Adaptive grid methods for Q-tensor theory of liquid crystals : a one-dimensional feasibility study

This paper illustrates the use of moving mesh methods for solving partial differential equation (PDE) problems in Q-tensor theory of liquid crystals. We present the results of an initial study using a simple one-dimensional test problem which illustrates the feasibility of applying adaptive grid techniques in such situations. We describe how the grids are computed using an equidistribution principle, and investigate the comparative accuracy of adaptive and uniform grid strategies, both theoretically and via numerical examples

Functional outcomes with handsewn versus stapled anastomoses in the treatment of ultralow rectal cancer

Adequate oncological outcomes have been demonstrated with rectal resection and handsewn coloanal anastomosis (CAA) in tumours in close proximity to the internal anal sphincter. Our aim was to assess functional differences between handsewn CAA and ultralow stapled anastomosis. Participants were identified from a single-surgeon series. Included participants underwent anorectal physiology testing of anal sphincter function, in addition to completion of several questionnaires: Wexner Incontinence Score (WIS); Birmingham Bowel, Bladder and Urinary Symptom Questionnaire (BBUSQ); Low Anterior Resection Syndrome (LARS) Score; SF36. Non-parametric data compared using the Mann-Whitney U test. 20 participants were included; 11 stapled and 9 handsewn. Mean follow-up was 2.95 ± 1.97 years. The mean LARS score was 21.9 ± 1.97 years in the stapled group versus 29.4 ± 9.57 in the handsewn group (p = 0.133). The Wexner incontinence score was significantly higher in the handsewn group (p = 0.0076), with a mean score of 4.6 ± 3.69 versus 10.9 ± 4.76. The incontinence domain of the BBUSQ was also significantly worse in patients with a handsewn anastomosis (p = 0.001). With the exception of general health (p = 0.035) and social functioning (p = 0.035), which were worse in the handsewn groups, the other six domains of the SF-36 showed no statistical difference between groups. Anorectal physiology scores were not significantly different. Handsewn CAA anastomosis is known to be safe and oncologically feasible. Patient selection should be vigorous, with preoperative counseling regarding the likelihood of incontinence to manage patients' expectations and promote comparable quality of life in the long-term

Hsp90 governs dispersion and drug resistance of fungal biofilms

Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving clinical outcome in the treatment of biofilm infections

The nature and prevalence of psychological problems in New Zealand primary healthcare: a report on Mental Health and General Practice Investigation ( MaGPIe)

Aims This paper describes the methods used in a study of the prevalence and types of common mental disorders among patients attending New Zealand general practices, and reports some key findings from the first phase of the study. The study also aimed to determine the degree of associated disability and other factors influencing recognition, management, course and outcome of these disorders, and subsequent papers will address these issues. Methods General practitioners (GPs) were selected randomly. In the first phase of the study, all adult attenders at each practice on selected days were administered a short questionnaire, the General Health Questionnaire (GHQ-12), which screens for psychological symptoms. The GP recorded the reasons for each consultation, and was interviewed at the end of each day about selected patients to determine their opinion about the type of psychological problems experienced. Selected patients were then visited in their own homes and an extensive interview conducted, which included the Composite International Diagnostic Interview (CIDI) to determine mental health status, the World Health Organization’s Disability Assessment Schedule (WHODAS) to determine disability, and a detailed exploration of use of health services. In the second phase of the study, patients were contacted by telephone at three, six, nine and 12 months, and both patients and GPs were re-interviewed at 12 months. Results The study achieved a very high response rate among the GPs (90%). Nearly all eligible patients (93%) completed the GHQ screening, and their response rate was 70% for the first-phase interview. GPs thought that 54% of female and 46% of male patients had experienced some level of psychological problems in the past year. GHQ screening also found that more than half of those attending their general practitioner experienced some psychological symptoms at initial screening, and the CIDI interview found that more than one in three had a diagnosable mental disorder during the past 12 months. The most common mental disorders were depressive, anxiety and substance use disorders. These disorders were more common among younger than older general practice attenders, and comorbidity was high. Conclusions Mental health problems are very common among general practice attenders. Contrary to the prevailing view that general practitioners seldom identify psychological problems in their patients, they identified about half their patients as having some type of psychological problems in the past year, although they considered that these were moderate or severe in about only one in ten patients. Further work from this large New Zealand study will focus on the nature of the relationship between disorder and disability, and on the recognition, management and outcome of psychological problems

Candida albicans forms biofilms on the vaginal mucosa

Current understanding of resistance and susceptibility to vulvovaginal candidiasis challenges existing paradigms of host defence against fungal infection. While abiotic biofilm formation has a clearly established role during systemic Candida infections, it is not known whether C. albicans forms biofilms on the vaginal mucosa and the possible role of biofilms in disease. In vivo and ex vivo murine vaginitis models were employed to examine biofilm formation by scanning electron and confocal microscopy. C. albicans strains included 3153A (lab strain), DAY185 (parental control strain), and mutants defective in morphogenesis and/or biofilm formation in vitro (efg1/efg1 and bcr1/bcr1). Both 3153A and DAY815 formed biofilms on the vaginal mucosa in vivo and ex vivo as indicated by high fungal burden and microscopic analysis demonstrating typical biofilm architecture and presence of extracellular matrix (ECM) co-localized with the presence of fungi. In contrast, efg1/efg1 and bcr1/bcr1 mutant strains exhibited weak or no biofilm formation/ECM production in both models compared to wild-type strains and complemented mutants despite comparable colonization levels. These data show for the first time that C. albicans forms biofilms in vivo on vaginal epithelium, and that in vivo biotic biofilm formation requires regulators of biofilm formation (BCR1) and morphogenesis (EFG1)

Linking geographic vocabularies through WordNet

The linked open data (LOD) paradigm has emerged as a promising approach to structuring and sharing geospatial information. One of the major obstacles to this vision lies in the difficulties found in the automatic integration between heterogeneous vocabularies and ontologies that provides the semantic backbone of the growing constellation of open geo-knowledge bases. In this article, we show how to utilize WordNet as a semantic hub to increase the integration of LOD. With this purpose in mind, we devise Voc2WordNet, an unsupervised mapping technique between a given vocabulary and WordNet, combining intensional and extensional aspects of the geographic terms. Voc2WordNet is evaluated against a sample of human-generated alignments with the OpenStreetMap (OSM) Semantic Network, a crowdsourced geospatial resource, and the GeoNames ontology, the vocabulary of a large digital gazetteer. These empirical results indicate that the approach can obtain high precision and recall

Dispersion as an Important Step in the Candida albicans Biofilm Developmental Cycle

Biofilms are dynamic microbial communities in which transitions between planktonic and sessile modes of growth occur interchangeably in response to different environmental cues. In the last decade, early events associated with C. albicans biofilm formation have received considerable attention. However, very little is known about C. albicans biofilm dispersion or the mechanisms and signals that trigger it. This is important because it is precisely C. albicans cells dispersed from biofilms that are the main culprits associated with candidemia and establishment of disseminated invasive disease, two of the gravest forms of candidiasis. Using a simple flow biofilm model recently developed by our group, we have performed initial investigations into the phenomenon of C. albicans biofilm dispersion, as well as the phenotypic characteristics associated with dispersed cells. Our results indicate that C. albicans biofilm dispersion is dependent on growing conditions, including carbon source and pH of the media used for biofilm development. C. albicans dispersed cells are mostly in the yeast form and display distinct phenotypic properties compared to their planktonic counterparts, including enhanced adherence, filamentation, biofilm formation and, perhaps most importantly, increased pathogenicity in a murine model of hematogenously disseminated candidiasis, thus indicating that dispersed cells are armed with a complete arsenal of “virulence factors” important for seeding and establishing new foci of infection. In addition, utilizing genetically engineered strains of C. albicans (tetO-UME6 and tetO-PES1) we demonstrate that C. albicans biofilm dispersion can be regulated by manipulating levels of expression of these key genes, further supporting the evidence for a strong link between biofilms and morphogenetic conversions at different stages of the C. albicans biofilm developmental cycle. Overall, our results offer novel and important insight into the phenomenon of C. albicans biofilm dispersion, a key part of the biofilm developmental cycle, and provide the basis for its more detailed analysis

Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues

In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27–1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89–4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 – not reached) with pasireotide versus 6.8 months (5.6 – not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20–0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR

The transport of liquids in softwood: timber as a model porous medium

Abstract: Timber is the only widely used construction material we can grow. The wood from which it comes has evolved to provide structural support for the tree and to act as a conduit for fluid flow. These flow paths are crucial for engineers to exploit the full potential of timber, by allowing impregnation with liquids that modify the properties or resilience of this natural material. Accurately predicting the transport of these liquids enables more efficient industrial timber treatment processes to be developed, thereby extending the scope to use this sustainable construction material; moreover, it is of fundamental scientific value — as a fluid flow within a natural porous medium. Both structural and transport properties of wood depend on its micro-structure but, while a substantial body of research relates the structural performance of wood to its detailed architecture, no such knowledge exists for the transport properties. We present a model, based on increasingly refined geometric parameters, that accurately predicts the time-dependent ingress of liquids within softwood timber, thereby addressing this long-standing scientific challenge. Moreover, we show that for the minimalistic parameterisation the model predicts ingress with a square-root-of-time behaviour. However, experimental data show a potentially significant departure from this t behaviour — a departure which is successfully predicted by our more advanced parametrisation. Our parameterisation of the timber microstructure was informed by computed tomographic measurements; model predictions were validated by comparison with experimental data. We show that accurate predictions require statistical representation of the variability in the timber pore space. The collapse of our dimensionless experimental data demonstrates clear potential for our results to be up-scaled to industrial treatment processes