability within trios. Finally, we observed that a subset of allelic chromatin domains is regulated by DNase I-sensitive quantitative trait loci and that these domains are significantly enriched for genome-wide association studies hits, with autoimmune disease associated SNPs specifically enriched in lymphoblasts. This study provides the first genome-wide maps of allelic-imbalance for five histone marks. Our results provide new insights into the role of chromatin in cis-regulation and highlight the need for high-depth sequencing in ChIP-seq studies along with the need to improve allele-specificity of ChIP-enrichment.


Opportunistic preventive services delivery. Are time limitations and patient satisfaction barriers?
The use of illness visits as opportunities to increase the delivery of preventive services has been widely recommended, but its feasibility in community practice is not known. We examined the prevalence of this opportunistic approach to providing preventive services, and the degree to which patient satisfaction and time limitation are barriers. Consecutive patient illness visits to 138 community family physicians were directly observed. Visits by patients who received at least one preventive service recommended by the US Preventive Services Task Force were compared with visits by patients not receiving any recommended preventive services, controlling for potentially confounding patient characteristics. Among 3547 illness visits, preventive services were delivered during 39% of visits for chronic illness and 30% of visits for acute illness. Opportunistic health habits counseling occurred more frequently than screening or immunization. Visit satisfaction reported by 2454 patients using the Medical Outcomes Survey 9-item Visit Rating Scale was not different during illness visits with or without the delivery of preventive services. The duration of illness visits that included preventive services was an average of 2.1 minutes longer than illness visits without such interventions (95% confidence interval, 1.7-2.4). The delivery of preventive services during illness visits is common in community practice and is well accepted by patients. The expansion of an opportunistic approach to providing preventive services will require attention to time-efficient approaches.


Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette's syndrome and OCD.
Obsessive-compulsive disorder (OCD) and Tourette's syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette's syndrome and OCD. The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette's syndrome, 579 with OCD plus Tourette's syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders. Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10(-4)), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette's syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette's syndrome/chronic tics were included in the analysis (p=0.01). Previous work has shown that Tourette's syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette's syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.


Levonorgestrel-releasing intrauterine system and the risk of breast cancer: A nationwide cohort study.
Prolonged steroid hormone therapy increases the risk of breast cancer, especially the risk of lobular cancer, but the effect of the levonorgestrel-releasing intrauterine system (LNG-IUS) use is controversial. In this study we aimed to test the hypothesis that risk for lobular breast cancer is elevated among LNG-IUS users. We identified from the national Medical Reimbursement Registry of Finland the women aged 30-49 who had used LNG-IUS for the treatment or prevention of menorrhagia in 1994-2007, and from the Finnish Cancer Registry breast cancers diagnosed before the age of 55 and by the end of 2012. A total of 2015 women had breast cancer diagnosed in a cohort of 93 843 LNG-IUS users during follow-up consisting of 1 032 767 women-years. The LNG-IUS users had an increased risk for both ductal breast cancer [standardized incidence ratio (SIR) 1.20, 95% confidence interval (CI) 1.14-1.25] and for lobular breast cancer (SIR 1.33, 95% CI 1.20-1.46), as compared with the general female population. The highest risk was found in LNG-IUS users who purchased the device at least twice, whose SIR for lobular cancer was 1.73 (95% CI 1.37-2.15). The results imply that intrauterine administration of levonorgestrel is not only related to an excess risk of lobular breast cancer but also, in contrary to previous assumptions, to an excess risk of ductal breast cancer.


Schistosoma and Other Relevant Helminth Infections in HIV-Positive Individuals-an Overview.
For many years, researchers have postulated that helminthic infections may increase susceptibility to HIV, and that immune activation may have contributed to the extensive spread of HIV in sub-Saharan Africa. In the meantime, immunological studies have provided some evidence in support of this hypothesis, while cross-sectional clinical studies were able to further support the assumed association between HIV infection and selected helminthic co-infections. However, as many of the helminthic infections relevant to HIV-infected patients belong to the group of "neglected tropical diseases", as defined by the World Health Organization, a certain lack of attention has inhibited progress in fully scaling up treatment and prevention efforts. In addition, despite the fact that the challenges of co-infections have preoccupied clinicians for over two decades, relevant research questions remain unanswered. The following review aims to provide a concise overview of associations between HIV and selected helminthic co-infections concerning aspects of HIV acquisition and transmission, clinical and immunological findings in co-infected individuals, as well as treatment and prevention efforts.


In utero and Lactational Exposure to Acetamiprid Induces Abnormalities in Socio-Sexual and Anxiety-Related Behaviors of Male Mice.
Neonicotinoids, a widely used group of pesticides designed to selectively bind to insect nicotinic acetylcholine receptors, were considered relatively safe for mammalian species. However, they have been found to activate vertebrate nicotinic acetylcholine receptors and could be toxic to the mammalian brain. In the present study, we evaluated the developmental neurotoxicity of acetamiprid (ACE), one of the most widely used neonicotinoids, in C57BL/6J mice whose mothers were administered ACE via gavage at doses of either 0 mg/kg (control group), 1.0 mg/kg (low-dose group), or 10.0 mg/kg (high-dose group) from gestational day 6 to lactation day 21. The results of a battery of behavior tests for socio-sexual and anxiety-related behaviors, the numbers of vasopressin-immunoreactive cells in the paraventricular nucleus of the hypothalamus, and testosterone levels were used as endpoints. In addition, behavioral flexibility in mice was assessed in a group-housed environment using the IntelliCage, a fully automated mouse behavioral analysis system. In adult male mice exposed to ACE at both low and high doses, a significant reduction of anxiety level was found in the light-dark transition test. Males in the low-dose group also showed a significant increase in sexual and aggressive behaviors. In contrast, neither the anxiety levels nor the sexual behaviors of females were altered. No reductions in the testosterone level, the number of vasopressin-immunoreactive cells, or behavioral flexibility were detected in either sex. These results suggest the possibility that in utero and lactational ACE exposure interferes with the development of the neural circuits required for executing socio-sexual and anxiety-related behaviors in male mice specifically.


A Meta-Analysis Comparing Open-Label versus Placebo-Controlled Clinical Trials for Aripiprazole Augmentation in the Treatment of Major Depressive Disorder: Lessons and Promises.
The present study is to provide whether open-label studies (OLS) may properly foresee the efficacy of randomized, placebo-controlled trials (RCTs) using OLSs and RCTs data for aripiprazole in the treatment of MDD, with the use of meta-analysis approach. A search of the studies used the key terms "depression and aripiprazole" from the databases of PubMed/PsychInfo from Jan 2005 through July 2013. The data were selected and verified for publication in English-based peer-reviewed journals based on rigorous inclusion criteria. Extracted data were delivered into and run by the Comprehensive Meta Analysis program v2. The pooled SMDs for the primary efficacy measure was statistically significant, pointing out the significant reduction of depressive symptoms after aripiprazole augmentation (AA) to current antidepressant treatment in OLSs (pooled SMD=-2.114, z=-9.625, p<0.001); similar results were also found in RCTs (pooled SMD=-2.202, z=-6.862, p<0.001). The meta-regression analysis revealed no influence of the study design for treatment outcome. There was no difference in the treatment effects of aripiprazole as an augmentation therapy in both OLSs and RCTs, indicating that open-label design may be a potentially useful predictor for treatment outcomes of controlled-clinical trials. The proper conduction of OLSs may provide informative, useful and preliminary clinical data and factors to be involved in controlled-clinical trials, by which we may have better understanding on the role of AA (e.g., dosing issues, proper duration of treatment, specific population for AA) implicated in the treatment of MDD in clinical practice.


Discriminative stimulus effects of atypical anxiolytics in baboons and rats.
Baboons and rats were trained to discriminate lorazepam and pentobarbital in a food-maintained two-lever drug vs. no-drug discrimination procedure. Previous research showed that benzodiazepines, but not barbiturates, occasioned drug lever responding in the lorazepam-trained animals. Lorazepam and six nonbenzodiazepines that have been proposed as anxiolytics (CGS 9896, CL 218,872, PK 9084, zopiclone, buspirone and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) were studied in test sessions in which responding on either level produced food. Of the nonbenzodiazepine compounds studied that displace 3H-benzodiazepines in vitro, CL 218,872 and zopiclone occasioned drug lever responding in all animals; PK 9084 did not occasion drug lever responding in any animal; and CGS 9896 did not occasion drug lever responding in lorazepam- or pentobarbital-trained baboons or in lorazepam-trained rats, but did so in the pentobarbital-trained rats. Buspirone, a nonbenzodiazepine anxiolytic with prominent dopaminergic activity, and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, a gamma-aminobutyric acid agonist, also did not occasion drug lever responding in either baboons or rats, regardless of training drug. Time course studies in baboons with CGS 9896, PK 9084, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol and buspirone did not reveal delayed onset of drug stimulus generalization. Some differences in potency as a function of route of administration were found with CL 218,872, zopiclone and buspirone. The discriminative stimulus effects of lorazepam, CL 218,872 and zopiclone were antagonized by the benzodiazepine receptor antagonist Ro 15-1788. It is concluded that the discriminative stimulus properties of these nonbenzodiazepine compounds thus do not co-vary with their antipunishment effects, with their clinical efficacy as anxiolytics or with benzodiazepine receptor binding.


Recurrence in the thyroidectomy bed: sonographic findings.
The purpose of this article is to characterize sonographic features of differentiated thyroid cancer recurrence in the thyroidectomy bed. Patients referred for biopsy of thyroidectomy bed lesions between February 2006 and December 2009 were identified. Patient data and gray-scale and color Doppler features were recorded. Results of ultrasound-guided biopsies of 30 nodules in 27 patients were reviewed. Twenty-five lesions yielded diagnostic findings, including 22 recurrences in 19 patients and three benign lesions in three patients. Five biopsies were nondiagnostic. Among the 22 recurrences, 21 (95%) were hypoechoic and one (5%) was mixed hypoechoic and hyperechoic on gray-scale imaging. On Doppler imaging, 100% of recurrences had detectable vascularity. Eight lesions (36%) had microcalcifications, and five (23%) had coarse calcifications; the average long-axis dimension was 1.5 cm. Of the five nondiagnostic lesions, four (80%) were hypoechoic, one (20%) was isoechoic, one (20%) had microcalcifications, none had coarse calcifications, and two (40%) had vascularity; the average long-axis dimension was 0.6 cm. Of the negative lesions, three (100%) were hypoechoic, two (66%) had vascularity, and two (66%) had coarse calcifications. No microcalcifications were seen, and the average long-axis dimension was 2 cm. Serum thyroglobulin (Tg) or anti-Tg antibodies were elevated in 12 (63%) of 19 patients with recurrence (eight [42%] with elevated Tg levels and four [21%] with elevated anti-Tg antibody levels). An ultrasound finding of a hypoechoic thyroidectomy bed lesion with internal vascularity and size greater than 6 mm is highly sensitive in predicting recurrence. Serum Tg levels were less sensitive than ultrasound in detection of recurrence in the thyroidectomy bed.


Chemotherapy and its evolving role in the management of advanced prostate cancer.
Advanced prostate cancer has been recognized as being responsive to androgen deprivation since the 1940s when Charles Huggins first described the role of surgical castration in managing these patients. However, androgen deprivation only results in transient disease control for the vast majority of men, with those progressing in spite of castrate testosterone levels labeled as having castrate-resistant prostate cancer (CRPC). Until 2004, the therapeutic arena for these patients had remained stagnant, with no agent having shown a survival gain in the CRPC setting. Two landmark publications changed the prostate cancer treatment landscape by providing 'level-1 evidence' that docetaxel-based chemotherapy led to prolongation in overall survival (OS). This was followed by the approval of cabazitaxel in 2010 on the basis of Phase III data demonstrating its efficacy in patients pretreated with docetaxel. More recently, a number of next-generation androgen-directed agents (e.g. abiraterone and enzalutamide) have also been shown to lead to a survival benefit in men with CRPC. With so many new treatment options available, a number of questions remain. These include: how to best sequence chemotherapy with these newer hormonal agents, the clinical implication of cross-resistance between taxanes and androgen-directed agents and which subsets of patients may benefit most from early use of chemotherapy. This review will provide an overview of the evolving role of chemotherapy in the management of advanced prostate cancer in the current era.


THz spectroscopy of weakly bound cluster molecules in solid para-hydrogen: a sensitive probe of van der Waals interactions.
The present work demonstrates that 99.9% enriched solid para-H2 below 3 K provides an excellent inert and transparent medium for the exploration of large-amplitude intermolecular vibrational motion of weakly bound van der Waals cluster molecules in the THz spectral region. THz absorption spectra have been generated for CO2/H2O and CS2/H2O mixtures embedded in enriched solid para-H2 and numerous observed transitions associated with large-amplitude librational motion of the weakly bound binary CO2H2O and CS2H2O van der Waals cluster molecules have been assigned together with tentative assignments for the ternary CS2(H2O)2 system. The interaction strength, directionality and anharmonicity of the weak van der Waals "bonds" between the molecules can be characterized via these THz spectral signatures and yield rigorous benchmarks for high-level ab initio methodologies. It is suggested that even a less stable linear conformation of the ternary CS2(H2O)2 system, where one H2O molecule is linked to each S atom of the CS2 subunit, may be formed due to the kinetics associated with the mobility of free H2O molecules in the soft para-H2 medium. In addition, the spectroscopic observations confirm a linear and planar global intermolecular potential energy minimum for the binary CS2H2O system with C2v symmetry, where the O atom on the H2O molecule is linked to one of the S atoms on the CS2 subunit. A semi-experimental value for the vibrational zero-point energy contribution of 1.93 ± 0.10 kJ mol-1 from the class of large-amplitude intermolecular vibrational modes is proposed. The combination with CCSD(T)/CBS electronic energy predictions provides a semi-experimental estimate of 5.08 ± 0.15 kJ mol-1 for the binding energy D0 of the CS2H2O van der Waals system.


Assessing the relevance of higher education courses.
The establishment of the European Higher Education Area has involved specifying lists of professional competencies that programs are expected to develop, and with this the need for procedures to measure how every course within a higher education program is aligned with the program's competencies. We propose an instrument for characterizing this alignment, a process that we call assessing the relevance of a course. Using information from the course syllabus (objectives, contents and assessment scheme), our instrument produces indicators for characterizing the syllabus in terms of a competence list and for assessing its coherence. Because assessment involves quality, the results obtained can also be used to revise and improve the course syllabus. We illustrate this process with an example of a methods course from a mathematics teacher education program at a Spanish university.


The Early Detection Research Network's Specimen reference sets: paving the way for rapid evaluation of potential biomarkers.
The mission of the National Cancer Institute's Early Detection Research Network (EDRN) is to identify and validate cancer biomarkers for clinical use. Since its inception, EDRN investigators have learned a great deal about the process of validating biomarkers for clinical use. Translational research requires a broad spectrum of research expertise, and coordinating collaborative activities can be challenging. The EDRN has developed a robust triage and validation system that serves the roles of both "facilitator" and "brake." The system consists of (a) establishing a reference set of specimens collected under PRoBE (Prospective Specimen Collection Retrospective Blinded Evaluation) design criteria; (b) using the reference set to prevalidate candidate biomarkers before committing to full-scale validation; (c) performing full-scale validation for those markers that pass prevalidation testing; and (d) ensuring that the reference set is sufficiently large in numbers and volumes of sample that it can also be used to study future candidate biomarkers. This system provides rigorous and efficient evaluation of candidate biomarkers and biomarker panels. Reference sets should also be constructed to enable high-quality biomarker-discovery research. We describe the process of establishing our system in the hope that it will serve as an example of how to validate biomarkers for clinical application. We also hope that this description of the biospecimen reference sets available from the EDRN will encourage the biomarker research community--from academia or industry--to use this resource to advance biomarkers into clinical use.


Risk factors for tail injuries in dogs in Great Britain.
The aim of the current study was to quantify the risk of tail injury, to evaluate the extent to which tail docking reduces this risk, and to identify other major risk factors for tail injury in dogs in Great Britain. A nested case-control study was conducted during 2008 and 2009. Data were obtained from a stratified random sample of veterinary practices throughout Great Britain, and questionnaires were sent to owners of dogs with tail injuries and owners of a randomly selected sample of dogs without tail injuries. The risks of injury were reported adjusting for the sampling approach, and mixed effects logistic regression was used to develop a multivariable model for risk factors associated with tail injury. Two hundred and eighty-one tail injuries were recorded from a population of 138,212 dogs attending 52 participating practices. The weighted risk of tail injuries was 0.23 per cent (95 per cent confidence interval 0.20 to 0.25 per cent). Thirty-six per cent of injuries were reportedly related to injuries sustained in the home, 17.5 per cent were outdoor-related injuries, 14.4 per cent were due to the tail being caught in a door, for 16.5 per cent the cause was unknown and the remainder were due to other causes. Dogs with a wide angle of wag and dogs kept in kennels were at significantly higher risk of sustaining a tail injury. Dogs with docked tails were significantly less likely to sustain a tail injury; however, approximately 500 dogs would need to be docked in order to prevent one tail injury. English springer spaniels, cocker spaniels, greyhounds, lurchers and whippets were all at significantly higher risk when compared to labradors and other retrievers. Differences between countries (England, Scotland and Wales) and between rural and urban environments were not significant.


Can micronutrients improve neurocognitive functioning in adults with ADHD and severe mood dysregulation? A pilot study.
Little research has investigated how micronutrients (minerals and vitamins) affect cognitive functioning, despite preliminary studies showing they may improve psychiatric functioning. This pilot study investigated the impact of a 36-ingredient micronutrient formula consisting mainly of vitamins and minerals on neurocognitive functioning in 14 adults with attention-deficit/hyperactivity disorder (ADHD) and severe mood dysregulation. The formula was consumed in an open-label trial over an 8-week period. The participants completed tests of memory (Wide Range Assessment of Memory and Learning) and executive functioning (Delis-Kaplan Executive Functioning System and Conners Continuous Performance Test) at baseline and at the end of the trial. A gender- and age-matched control group of 14 non-ADHD adults not taking the formula were assessed on the same tests 8 weeks apart in order to investigate the impact of practice on the results. There were no group differences in ethnicity, socio-economic status and estimated IQ. Significant improvement was observed in the ADHD group, but not the control group, across a range of verbal abilities including verbal learning, verbal cognitive flexibility and fluency, and verbal inhibition. These neurocognitive improvements were large and consistent with improved psychiatric functioning. No changes were noted above a practice effect in visual-spatial memory and there were no improvements noted in reaction time, working memory, or rapid naming for either groups. Although the pilot and open-label design of the study limits the generalizability of the results, it supports a growing body of literature recognizing the importance of nutrients for mental health and cognition. The results also provide evidence supporting the need for randomized clinical trials of micronutrients as well as other experimental studies in order to better assess whether improved neurocognitive functioning may contribute to improved psychiatric symptoms.


Selective Nuclear Export Inhibitor KPT-330 Enhances the Antitumor Activity of Gemcitabine in Human Pancreatic Cancer.
Pancreatic cancer is an aggressive and deadly malignancy responsible for the death of over 37,000 Americans each year. Gemcitabine-based therapy is the standard treatment for pancreatic cancer but has limited efficacy due to chemoresistance. In this study, we evaluated the in vitro and in vivo effects of gemcitabine combined with the selective nuclear export (CRM1) inhibitor KPT-330 on pancreatic cancer growth. Human pancreatic cancer MiaPaCa-2 and metastatic pancreatic cancer L3.6pl cell lines were treated with different concentrations of KPT-330 and gemcitabine alone or in combination, and anchorage-dependent/independent growth was recorded. In addition, L3.6pl cells with luciferase were injected orthotopically into the pancreas of athymic nude mice, which were treated with (i) vehicle (PBS 1 mL/kg i.p., 2/week and povidone/pluronic F68 1 mL/kg p.o., 3/week), (ii) KPT-330 (20 mg/kg p.o., 3/week), (iii) gemcitabine (100 mg/kg i.p., 2/week), or (iv) KPT-330 (10 mg/kg) + gemcitabine (50 mg/kg) for 4 weeks. KPT-330 and gemcitabine alone dose-dependently inhibited anchorage-dependent growth in vitro and tumor volume in vivo compared with vehicle treatment. However, the combination inhibited growth synergistically. In combination, KPT-330 and gemcitabine acted synergistically to enhance pancreatic cancer cell death greater than each single-agent therapy. Mechanistically, KPT-330 and gemcitabine promoted apoptosis, induced p27, depleted survivin, and inhibited accumulation of DNA repair proteins. Together, our data suggest that KPT-330 potentiates the antitumor activity of gemcitabine in human pancreatic cancer through inhibition of tumor growth, depletion of the antiapoptotic proteins, and induction of apoptosis.


Lactobacillus suntoryeus sp. nov., isolated from malt whisky distilleries.
Eight strains of Lactobacillus with identical partial 16S rRNA gene sequences and similar randomly amplified polymorphic DNA patterns were isolated from fermentation samples from Japanese and Scottish malt whisky distilleries. Phylogenetic analysis of almost complete 16S rRNA gene sequences from three representative strains (two from Japan, one from Scotland) placed them in the genus Lactobacillus as members of the Lactobacillus acidophilus group. Lactobacillus helveticus and Lactobacillus gallinarum were the most closely related species, with 16S rRNA gene similarities of 99.3 and 98.1 %, respectively. A similar phylogeny was derived from partial sequences of elongation factor Tu (tuf) genes in which the alleles from the three distillery isolates were identical and shared 99.0 % similarity with L. helveticus and L. gallinarum tuf genes. S-layer (slp) gene sequences suggested different relationships among the strains and the distillery isolates no longer formed a monophyletic group. The alleles from the Japanese and Scottish strains shared only 54 % similarity. Chromosomal DNA from the distillery strains gave DNA-DNA hybridization values between 79 and 100 % but showed less than 43 and 22 % reassociation with L. helveticus and L. gallinarum DNA, respectively. The name Lactobacillus suntoryeus sp. nov. is proposed for this novel taxon; the type strain is strain SAT (=LMG 22464T=NCIMB 14005T).


A systematic review of technology-based interventions for unintentional injury prevention education and behaviour change.
The aims of this literature review are to (1) summarise how computer and mobile technology-based health behaviour change applications have been evaluated in unintentional injury prevention, (2) describe how these successes can be applied to injury-prevention programmes in the future and (3) identify research gaps. Studies included in this systematic review were education and behaviour change intervention trials and programme evaluations in which the intervention was delivered by either a computer or mobile technology and addressed an unintentional injury prevention topic. Articles were limited to those published in English and after 1990. Among the 44 technology-based injury-prevention studies included in this review, 16 studies evaluated locally hosted software programmes, 4 studies offered kiosk-based programmes, 11 evaluated remotely hosted internet programmes, 2 studies used mobile technology or portable devices and 11 studies evaluated virtual-reality interventions. Locally hosted software programmes and remotely hosted internet programmes consistently increased knowledge and behaviours. Kiosk programmes showed evidence of modest knowledge and behaviour gains. Both programmes using mobile technology improved behaviours. Virtual-reality programmes consistently improved behaviours, but there were little gains in knowledge. No studies evaluated text-messaging programmes dedicated to injury prevention. There is much potential for computer-based programmes to be used for injury-prevention behaviour change. The reviewed studies provide evidence that computer-based communication is effective in conveying information and influencing how participants think about an injury topic and adopt safety behaviours.


Biodegradation of phenol in static cultures by Penicillium chrysogenum ERK1: catalytic abilities and residual phytotoxicity.
A phenol-degrading fungus was isolated from crop soils. Molecular characterization (using internal transcribed spacer, translation elongation factor and beta-tubulin gene sequences) and biochemical characterization allowed to identify the fungal strain as Penicillium chrysogenum Thom ERK1. Phenol degradation was tested at 25 degrees C under resting mycelium conditions at 6, 30, 60, 200, 350 and 400 mg/l of phenol as the only source of carbon and energy. The time required for complete phenol degradation increased at different initial phenol concentrations. Maximum specific degradation rate (0.89978 mg of phenol/day/mg of dry weight) was obtained at 200 mg/l. Biomass yield decreased at initial phenol concentrations above 60 mg/l. Catechol was identified as an intermediate metabolite by HPLC analysis and catechol dioxygenase activity was detected in plate assays, suggesting that phenol metabolism could occur via ortho fission of catechol. Wheat seeds were used as phytotoxicity indicators of phenol degradation products. It was found that these products were not phytotoxic for wheat but highly phytotoxic for phenol. The high specific degradation rates obtained under resting mycelium conditions are considered relevant for practical applications of this fungus in soil decontamination processes.


Annexin A2 interactions with Rab14 in alveolar type II cells.
Annexin A2, a calcium-dependent phospholipid-binding protein, is abundantly expressed in alveolar type II cells where it plays a role in lung surfactant secretion. Nevertheless, little is known about the details of its cellular pathways. To identify annexin A2-regulated or associated proteins, we silenced endogenous annexin A2 expression in rat alveolar type II cells by RNA interference and assessed the change of the cellular transcriptome by DNA microarray analysis. The loss of annexin A2 resulted in the change of 61 genes. Thirteen of the selected genes (11 down-regulated and 2 up-regulated genes) were validated by real time quantitative PCR. When the loss of rat annexin A2 was rescued by overexpressing EGFP-tagged human annexin A2, six of seven selected targets returned to their normal expression level, indicating that these genes are indeed annexin A2-associated targets. One of the targets, Rab14, co-immunoprecipitated with annexin A2. Rab14 also co-localized in part with annexin A2 and lamellar bodies in alveolar type II cells. The silencing of Rab14 resulted in a decrease in surfactant secretion, suggesting that Rab14 may play a role in surfactant secretion.


Personal and family medical history correlates of rheumatoid arthritis.
Patients with rheumatoid arthritis (RA) often have comorbidities related to immune dysfunction, however, the timing of comorbidities relative to RA diagnosis and treatment is not clear. We studied personal and family medical history correlates of incident and prevalent RA in women. We used a nested case-control design including women in the Agricultural Health Study (AHS). Physician-confirmed cases of RA (n = 135) were matched to five controls each (n = 675) by birth date. We used logistic regression to examine associations between conditions listed in personal and family medical histories and both incident and prevalent RA, as estimated by odds ratios (ORs) and 95% confidence intervals (CIs). The risk of incident RA was associated with personal medical history of nonmelanoma skin cancer (OR = 4.4, 95% CI: 1.4-14.1), asthma or reactive lung disease (OR = 3.7, 95% CI: 1.3-10.5), and cataract (OR = 3.3, 95% CI: 1.0-10.8). Personal history of herpes zoster was associated with prevalent RA (OR = 2.4, 95% CI: 1.2-4.8), but not with incident RA. There were no consistent associations between family medical history and RA. Patients with medical conditions indicating compromised immunity are at increased risk of developing RA. These results may indicate common pathogenesis of an environmental or genetic nature between such diseases.


Ageing without remembering: Fantasy, memory and loss in Kazuo Ishiguro's The Buried Giant.
In his most recent novel, The Buried Giant (2015), Ishiguro presents an elderly couple, Axl and Beatrice, who live in a Britain afflicted by a mist that makes everyone forget not only their common historical past but also their own life experiences and memories. By focusing on the journey of the two elderly and increasingly frail protagonists within a fantastic, neomedieval world, the novel challenges the chronometric and future-oriented model of time in which youth is an asset and old age inevitably a burden. Related to this, the novel interrogates the model of generational succession as straightforward renewal and progress, instead positing a cyclical movement through which the mistakes of past generations are repeated once and again. In this novel, endurance in the face of vulnerability, as experienced by the elderly characters of the novel, seems to be the only plausible answer to an inevitable repetition of mistakes and the cyclical nature of trauma.


Adducts from in vivo action of the carcinogen 4-hydroxyaminoquinoline 1-oxide in rats and from in vitro reaction of 4-acetoxyaminoquinoline 1-oxide with DNA and polynucleotides.
In vivo 4-hydroxyamino[2-3H]quinoline 1-oxide-modified DNA and in vitro 4-acetoxyamino[2-3H]quinoline 1-oxide-modified DNA were enzymatically hydrolyzed, and the hydrolysates were analyzed by high-performance liquid chromatography. The two patterns were compared, and we showed that all of the high-performance liquid chromatography peaks which were recovered from in vivo-modified DNA were present in the hydrolysate of in vitro-modified DNA. Therefore, we used the in vitro 4-acetoxyamino[2-3H]quinoline 1-oxide-modified DNA to investigate the quinoline-purine adducts which are characteristics of the mode of action of the carcinogen 4-nitroquinoline 1-oxide. By comparison with the enzymatic hydrolysates of 4-acetoxyamino[2-3H]quinoline 1-oxide-modified covalent poly(deoxyadenylate-deoxythymidylate) X poly(deoxyadenylate-deoxythymidylate) and covalent poly(deoxyguanylate-deoxycytidylate) X poly(deoxyguanylate-deoxycytidylate) three nitroquinoline adducts were enumerated on the modified DNA. One of them was previously characterized as a C8-guanyl adduct. We proved that the two other are a guanine and an adenine adduct, respectively. A quinoline derivative was identified in the hydrolysates of the in vivo- and in vitro-modified DNAs as 4-aminoquinoline 1-oxide, the origin of which was postulated to be a degradation compound of one (or more) adduct(s). Moreover, the presence of two degradation compounds of the C8-guanyl adduct was shown in mild alkaline conditions. We suspected an imidazole ring-opened form.


Prevention and practice during the COVID-19 emergency declaration period in Japanese obstetrical/gynecological facilities.
A nationwide questionnaire survey was performed to evaluate how Japanese Society of Obstetrics and Gynecology (JSOG) members dealt with the coronavirus disease (COVID-19) pandemic during the declared nationwide emergency. We sent questionnaires to members of JSOG via official email. Participants answered anonymously using Google forms. Two (0.08%) JSOG members had contracted COVID-19. There was a clear decrease in the number of patients scheduled for operation, not only for malignant but also for benign diseases. A decrease in the number of outpatients for infertility treatment was also observed. Polymerase chain reaction testing for severe acute respiratory syndrome coronavirus 2 was available in 20.4% of the facilities. Inpatients and outpatients were requested to wear masks, limit the number of contacts and check body temperature when visiting hospitals/clinics. During parturition care, caregivers and physicians wore gloves, masks (other than N-95), face shields and gowns. About 66% and 80% of the facilities decided to transfer pregnant women if they had asymptomatic and symptomatic infection, respectively. Cesarean section was typically chosen as delivery mode in infected women. The COVID-19 pandemic provoked significant changes in obstetrics and gynecology practices in Japan. Apparently, nosocomial infections were largely prevented due to these changes, although some of them might not have been necessary.


Comparing the importance of different aspects of quality of life to older adults across diverse cultures.
there is limited research examining the relative importance of aspects of quality of life (QOL) to older adults across cultures. to examine the relative importance of 31 internationally agreed areas of QOL to older adults in 22 countries in relation to health status, age and level of economic development. a survey quota sampling design was used to collect cross-cultural data. This study reports a secondary analysis of WHOQOL-OLD pilot study, which was collected simultaneously in 22 centres. a variety of community, primary, secondary and tertiary health care settings located in Australia, France, Switzerland, England, Scotland, USA, Israel, Spain, Japan, China (mainland and Hong Kong), Turkey, Lithuania, Czech Republic, Hungary, Canada, Norway, Sweden, Denmark, Germany, Brazil and Uruguay. the total sample contained 7,401 people over 60 years with a mean age of 73.1 years; 57.8% were women and 70.1% considered themselves 'healthy'. there were significant differences in the importance given to various aspects of QOL for people living in medium and high-development countries. Culture explained 15.9% of the variance in the importance ratings of QOL. However, the interaction showed that cultural differences were reduced once health status, gender and age were taken into account. The importance of QOL to age bands in different cultures was not significantly affected by whether or not participants perceived themselves to be healthy. understanding the self-reported importance of diverse aspects of QOL for different cultures and for healthy and less healthy people may assist national and international policy makers to decide on priorities for the development of programmes for the ageing population.


Distribution of neuroendocrine cells in the small and large intestines of the one-humped camel (Camelus dromedarius).
The distribution and relative frequency of neuroendocrine cells in the small and large intestines of one-humped camel were studied using antisera against 5-hydroxytryptamine (5-HT), cholecystokinin (CCK-8), somatostatin (SOM), peptide tyrosine tyrosine (PYY), gastric inhibitory polypeptide (GIP), neuronal nitric oxide synthase (nNOS), gastrin releasing peptide (GRP), substance P (SP), and neurokinin A (NKA). Among these cell types, CCK-8 immunoreactive (IR) cells were uniformly distributed in the mucosa, while others showed varied distribution in the villi or crypts of the small intestine. Immunoreactive cells like 5HT, CCK-8, and SOM showed peak density in the villi and crypts of the small intestine and in the colonic glands of the large intestine, while cells containing SP were discerned predominately in the crypts. 5-HT, CCK-8 and SOM cells were mainly flask-shaped and of the open-variety, while PYY and SP immunoreactive cells were mainly rounded or basket-shaped and of the closed variety. Basically the distribution pattern of the endocrine cells in the duodenum, jejunum and colon of the one-humped camel is similar to that of other mammals. Finally, the distribution of these bioactive agents may give clues as to how these agents aid in the function of the intestinal tract of this desert animal.


Prostanoids contribute to endothelium-dependent coronary vasodilation in guinea pigs.
This study characterizes the contribution of prostanoids to endothelium-dependent responses in two vascular regions of the guinea pig. We compared the mechanisms of relaxation responses to acetylcholine and adenosine triphosphate (ATP) in the coronary vasculature and in the abdominal aorta of the guinea pig. Endothelium-dependent responses were examined in an isolated, potassium-arrested guinea pig heart utilizing a modified Langendorff preparation. Coronary vessels were constricted with prostaglandin F2 alpha and dilated with acetylcholine (10(-9)-10(-6) mol) or ATP (10(-10)-10(-7) mol) before and after exposure to indomethacin (14 microM, n = 6) or ibuprofen (150 microM, n = 5). Helically cut strips of abdominal aorta (n = 6) were suspended in isolated tissue baths for measurement of isometric force. Relaxation to acetylcholine (5.5 x 10(-7) M) and ATP (10(-5) M) was quantified in strips contracted with norepinephrine before and after exposure to indomethacin (14 microM). In addition, the endothelium was damaged by exposing vessels to free radicals generated by electrolysis of the buffer (4 Hz, 9 V, 1 ms, 5 min). Following electrolysis of the buffer, relaxation responses to acetylcholine and ATP were significantly attenuated in both preparations. In the perfused heart, endothelium-dependent dilatation to acetylcholine, but not ATP were significantly inhibited in the presence of indomethacin or ibuprofen. In contrast, acetylcholine- and ATP-induced relaxation responses in the aorta were not altered by indomethacin. We conclude that prostaglandins contribute to acetylcholine-induced dilatation in the coronary bed but not in the abdominal aorta of the guinea pig. Furthermore, in the coronary bed, different endothelial factors mediate relaxation to acetylcholine and ATP.


Developmental regulation of spontaneous activity in the Mammalian cochlea.
Neurons in the developing auditory system fire bursts of action potentials before the onset of hearing. This spontaneous activity promotes the survival and maturation of auditory neurons and the refinement of synaptic connections in auditory nuclei; however, the mechanisms responsible for initiating this activity remain uncertain. Previous studies indicate that inner supporting cells (ISCs) in the developing cochlea periodically release ATP, which depolarizes inner hair cells (IHCs), leading to bursts of action potentials in postsynaptic spiral ganglion neurons (SGNs). To determine when purinergic signaling appears in the developing cochlea and whether it is responsible for initiating auditory neuron activity throughout the prehearing period, we examined spontaneous activity from ISCs, IHCs, and SGNs in cochleae acutely isolated from rats during the first three postnatal weeks. We found that ATP was released from ISCs within the cochlea from birth until the onset of hearing, which led to periodic inward currents, Ca(2+) transients, and morphological changes in these supporting cells. This spontaneous release of ATP also depolarized IHCs and triggered bursts of action potentials in SGNs for most of the postnatal prehearing period, beginning a few days after birth as IHCs became responsive to ATP, until the onset of hearing when ATP was no longer released from ISCs. When IHCs were not subject to purinergic excitation, SGNs exhibited little or no activity. These results suggest that supporting cells in the cochlea provide the primary excitatory stimulus responsible for initiating bursts of action potentials in auditory nerve fibers before the onset of hearing.


The evolution of the class A scavenger receptors.
The class A scavenger receptors are a subclass of a diverse family of proteins defined based on their ability to bind modified lipoproteins. The 5 members of this family are strikingly variable in their protein structure and function, raising the question as to whether it is appropriate to group them as a family based on their ligand binding abilities. To investigate these relationships, we defined the domain architecture of each of the 5 members followed by collecting and annotating class A scavenger receptor mRNA and amino acid sequences from publicly available databases. Phylogenetic analyses, sequence alignments, and permutation tests revealed a common evolutionary ancestry of these proteins, indicating that they form a protein family. We postulate that 4 distinct gene duplication events and subsequent domain fusions, internal repeats, and deletions are responsible for the diverse protein structures and functions of this family. Despite variation in domain structure, there are highly conserved regions across all 5 members, indicating the possibility that these regions may represent key conserved functional motifs. We have shown with significant evidence that the 5 members of the class A scavenger receptors form a protein family. We have indicated that these receptors have a common origin which may provide insight into future functional work with these proteins.


Opioid detoxification and naltrexone induction strategies: recommendations for clinical practice.
Opioid dependence is a significant public health problem associated with high risk for relapse if treatment is not ongoing. While maintenance on opioid agonists (i.e., methadone, buprenorphine) often produces favorable outcomes, detoxification followed by treatment with the μ-opioid receptor antagonist naltrexone may offer a potentially useful alternative to agonist maintenance for some patients. Treatment approaches for making this transition are described here based on a literature review and solicitation of opinions from several expert clinicians and scientists regarding patient selection, level of care, and detoxification strategies. Among the current detoxification regimens, the available clinical and scientific data suggest that the best approach may be using an initial 2-4 mg dose of buprenorphine combined with clonidine, other ancillary medications, and progressively increasing doses of oral naltrexone over 3-5 days up to the target dose of naltrexone. However, more research is needed to empirically validate the best approach for making this transition.


Global Genetic Networks and the Genotype-to-Phenotype Relationship.
Genetic interactions identify combinations of genetic variants that impinge on phenotype. With whole-genome sequence information available for thousands of individuals within a species, a major outstanding issue concerns the interpretation of allelic combinations of genes underlying inherited traits. In this Review, we discuss how large-scale analyses in model systems have illuminated the general principles and phenotypic impact of genetic interactions. We focus on studies in budding yeast, including the mapping of a global genetic network. We emphasize how information gained from work in yeast translates to other systems, and how a global genetic network not only annotates gene function but also provides new insights into the genotype-to-phenotype relationship.


Hospitals' use of hospitalists: Implications for financial performance.
Hospitalists, or physicians specializing in hospital-based practice, have grown significantly since they were first introduced in the United States in the mid-1990s. Prior studies on the impact of hospitalists have focused on costs and length of stay. However, there is dearth of research exploring the relationship between hospitals' use of hospitalists and organizational performance. Using a national longitudinal sample of acute care hospitals operating in the United States between 2007 and 2014, this study explores the impact of hospitalists staffing intensity on hospitals' financial performance. Data sources for this study included the American Hospital Association Annual Survey, the Area Health Resources File, and the Centers for Medicare & Medicaid Services' costs reports and Case Mix Index files. Data were analyzed using a panel design with facility and year fixed effects regression. Results showed that hospitals that switched from not using hospitalists to using a high hospitalist staffing intensity had both increased patient revenues and higher operating costs per adjusted patient day. However, the higher operating costs from high hospitalist staffing intensity were offset by increased patient revenues, resulting in a marginally significant increase in operating profitability (p < .1). These findings suggest that the rise in the use of hospitalists may be fueled by financial incentives such as increased revenues and profitability in addition to other drivers of adoption.


Meta-analysis using effect size distributions of only statistically significant studies.
Publication bias threatens the validity of meta-analytic results and leads to overestimation of the effect size in traditional meta-analysis. This particularly applies to meta-analyses that feature small studies, which are ubiquitous in psychology. Here we develop a new method for meta-analysis that deals with publication bias. This method, p-uniform, enables (a) testing of publication bias, (b) effect size estimation, and (c) testing of the null-hypothesis of no effect. No current method for meta-analysis possesses all 3 qualities. Application of p-uniform is straightforward because no additional data on missing studies are needed and no sophisticated assumptions or choices need to be made before applying it. Simulations show that p-uniform generally outperforms the trim-and-fill method and the test of excess significance (TES; Ioannidis & Trikalinos, 2007b) if publication bias exists and population effect size is homogenous or heterogeneity is slight. For illustration, p-uniform and other publication bias analyses are applied to the meta-analysis of McCall and Carriger (1993) examining the association between infants' habituation to a stimulus and their later cognitive ability (IQ). We conclude that p-uniform is a valuable technique for examining publication bias and estimating population effects in fixed-effect meta-analyses, and as sensitivity analysis to draw inferences about publication bias.


Unified theory of inertial granular flows and non-Brownian suspensions.
Rheological properties of dense flows of hard particles are singular as one approaches the jamming threshold where flow ceases both for aerial granular flows dominated by inertia and for over-damped suspensions. Concomitantly, the length scale characterizing velocity correlations appears to diverge at jamming. Here we introduce a theoretical framework that proposes a tentative, but potentially complete, scaling description of stationary flows. Our analysis, which focuses on frictionless particles, applies both to suspensions and inertial flows of hard particles. We compare our predictions with the empirical literature, as well as with novel numerical data. Overall, we find a very good agreement between theory and observations, except for frictional inertial flows whose scaling properties clearly differ from frictionless systems. For overdamped flows, more observations are needed to decide if friction is a relevant perturbation. Our analysis makes several new predictions on microscopic dynamical quantities that should be accessible experimentally.


Relationship between diagnostic imaging features and prognostic outcomes in gastrointestinal stromal tumors (GIST).
Gastrointestinal stromal tumors (GISTs), the most frequent mesenchymal neoplasms of the gastrointestinal tract, are a relatively recently described entity. GISTs can occur across any age but are more common in patients older than 50 years. GISTs most commonly are in the stomach (60-70%), followed by the small intestine (20%-30%); they also rarely occur in the abdominal cavity, such as in the mesentery, the omentum and the retroperitoneum. Contrast-enhanced multi-detector computed tomography (MDCT) is the most largely used imaging modality for the localization, characterization and staging of GISTs. All patterns of enhancement on contrast-enhanced MDCT can be seen with GISTs, including hypoenhancing, isoenhancing, and hyperenhancing neoplasms. A lot of prognostication systems have been proposed for the risk stratification of GISTs. This review outlines the relationship between different diagnostic imaging features and prognostic outcomes in GISTs.


Splice variants of SmgGDS control small GTPase prenylation and membrane localization.
Ras and Rho small GTPases possessing a C-terminal polybasic region (PBR) are vital signaling proteins whose misregulation can lead to cancer. Signaling by these proteins depends on their ability to bind guanine nucleotides and their prenylation with a geranylgeranyl or farnesyl isoprenoid moiety and subsequent trafficking to cellular membranes. There is little previous evidence that cellular signals can restrain nonprenylated GTPases from entering the prenylation pathway, leading to the general belief that PBR-possessing GTPases are prenylated as soon as they are synthesized. Here, we present evidence that challenges this belief. We demonstrate that insertion of the dominant negative mutation to inhibit GDP/GTP exchange diminishes prenylation of Rap1A and RhoA, enhances prenylation of Rac1, and does not detectably alter prenylation of K-Ras. Our results indicate that the entrance and passage of these small GTPases through the prenylation pathway is regulated by two splice variants of SmgGDS, a protein that has been reported to promote GDP/GTP exchange by PBR-possessing GTPases and to be up-regulated in several forms of cancer. We show that the previously characterized 558-residue SmgGDS splice variant (SmgGDS-558) selectively associates with prenylated small GTPases and facilitates trafficking of Rap1A to the plasma membrane, whereas the less well characterized 607-residue SmgGDS splice variant (SmgGDS-607) associates with nonprenylated GTPases and regulates the entry of Rap1A, RhoA, and Rac1 into the prenylation pathway. These results indicate that guanine nucleotide exchange and interactions with SmgGDS splice variants can regulate the entrance and passage of PBR-possessing small GTPases through the prenylation pathway.


Implications of diabetes in patients with acute coronary syndromes. The Global Registry of Acute Coronary Events.
There are limited data describing the presenting characteristics, management, and outcomes of diabetic and nondiabetic patients with an acute coronary syndrome (ACS). To examine differences in these factors, patients with ST-segment elevation acute myocardial infarction, non-ST-segment elevation acute myocardial infarction, and unstable angina were enrolled in a large multinational coronary disease registry. The Global Registry of Acute Coronary Events is a prospective observational study of patients hospitalized with an ACS at 94 hospitals in 14 countries. The study sample consisted of 5403 patients with ST-segment elevation acute myocardial infarction, 4725 with non-ST-segment elevation acute myocardial infarction, and 5988 with unstable angina. Approximately 1 in 4 patients presented to participating hospitals with a history of diabetes. Patients with diabetes were older, more often women, with a greater prevalence of comorbidities, and they were less likely to be treated with effective cardiac therapies than nondiabetic patients. Patients with diabetes who developed an ACS were at increased risk for each hospital outcome examined including heart failure, renal failure, cardiogenic shock, and death. These differences remained after adjustment for potentially confounding prognostic factors. A considerable proportion of patients with an ACS has diabetes and is at increased risk for adverse outcomes compared with patients without diabetes. There are certain proven therapeutic strategies that remain underused in the diabetic population. A more widespread awareness of this increased risk and a more diligent use of proven cardiac treatment approaches are indicated for patients with diabetes who develop an ACS.


The Effect of Rib Shape on Stiffness.
This study investigates the isolated effect of rib shape on the mechanical characteristics of ribs subjected to multiple forms of loading. It aims to measure the variation in stiffness due to shape that is seen throughout the population and, in particular, provide a tool for researchers to better understand the influence of shape on resulting stiffness. A previously published six-parameter shape model of the central axis of human ribs was used. It has been shown to accurately model the overall rib path using intrinsic geometric properties such as size, aspect ratio, and skewness, through shapes based on logarithmic spirals with high curvature continuity. In this study the model was fitted to 19,500 ribs from 989 adult female and male CT scans having demographic distributions matching the US adult population. Mechanical loading was simulated through a simplified finite element model aimed at isolating rib shape from other factors influencing mechanical response. Four loading scenarios were used representing idealized free and constrained loading conditions in axial (body-anterior) and lateral directions. Characteristic rib stiffness and maximum stress location were tracked as simulation output measures. Regression models of rib stiffness found that all shape model parameters added information when predicting stiffness under each loading condition, with their linear combination able to account for 95% of the population stiffness variation due to shape in midlevel ribs for free axial loading, and 92%-98% in other conditions. Full regression models including interactive terms explained up to 99% of population variability. Results allow researchers to better evaluate the differences in stiffness results that are obtained from physical testing by providing a framework with which to explain variation due to rib shape.


Stoichiometry and specificity of in vitro phosphopantetheinylation and aminoacylation of the valine-activating module of surfactin synthetase.
Surfactin synthetase is the enzyme responsible for biosynthesis of the lipoheptapeptide antibiotic surfactin by Bacillus subtilis. Fragments of SrfB1, the L-valine-activating module of the second subunit of surfactin synthetase, were overproduced in Escherichia coli. In addition to a 143-kDa SrfB1 fragment that contains four domains putatively involved in activation (adenylation domain), autoaminoacylation (peptidyl carrier protein (PCP) domain), and peptide bond formation (two condensation domains), subfragments comprising two domains (104-kDa condensation-adenylation and 73-kDa adenylation-PCP), and one domain (18-kDa PCP) were also overproduced in and purified from E. coli as N-terminal hexahistidine fusion proteins. Incubation of these domains with pure Sfp, a phosphopantetheinyl transferase (PPTase) from B. subtilis, and CoA allowed quantitation of posttranslational phosphopantetheinylation of Ser999 by mass spectrometry for the 18-kDa PCP fragment and by radioassay using cosubstrate [3H] pantetheinyl-coenzyme A for all PCP-containing constructs. The phosphopantetheine stoichiometry correlated with the subsequent mole fractions of [14C] valyl groups that could be covalently transferred to these holo-PCP domains. In turn, the catalytic efficiency of intramolecular aminoacylation of the 143-kDa fragment could be compared with the reaction "in trans" between adenylation and PCP fragments of SrfB1. The corresponding holo-PCP domain of the next module, SrfB2, was not detectably aminoacylated by SrfB1, indicative of protein-protein recognition between adenylation and cognate PCP domains. These results should permit future exploration of the timing and specificity of peptide bond formation by this class of biosynthetic enzymes.


Metal deposition at the bone-cartilage interface in articular cartilage.
There is a growing interest being shown in the changes occurring in elemental distribution at the bone-cartilage interface, the changes either being a result of mechanical damage or disease. In particular, such investigations have tended to concern the elemental alterations associated with the osteoarthritic wear and tear damage occurring to the cartilage and subchondral bone of synovial joints or that associated with disease processes such as rheumatic arthritis. Present studies examine sections of femoral head obtained from total hip replacement surgery, use being made of micro-proton-induced X-ray emission (micro-PIXE) and the Rutherford back scattering (RBS) techniques. Enhancements of Zn, Ca and P have been observed at the bone-cartilage interface. Further, the concentration of Zn in spongy bone underlying the subchondral surface of a section of the femoral head has been measured, obtaining 136 microg g(-1) bone, the presence of Ca and P at the same position being 0.235 and 0.0451 g g(-1) bone, respectively. These values are slightly different to figures recently published by other authors using similar techniques.


Noninvasive Anatomical and Functional Imaging of Orthotopic Glioblastoma Development and Therapy using Multispectral Optoacoustic Tomography.
Here we demonstrate the potential of multispectral optoacoustic tomography (MSOT), a new non-invasive structural and functional imaging modality, to track the growth and changes in blood oxygen saturation (sO2) in orthotopic glioblastoma (GBMs) and the surrounding brain tissues upon administration of a vascular disruptive agent (VDA). Nude mice injected with U87MG tumor cells were longitudinally monitored for the development of orthotopic GBMs up to 15 days and observed for changes in sO2 upon administration of combretastatin A4 phosphate (CA4P, 30 mg/kg), an FDA approved VDA for treating solid tumors. We employed a newly-developed non-negative constrained approach for combined MSOT image reconstruction and unmixing in order to quantitatively map sO2 in whole mouse brains. Upon longitudinal monitoring, tumors could be detected in mouse brains using single-wavelength data as early as 6 days post tumor cell inoculation. Fifteen days post-inoculation, tumors had higher sO2 of 63 ± 11% (n = 5, P < .05) against 48 ± 7% in the corresponding contralateral brain, indicating their hyperoxic status. In a different set of animals, 42 days post-inoculation, tumors had lower sO2 of 42 ± 5% against 49 ± 4% (n = 3, P < .05) in the contralateral side, indicating their hypoxic status. Upon CA4P administration, sO2 in 15 days post-inoculation tumors dropped from 61 ± 9% to 36 ± 1% (n = 4, P < .01) within one hour, then reverted to pre CA4P treatment values (63 ± 6%) and remained constant until the last observation time point of 6 hours. With the help of advanced post processing algorithms, MSOT was capable of monitoring the tumor growth and assessing hemodynamic changes upon administration of VDAs in orthotopic GBMs.


Mortality related to spotted ratfish (Hydrolagus colliei) in Pacific harbor seals (Phoca vitulina) in Washington State.
Tissue perforation and penetration by dorsal fin spines of spotted ratfish (Hydrolagus colliei) were responsible for the death of seven harbor seals (Phoca vitulina) in Washington State (USA) between 2006 and 2011. In six animals, necropsy revealed spines or spine parts that had perforated the esophagus or stomach and migrated into vital tissues, resulting in hemothorax, pneumothorax, pleuritis, and peritonitis. In a seventh case, a ratfish spine was recovered from the mouth of a harbor seal euthanized due to clinical symptoms of encephalitis. Gross examination revealed an abscess within the left cerebrum, which was attributed to direct extension of inflammatory infiltrate associated with the ratfish spine. Between 2009 and 2011, spotted ratfish spines were also recovered from the head or neck region of three Steller sea lions (Eumetopias jubatus) and one California sea lion (Zalophus californianus). Ratfish-related trauma appears to be a novel mortality factor for harbor seals in Washington State and could be related to increased ratfish abundance and a shifting prey base for harbor seals.


Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies.
Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled. Patients (n=540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour and prognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy. In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95%confidence interval (CI) 0.41-0.99; P=0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44-0.89; P=0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P=0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P=0.01). Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemotherapy improves the results.


Measuring patient-centered communication in cancer care: a literature review and the development of a systematic approach.
Patient-centered communication (PCC) is a critical element of patient-centered care, which the Institute of Medicine (Committee on Quality of Health Care in America, 2001) promulgates as essential to improving healthcare delivery. Consequently, the US National Cancer Institute's Strategic Plan for Leading the Nation (2006) calls for assessing the delivery of PCC in cancer care. However, no comprehensive measure of PCC exists, and stakeholders continue to embrace different conceptualizations and assumptions about how to measure it. Our approach was grounded in the PCC conceptual framework presented in a recent US National Cancer Institute monograph (Epstein & Street, 2007). In this study, we developed a comprehensive inventory of domains and subdomains for PCC by reviewing relevant literature and theories, interviewing a limited number of cancer patients, and consulting experts. The resulting measurement domains are organized under the six core functions specified in the PCC conceptual framework: exchanging information, fostering healing relationships, recognizing and responding to emotions, managing uncertainty, making decisions, and enabling patient self-management. These domains represent a promising platform for operationalizing the complicated PCC construct. Although this study focused specifically on cancer care, the PCC measurements are relevant to other clinical contexts and illnesses, given that patient-centered care is a goal across all healthcare. Finally, we discuss considerations for developing PCC measures for research, quality assessment, and surveillance purposes. United States Department of Health and Human Services, National Institutes of Health, National Cancer Institute (2006). The NCI Strategic Plan for Leading the Nation: To Eliminate the Suffering and Death Due to Cancer. NIH Publication No. 06-5773.


Beneficial Effects of a Protein Rich Diet on Coping Neurotrans-mitter Levels During Ampicillin-Induced Neurotoxicity Compared to Propionic-Acid Induced Autistic Biochemical Features.
This study examined the effects of a protein rich diet on coping neurotransmitter levels in orally administered ampicillin-induced neurotoxic rats compared with propionic acid (PA) models of autism. 40 young male western albino rats were divided into four groups. The first group served as control and received phosphate buffered saline orally; the second group serving as autistic model was treated with oral dose of PA (250 mg/kg body weight/day for 3 days); the third group was treated with the neurotoxic dose of ampicillin (50 mg/kg for three weeks); the fourth group received the same dose of ampicillin and was fed with special protein rich diets. Noradrenaline, dopamine, serotonin glutamate, glutamine and interleukin 6 (IL-6) were measured in the brain homogenate of all tested groups. Specified doses of PA and ampicillin significantly (P<0.001) decreased noradrenaline, dopamine, and serotonin levels when compared to control. Also glutamate, IL-6 levels were significantly (P<0.001) increased in PA treated group while non-significant increase was found in ampicillin treated group. Non-significant increase of glutamine was found in PA treated group with a significant increase in ampicillin treated group. The effects of ampicillin on these parameters were found to be potentiated when the rats were fed on a protein rich diet. Our results end with the conclusion that dietary protein level may be a useful tool to find out a path to restrict neurotransmitter alterations in neurodevelopmental disorders like autism.


GH16 and GH81 family β-(1,3)-glucanases in Aspergillus fumigatus are essential for conidial cell wall morphogenesis.
The fungal cell wall is a rigid structure because of fibrillar and branched β-(1,3)-glucan linked to chitin. Softening of the cell wall is an essential phenomenon during fungal morphogenesis, wherein rigid cell wall structures are cleaved by glycosylhydrolases. During the search for glycosylhydrolases acting on β-(1,3)-glucan, we identified seven genes in the Aspergillus fumigatus genome coding for potential endo-β-(1,3)-glucanase. ENG1 (previously characterized and named ENGL1, Mouyna et al., ), belongs to the Glycoside-Hydrolase 81 (GH81) family, while ENG2 to ENG7, to GH16 family. ENG1 and four GH16 genes (ENG2-5) were expressed in the resting conidia as well as during germination, suggesting an essential role during A. fumigatus morphogenesis. Here, we report the effect of sequential deletion of AfENG2-5 (GH16) followed by AfENG1 (GH81) deletion in the Δeng2,3,4,5 mutant. The Δeng1,2,3,4,5 mutant showed conidial defects, with linear chains of conidia unable to separate while the germination rate was not affected. These results show, for the first time in a filamentous fungus, that endo β-(1,3)-glucanases are essential for proper conidial cell wall assembly and thus segregation of conidia during conidiation.


Are mastectomy rates really increasing in the United States?
After the National Institutes of Health Consensus Statement in 1990, breast-conserving surgery (BCS) became more common while mastectomy rates decreased. However, several recently published single-institution studies have reported an increase in mastectomy rates in the past decade. We conducted a population-based study to evaluate national trends in the surgical treatment of breast cancer from 2000 through 2006. Using the Surveillance, Epidemiology, and End Results database, we conducted a retrospective cohort analysis of women undergoing surgical treatment for breast cancer. We evaluated variation in mastectomy rates by demographic and tumor factors and calculated differences in mastectomy rates across time. We utilized logistic regression to identify time trends and patient and tumor factors associated with mastectomy, testing for significance using two-sided methods. We identified 233,754 patients diagnosed with ductal carcinoma in situ or stage I to III unilateral breast cancer from 2000 to 2006. The proportion of women treated with mastectomy decreased from 40.8% in 2000 to 37.0% in 2006 (P < .001). These patterns were maintained across patient and tumor factors. Although the unilateral mastectomy rate decreased during the study period, the contralateral prophylactic mastectomy rate increased. Women were less likely to receive mastectomy over time (odds ratio, 1.18 for 2000 v 2006; 95% CI, 1.14 to 1.23; P < .0001), after adjusting for patient and tumor factors. In contrast to single-institution studies, our population-based analysis found a decrease in unilateral mastectomy rates from 2000 to 2006 in the United States. Variations in referral patterns and patient selection are potential explanations for these differences between single institutions and national trends.


Management of pharmaceutical substances in the environment: Lithuanian case study.
Investigation on the sources, discharges and related risks for the environment of the pharmaceutical substance (PhS) diclofenac (DCF) was performed in Lithuania, a country of the Baltic Sea region, for the first time. The investigation only refers to DCF as a PhS for human use; emissions from animal husbandry were not considered. In the first stage of the research, the main sources and pathways of DCF via substance flow analysis were identified within the country. During the second stage, DCF flows along the wastewater treatment plants (WWTPs) in two different cities were measured in order to assess the current levels of pharmaceutical residues in the environment. Furthermore, environmental risk assessment was carried out by taking into account the parameters of consumption data and elimination rate in WWTPs. Then, the assessment of different technical and managerial removal approaches was accomplished in an environmental management model of wastewater containing PhS, based on the framework of environmental systems theory.


Development of 2-(4-pyridyl)-benzimidazoles as PKN2 chemical tools to probe cancer.
Kinases are signalling proteins which have proven to be successful targets for the treatment of a variety of diseases, predominantly in cancers. However, only a small proportion of kinases (<20%) have been investigated for their therapeutic viability, likely due to the lack of available chemical tools across the kinome. In this work we describe initial efforts in the development of a selective chemical tool for protein kinase N2 (PKN2), a relatively unexplored kinase of interest in several types of cancer. The most successful compound, 5, has a measured IC50 of 0.064 μM against PKN2, with ca. 17-fold selectivity over close homologue, PKN1.


Impact of the COVID-19 pandemic on the detection and management of colorectal cancer in England: a population-based study.
There are concerns that the COVID-19 pandemic has had a negative effect on cancer care but there is little direct evidence to quantify any effect. This study aims to investigate the impact of the COVID-19 pandemic on the detection and management of colorectal cancer in England. Data were extracted from four population-based datasets spanning NHS England (the National Cancer Cancer Waiting Time Monitoring, Monthly Diagnostic, Secondary Uses Service Admitted Patient Care and the National Radiotherapy datasets) for all referrals, colonoscopies, surgical procedures, and courses of rectal radiotherapy from Jan 1, 2019, to Oct 31, 2020, related to colorectal cancer in England. Differences in patterns of care were investigated between 2019 and 2020. Percentage reductions in monthly numbers and proportions were calculated. As compared to the monthly average in 2019, in April, 2020, there was a 63% (95% CI 53-71) reduction (from 36 274 to 13 440) in the monthly number of 2-week referrals for suspected cancer and a 92% (95% CI 89-95) reduction in the number of colonoscopies (from 46 441 to 3484). Numbers had just recovered by October, 2020. This resulted in a 22% (95% CI 8-34) relative reduction in the number of cases referred for treatment (from a monthly average of 2781 in 2019 to 2158 referrals in April, 2020). By October, 2020, the monthly rate had returned to 2019 levels but did not exceed it, suggesting that, from April to October, 2020, over 3500 fewer people had been diagnosed and treated for colorectal cancer in England than would have been expected. There was also a 31% (95% CI 19-42) relative reduction in the numbers receiving surgery in April, 2020, and a lower proportion of laparoscopic and a greater proportion of stoma-forming procedures, relative to the monthly average in 2019. By October, 2020, laparoscopic surgery and stoma rates were similar to 2019 levels. For rectal cancer, there was a 44% (95% CI 17-76) relative increase in the use of neoadjuvant radiotherapy in April, 2020, relative to the monthly average in 2019, due to greater use of short-course regimens. Although in June, 2020, there was a drop in the use of short-course regimens, rates remained above 2019 levels until October, 2020. The COVID-19 pandemic has led to a sustained reduction in the number of people referred, diagnosed, and treated for colorectal cancer. By October, 2020, achievement of care pathway targets had returned to 2019 levels, albeit with smaller volumes of patients and with modifications to usual practice. As pressure grows in the NHS due to the second wave of COVID-19, urgent action is needed to address the growing burden of undetected and untreated colorectal cancer in England. Cancer Research UK, the Medical Research Council, Public Health England, Health Data Research UK, NHS Digital, and the National Institute for Health Research Oxford Biomedical Research Centre.


The effectiveness of marine based fatty acid compound (PCSO-524) and firocoxib in the treatment of canine osteoarthritis.
NSAIDs are accepted as the most predictably efficacious medical treatment of the clinical signs of osteoarthritis (OA). The marine-based fatty-acid compound PCSO-524 has been proposed as an adjunctive treatment for canine OA, however benefits of this agent is still controversial. The purpose of this study was to evaluate and compare the effectiveness of PCSO-524 combined with the NSAID firocoxib using force plate gait analysis, orthopedic assessment score (OAS) and canine brief pain inventory score (CBPI) in dogs with OA. A prospective, randomized, double-blinded study was conducted. Seventy-nine dogs that had hip and/or stifle OA were assigned randomly into three treatment groups: firocoxib, PCSO-524 and combination of firocoxib and PCSO-524, orally for 4 weeks. Peak vertical force (PVF, expressed as a percentage of bodyweight), OAS, CBPI, serum prostaglandin E2 concentration, hematology and blood chemistry values were evaluated before treatment (Day0), as well as at the second (Day14) and fourth week (Day28) during treatment. Within group analysis revealed significant increases in PVF over the 4-week treatment period for firocoxib, PCSO-524 and the combination (p < 0.05). Mean increases in PVF were 3.25 ± 4.13, 2.01 ± 3.86, 4.11 ± 4.69%BW (mean ± SD) respectively. The OAS showed non-significant change in all treatment groups. There were significant decreases in CBPI pain severity score (PSS) and CBPI pain interference scores (PIS) within some groups over time, however no significant differences were found between the groups. Significantly decreased serum PGE2 concentration (p < 0.05) was found in the combination group. Significant increases in BUN and creatinine (p < 0.05) compared to pre-treatment values were found in the firocoxib and combination groups but not in the PCSO-524 group at day28, but all values in all dogs remained within the normal ranges. The results of this study suggested combination of both PCSO-524 and firocoxib is more effective in alleviation of inflammation and improvement of weight bearing ability when compared to the uses of either PCSO-524 or firocoxib alone. Further clinical studies are needed to confirm this, and to determine if there is any benefit of PCSO-524 over placebo.


Biochar-red clay composites for energy efficiency as eco-friendly building materials: Thermal and mechanical performance.
Biochar and red clay were used to develop eco-friendly building materials with improved thermal and mechanical performance. Rice husk, coconut shell, and bamboo were prepared by thermally decomposing as biochar. Thermal conductivity measurements, scanning electron microscopy imaging, compressive strength measurements, and an infrared heat transfer experiment were performed, and the results showed that the mixture of biochar tends to lower the thermal conductivity. The compressive strength of specimens mixed with rice husk decreased, but that of specimens mixed with coconut shell and bamboo tended to increase. The infrared heat transfer test showed that the thermal performance of the mixed rice husk specimens was significant, while the specimen mixed with coconut shell and bamboo showed thermal performance improvement. A comprehensive evaluation of the improvement in thermal performance and strength indicated that a 10 wt.% mixture of bamboo was the most effective. Therefore, it was possible to effectively determine the type and weight ratio of biochar to red clay binder an important step in the study of biochar and red clay building materials.


Microfluidic fabrication of polyethylene glycol microgel capsules with tailored properties for the delivery of biomolecules.
Microfluidic encapsulation platforms have great potential not only in pharmaceutical applications but also in the consumer products industry. Droplet-based microfluidics is increasingly used for the production of monodisperse polymer microcapsules for biomedical applications. In this work, a microfluidic technique is developed for the fabrication of monodisperse double emulsion droplets, where the shell is crosslinked into microgel capsules. A six-armed acrylated star-shaped poly(ethylene oxide-stat-propylene oxide) pre-polymer is used to form the microgel shell after a photo-initiated crosslinking reaction. The synthesized microgel capsules are hollow, enabling direct encapsulation of large amounts of multiple biomolecules with the inner aqueous phase completely engulfed inside the double emulsion droplets. The shell thickness and overall microgel sizes can be controlled via the flow rates. The morphology and size of the shells are characterized by cryo-SEM. The encapsulation and retention of 10 kDa FITC-dextran and its microgel degradation mediated release are monitored by fluorescence microscopy.


Mechanotransduction-Induced Reversible Phenotypic Switching in Prostate Cancer Cells.
Phenotypic plasticity is posed to be a vital trait of cancer cells such as circulating tumor cells, allowing them to undergo reversible or irreversible switching between phenotypic states important for tumorigenesis and metastasis. While irreversible phenotypic switching can be detected by studying the genome, reversible phenotypic switching is often difficult to examine due to its dynamic nature and the lack of knowledge about its contributing factors. In this study, we demonstrate that culturing cells in different physical environments, stiff, soft, or suspension, induced a phenotypic switch in prostate cancer cells via mechanotransduction. The mechanosensitive phenotypic switching in prostate cancer cells was sustainable yet reversible even after long-term culture, demonstrating the impact of mechanical signals on prostate cancer cell phenotypes. Importantly, such a mechanotransduction-mediated phenotypic switch in prostate cancer cells was accompanied by decreased sensitivity of the cells to paclitaxel, suggesting a role of mechanotransduction in the evolution of drug resistance. Multiple signaling pathways such as p38MAPK, ERK, and Wnt were found to be involved in the mechanotransduction-induced phenotypic switching of prostate cancer cells. Given that cancer cells experience different physical environments during disease progression, this study provides useful information about the important role of mechanotransduction in cancer, and how circulating tumor cells may be capable of continuously changing their phenotypes throughout the disease process.


Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma: results from the European Thoracic Oncology Platform Lungscape Project.
The prevalence of anaplastic lymphoma kinase (ALK) gene fusion (ALK positivity) in early-stage non-small-cell lung cancer (NSCLC) varies by population examined and detection method used. The Lungscape ALK project was designed to address the prevalence and prognostic impact of ALK positivity in resected lung adenocarcinoma in a primarily European population. Analysis of ALK status was performed by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) in tissue sections of 1,281 patients with adenocarcinoma in the European Thoracic Oncology Platform Lungscape iBiobank. Positive patients were matched with negative patients in a 1:2 ratio, both for IHC and for FISH testing. Testing was performed in 16 participating centers, using the same protocol after passing external quality assessment. Positive ALK IHC staining was present in 80 patients (prevalence of 6.2%; 95% CI, 4.9% to 7.6%). Of these, 28 patients were ALK FISH positive, corresponding to a lower bound for the prevalence of FISH positivity of 2.2%. FISH specificity was 100%, and FISH sensitivity was 35.0% (95% CI, 24.7% to 46.5%), with a sensitivity value of 81.3% (95% CI, 63.6% to 92.8%) for IHC 2+/3+ patients. The hazard of death for FISH-positive patients was lower than for IHC-negative patients (P = .022). Multivariable models, adjusted for patient, tumor, and treatment characteristics, and matched cohort analysis confirmed that ALK FISH positivity is a predictor for better overall survival (OS). In this large cohort of surgically resected lung adenocarcinomas, the prevalence of ALK positivity was 6.2% using IHC and at least 2.2% using FISH. A screening strategy based on IHC or H-score could be envisaged. ALK positivity (by either IHC or FISH) was related to better OS.