Pattern forming systems coupling linear bulk diffusion to dynamically active membranes or cells.

Some analytical and numerical results are presented for pattern formation properties associated with novel types of reaction-diffusion (RD) systems that involve the coupling of bulk diffusion in the interior of a multi-dimensional spatial domain to nonlinear processes that occur either on the domain boundary or within localized compartments that are confined within the domain. The class of bulk-membrane system considered herein is derived from an asymptotic analysis in the limit of small thickness of a thin domain that surrounds the bulk medium. When the bulk domain is a two-dimensional disk, a weakly nonlinear analysis is used to characterize Turing and Hopf bifurcations that can arise from the linearization around a radially symmetric, but spatially non-uniform, steady-state of the bulk-membrane system. In a singularly perturbed limit, the existence and linear stability of localized membrane-bound spike patterns is analysed for a Gierer-Meinhardt activator-inhibitor model that includes bulk coupling. Finally, the emergence of collective intracellular oscillations is studied for a class of PDE-ODE bulk-cell model in a bounded two-dimensional domain that contains spatially localized, but dynamically active, circular cells that are coupled through a linear bulk diffusion field. Applications of such coupled bulk-membrane or bulk-cell systems to some biological systems are outlined, and some open problems in this area are discussed. This article is part of the theme issue 'Recent progress and open frontiers in Turing's theory of morphogenesis'.

The protocol-guided rapid evaluation of veterans experiencing new transient neurological symptoms (PREVENT) quality improvement program: rationale and methods.

BACKGROUND: Transient ischemic attack (TIA) patients are at high risk of recurrent vascular events; timely management can reduce that risk by 70%. The Protocol-guided Rapid Evaluation of Veterans Experiencing New Transient Neurological Symptoms (PREVENT) developed, implemented, and evaluated a TIA quality improvement (QI) intervention aligned with Learning Healthcare System principles. METHODS: This stepped-wedge trial developed, implemented and evaluated a provider-facing, multi-component intervention to improve TIA care at six facilities. The unit of analysis was the medical center. The intervention was developed based on benchmarking data, staff interviews, literature, and electronic quality measures and included: performance data, clinical protocols, professional education, electronic health record tools, and QI support. The effectiveness outcome was the without-fail rate: the proportion of patients who receive all processes of care for which they are eligible among seven processes. The implementation outcomes were the number of implementation activities completed and final team organization level. The intervention effects on the without-fail rate were analyzed using generalized mixed-effects models with multilevel hierarchical random effects. Mixed methods were used to assess implementation, user satisfaction, and sustainability. DISCUSSION: PREVENT advanced three aspects of a Learning Healthcare System. Learning from Data: teams examined and interacted with their performance data to explore hypotheses, plan QI activities, and evaluate change over time. Learning from Each Other: Teams participated in monthly virtual collaborative calls. Sharing Best Practices: Teams shared tools and best practices. The approach used to design and implement PREVENT may be generalizable to other clinical conditions where time-sensitive care spans clinical settings and medical disciplines. TRIAL REGISTRATION: clinicaltrials.gov: NCT02769338 [May 11, 2016].

Participation in sport and physical activity in head and neck cancer survivors: associations with quality of life.

BACKGROUND: Head and neck cancer (HNC), and its treatment, is associated with significant side-effects which can affect quality of life (QOL). Physical activity (PA) is known to improve a number of QOL measures. We aimed to determine the prevalence of PA pre- and post-treatment of HNC and to determine associations with QOL. METHODS: A questionnaire-based survey of 172 patients pre- and post-treatment for HNC. RESULTS: A total of 62.2% of patients met current UK PA guidelines pre-treatment, reducing to 40.1% following treatment. There was a significant decrease in Metabolic equivalent task minutes/week post-treatment, with 71% of participants reporting less PA after diagnosis (P < 0.001). Swimming and cycling remained the two most practiced sports. There was a positive correlation between the post-treatment PA and QOL (P < 0.001). CONCLUSION: These data suggest that PA may improve QOL following treatment for HNC. We believe that further studies are warranted.

Efficient national surveillance for health-care-associated infections.

BACKGROUND: Detecting novel healthcare-associated infections (HCAI) as early as possible is an important public health priority. However, there is currently no evidence base to guide the design of efficient and reliable surveillance systems. Here we address this issue in the context of a novel pathogen spreading primarily between hospitals through the movement of patients. METHODS: Using a mathematical modelling approach we compare the current surveillance system for a HCAI that spreads primarily between hospitals due to patient movements as it is implemented in Scotland with a gold standard to determine if the current system is maximally efficient or whether it would be beneficial to alter the number and choice of hospitals in which to concentrate surveillance effort. RESULTS: We validated our model by demonstrating that it accurately predicts the risk of meticillin-resistant Staphylococcus aureus bacteraemia cases in Scotland. Using the 29 (out of 182) sentinel hospitals that currently contribute most of the national surveillance effort results in an average detection time of 117 days. A reduction in detection time to 87 days is possible by optimal selection of 29 hospitals. Alternatively, the same detection time (117 days) can be achieved using just 22 optimally selected hospitals. Increasing the number of sentinel hospitals to 38 (teaching and general hospitals) reduces detection time by 43 days; however decreasing the number to seven sentinel hospitals (teaching hospitals) increases detection time substantially to 268 days. CONCLUSIONS: Our results show that the current surveillance system as it is used in Scotland is not optimal in detecting novel pathogens when compared to a gold standard. However, efficiency gains are possible by better choice of sentinel hospitals, or by increasing the number of hospitals involved in surveillance. Similar studies could be used elsewhere to inform the design and implementation of efficient national, hospital-based surveillance systems that achieve rapid detection of novel HCAIs for minimal effort.

Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer.

BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) is associated with improved survival compared with HPV-negative disease. However, a minority of HPV-positive patients have poor prognosis. Currently, there is no generally accepted strategy for identifying these patients. METHODS: We retrospectively analysed 270 consecutively treated OPSCC patients from three centres for effects of clinical, pathological, immunological, and molecular features on disease mortality. We used Cox regression to examine associations between factors and OPSCC death, and developed a prognostic model for 3-year mortality using logistic regression analysis. RESULTS: Patients with HPV-positive tumours showed improved survival (hazard ratio (HR), 0.33 (0.21-0.53)). High levels of tumour-infiltrating lymphocytes (TILs) stratified HPV-positive patients into high-risk and low-risk groups (3-year survival; HPV-positive/TIL(high)=96%, HPV-positive/TIL(low)=59%). Survival of HPV-positive/TIL(low) patients did not differ from HPV-negative patients (HR, 1.01; P=0.98). We developed a prognostic model for HPV-positive tumours using a 'training' cohort from one centre; the combination of TIL levels, heavy smoking, and T-stage were significant (AUROC=0·87). This model was validated on patients from the other centres (detection rate 67%; false-positive rate 5.6%; AUROC=0·82). INTERPRETATION: Our data suggest that an immune response, reflected by TIL levels in the primary tumour, has an important role in the improved survival seen in most HPV-positive patients, and is relevant for the clinical evaluation of HPV-positive OPSCC.

Time-Scaled Evolutionary Analysis of the Transmission and Antibiotic Resistance Dynamics of Staphylococcus aureus Clonal Complex 398.

Staphylococcus aureus clonal complex 398 (CC398) is associated with disease in humans and livestock, and its origins and transmission have generated considerable interest. We performed a time-scaled phylogenetic analysis of CC398, including sequenced isolates from the United Kingdom (Scotland), along with publicly available genomes. Using state-of-the-art methods for mapping traits onto phylogenies, we quantified transitions between host species to identify sink and source populations for CC398 and employed a novel approach to investigate the gain and loss of antibiotic resistance in CC398 over time. We identified distinct human- and livestock-associated CC398 clades and observed multiple transmissions of CC398 from livestock to humans and between countries, lending quantitative support to previous reports. Of note, we identified a subclade within the livestock-associated clade comprised of isolates from hospital environments and newborn babies, suggesting that livestock-associated CC398 is capable of onward transmission in hospitals. In addition, our analysis revealed significant differences in the dynamics of resistance to methicillin and tetracycline related to contrasting historical patterns of antibiotic usage between the livestock industry and human medicine. We also identified significant differences in patterns of gain and loss of different tetracycline resistance determinants, which we ascribe to epistatic interactions between the resistance genes and/or differences in the modes of inheritance of the resistance determinants.

Electrokinesis is a microbial behavior that requires extracellular electron transport.

We report a previously undescribed bacterial behavior termed electrokinesis. This behavior was initially observed as a dramatic increase in cell swimming speed during reduction of solid MnO(2) particles by the dissimilatory metal-reducing bacterium Shewanella oneidensis MR-1. The same behavioral response was observed when cells were exposed to small positive applied potentials at the working electrode of a microelectrochemical cell and could be tuned by adjusting the potential on the working electrode. Electrokinesis was found to be different from both chemotaxis and galvanotaxis but was absent in mutants defective in electron transport to solid metal oxides. Using in situ video microscopy and cell tracking algorithms, we have quantified the response for different strains of Shewanella and shown that the response correlates with current-generating capacity in microbial fuel cells. The electrokinetic response was only exhibited by a subpopulation of cells closest to the MnO(2) particles or electrodes. In contrast, the addition of 1 mM 9,10-anthraquinone-2,6-disulfonic acid, a soluble electron shuttle, led to increases in motility in the entire population. Electrokinesis is defined as a behavioral response that requires functional extracellular electron transport and that is observed as an increase in cell swimming speeds and lengthened paths of motion that occur in the proximity of a redox active mineral surface or the working electrode of an electrochemical cell.

Detection of mammalian virulence determinants in highly pathogenic avian influenza H5N1 viruses: multivariate analysis of published data.

Highly pathogenic avian influenza (HPAI) virus H5N1 infects water and land fowl and can infect and cause mortality in mammals, including humans. However, HPAI H5N1 strains are not equally virulent in mammals, and some strains have been shown to cause only mild symptoms in experimental infections. Since most experimental studies of the basis of virulence in mammals have been small in scale, we undertook a meta-analysis of available experimental studies and used Bayesian graphical models (BGM) to increase the power of inference. We applied text-mining techniques to identify 27 individual studies that experimentally determined pathogenicity in HPAI H5N1 strains comprising 69 complete genome sequences. Amino acid sequence data in all 11 genes were coded as binary data for the presence or absence of mutations related to virulence in mammals or nonconsensus residues. Sites previously implicated as virulence determinants were examined for association with virulence in mammals in this data set, and the sites with the most significant association were selected for further BGM analysis. The analyses show that virulence in mammals is a complex genetic trait directly influenced by mutations in polymerase basic 1 (PB1) and PB2, nonstructural 1 (NS1), and hemagglutinin (HA) genes. Several intra- and intersegment correlations were also found, and we postulate that there may be two separate virulence mechanisms involving particular combinations of polymerase and NS1 mutations or of NS1 and HA mutations.

The endurance shuttle walk test: an alternative to the six-minute walk test for the assessment of ambulatory oxygen.

UK guidelines for domiciliary oxygen have suggested the six-minute walk test or shuttle walk tests as suitable functional measures for the clinical assessment of ambulatory oxygen (AO). To date, there is limited evidence that would support the use of shuttle walk tests as assessment tools for AO. The endurance shuttle walk test (ESWT) is used increasingly as an assessment tool within pulmonary rehabilitation (PR) but its potential as an investigative test for AO has not been explored. Using the same test for both PR and AO assessment is appealing since it would improve efficiency and act to standardise outcome measures in this patient population. The aim of this study was to examine the responsiveness and repeatability of the ESWT to AO and to compare the response with that of the six-minute walk test (6MWT). Twenty-three patients with chronic obstructive pulmonary disease (COPD) performed, in random order, the ESWT and the 6MWT on air and whilst breathing AO. Oxygen saturation and Borg ratings of breathlessness and perceived exertion were recorded. On a third day, eleven patients repeated the ESWT with AO in order to measure repeatability. There was a significantly greater change in the ESWT with oxygen than the change recorded from the 6MWT (66 [91] vs 6 [28] m respectively; P < .05). When repeated on a separate day, the mean difference (95% CI) between distances walked on the ESWT with AO was 0.91 (-47, 49) m. The ESWT was more responsive than the 6MWT for detecting improvements in walking endurance whilst breathing AO.

Incidence of breast lymphedema and predictors of its development in patients receiving whole breast radiation therapy after breast-conservation surgery.

One common adverse effect following breast-conservation surgery and adjuvant radiation is lymphedema. While lymphedema of the arm has been well-characterized, there has been less investigation into lymphedema of the breast. We sought to characterize rates of breast lymphedema (BLE) in women with early-stage breast cancer and identify potential predictors in its development. Two hundred and thirty consecutive patients treated with lumpectomy and adjuvant whole breast radiation therapy (WBRT) from January 2016 - June 2017 were included. All patients were seen in our lymphedema monitoring clinic for baseline and at least one follow-up lymphedema measurement. BLE grades were assigned by trained nurses in the lymphedema clinic. Data regarding patient demographic and treatment factors were extracted from the electronic medical record. Comparisons between groups were made using Chi-Square analysis performed in SAS. The median age of the sample was 62 (range 31-90). Median follow-up from surgery was 15.3 months. Forty-three patients were diagnosed with lymphedema of the breast (18.7%). Rates of grade 1 and 2 BLE were 93% and 7%, respectively; there were no cases of severe lymphedema. Sixty-three percent of cases resolved by last follow-up with treatment recommendations. There was no association between development of BLE and patient factors investigated, including age, T stage, radiation dose and fractionation, lymph node biopsy, number of lymph nodes removed, development of arm lymphedema, and use of chemotherapy. Tumor subtype was found to be significant (P = 0.04) and there was a trend towards significance for receipt of trastuzumab (P = 0.09). BLE is a distinct entity from arm lymphedema and is a common finding in women treated with breast-conserving surgery and adjuvant WBRT. It is a generally mild and self-limiting process. There were no treatment or patient-related factors that correlated with increased risk of lymphedema development in our sample except for HER-2 positive disease and receipt of trastuzamab.

Deterministic processes structure bacterial genetic communities across an urban landscape.

Land-use change is predicted to act as a driver of zoonotic disease emergence through human exposure to novel microbial diversity, but evidence for the effects of environmental change on microbial communities in vertebrates is lacking. We sample wild birds at 99 wildlife-livestock-human interfaces across Nairobi, Kenya, and use whole genome sequencing to characterise bacterial genes known to be carried on mobile genetic elements (MGEs) within avian-borne Escherichia coli (n = 241). By modelling the diversity of bacterial genes encoding virulence and antimicrobial resistance (AMR) against ecological and anthropogenic forms of urban environmental change, we demonstrate that communities of avian-borne bacterial genes are shaped by the assemblage of co-existing avian, livestock and human communities, and the habitat within which they exist. In showing that non-random processes structure bacterial genetic communities in urban wildlife, these findings suggest that it should be possible to forecast the effects of urban land-use change on microbial diversity.

Motility in Myxococcus xanthus and its role in developmental aggregation.

The Frz signal transduction system of Myxococcus xanthus was originally thought to be a simple variation of the well-characterized Che system of the enteric bacteria. Recently, however, many additional Frz proteins, along with alternative signal transduction systems, have been discovered. Together these signal transduction pathways coordinate cell-cell behavior, permitting the complex interactions required for developmental aggregation and fruiting body formation.

Interleukin 8: an autocrine growth factor for malignant mesothelioma.

Interleukin 8 (IL-8) is a potent chemokine that also has a direct growth-potentiating effect on certain tumors. In the present study, we determined IL-8 levels in human malignant mesothelioma (MM) effusions and congestive heart failure pleural fluids. We also investigated antigenic IL-8 production by different MM cell lines, and we describe the role of IL-8 in the autocrine growth regulation of MMs. Mesothelial (CRL-9444 = MC) and MM (CRL-2081 = MM-1, CRL-5915 = MM-2, and CRL-5820 = MM-3) cell lines were grown using standard culture methods. The bioactive IL-8 levels were measured in supernatants of cultured cells by ELISA, and the expression of cell-associated immunoreactive IL-8 was observed by immunohistochemistry. The proliferative activity was determined by thymidine ([3H]thymidine) incorporation and also by direct cell counts after incubation with varying concentrations of IL-8 in the presence/absence of specific polyclonal IL-8 antibody. We found significantly higher levels of IL-8 in mesothelioma pleural fluids than congestive heart failure and a time-dependent increase in IL-8 levels in MM-1 and MM-2 cell supernatants during 96 h of incubation. IL-8 levels were nearly undetectable in MM-3 and MC cell line supernatants. In MM-1 and MM-2 cells, IL-8 caused a dose-dependent increase of [3H]thymidine incorporation to maximal levels of 46.3 +/- 3.6% and 12.3 +/- 1.6% (P < 0.001), respectively, when compared with serum-free medium as control. Neutralization of IL-8 significantly decreased proliferative activity of MM-1 and MM-2. IL-8 did not induce proliferative activity in MM-3 and MC cells. We conclude that IL-8 had a direct growth-potentiating activity in MMs.

Patient reported outcome measures in septorhinoplasty surgery.

INTRODUCTION: Surgical procedures incorporating a cosmetic element such as septorhinoplasty and otoplasty are currently under threat in the National Health Service (NHS) as they are deemed to be procedures of 'limited clinical benefit' by many primary care providers. Patient reported outcome measures (PROMs), which assess the quality of care delivered from the patients' perspective, are becoming increasingly important in documenting the effectiveness of such procedures. METHODS: The Rhinoplasty Outcomes Evaluation (ROE) questionnaire, a validated PROM tool, was used to assess patient satisfaction in 141 patients undergoing septorhinoplasty surgery over a 90-month period at the University Hospital Southampton NHS Foundation Trust. RESULTS: Overall, 100 patients with a mean follow-up period of 36 months completed the study. The mean ROE score was 73.3%. In addition, 75% of patients questioned were happy with the final result of their operation and 83% would undergo the procedure again if required. These benefits occurred irrespective of age, sex and primary versus revision surgery, and were maintained for up to 71 months following surgery. CONCLUSIONS: This study has shown that patients are generally satisfied with their functional and cosmetic outcomes following septorhinoplasty surgery. These results help support the case for septorhinoplasty surgery to continue being funded as an NHS procedure.

Galaxy evolution. Black hole feedback in the luminous quasar PDS 456.

The evolution of galaxies is connected to the growth of supermassive black holes in their centers. During the quasar phase, a huge luminosity is released as matter falls onto the black hole, and radiation-driven winds can transfer most of this energy back to the host galaxy. Over five different epochs, we detected the signatures of a nearly spherical stream of highly ionized gas in the broadband x-ray spectra of the luminous quasar PDS 456. This persistent wind is expelled at relativistic speeds from the inner accretion disk, and its wide aperture suggests an effective coupling with the ambient gas. The outflow's kinetic power larger than 10(46) ergs per second is enough to provide the feedback required by models of black hole and host galaxy coevolution.

Torsion of normal uterine adnexa in childhood: case report.

A case of torsion of a normal right ovary and tube in an 8-year-old child is presented. True infarction of the adnexa can be prevented only by considering this diagnosis early in the course of right lower quadrant pain. It is recommended that a routine exploration of the pelvis be carried out in any patient explored for acute appendicitis in whom that diagnosis cannot be made at the operating table.

Localization of upstream silencer elements involved in the expression of cone transducin alpha-subunit (GNAT2).

PURPOSE: To localize cis-acting elements involved in the expression of the cone-specific G-protein, cone transducin alpha-subunit (GNAT2). METHODS: In this study, the authors used a genomic clone, HGLG3, to sequence 3139 base pairs of the upstream region of the GNAT2 gene and to localize cis-acting elements involved in the expression of GNAT2. Upstream elements were localized functionally by transfection of chloramphenicol acetyltransferase gene constructs containing nested deletions of this upstream region into WERI-Rb1 cells. Cell specificity of the localized elements was determined by transfection of the HeLa cells. Trans-acting factor-binding sites to functional cis-acting elements were determined by DNasel footprinting. Cell specificity of protein interaction with footprinted regions was tested by electrophoretic mobility shifts with nuclear extracts from WERI-Rb1 and HeLa cells. RESULTS: Transfection of WERI-Rb1 and HeLa cells revealed the presence of a strong, noncell-specific silencer region between -1130 and -23, a weak, cell-specific promoter between -151 and -10, and a stronger, noncell-specific element between +143 and +167. DNaseI footprinting showed three major footprints (S1, S2, and S3) between -807 and -176, indicating the binding sites for putative negative trans-acting factors. Individual footprinted sequences had similar electrophoretic mobility shifts when they were incubated with nuclear extracts from either WERI-Rb1 or HeLa cells, suggesting that these cells express the same negative factors. CONCLUSIONS: The expression of the GNAT2 gene is controlled by a strong silencer region, a weak upstream cell-specific promoter, and a strong downstream element. The silencer region interacts with similar proteins from retina- and nonretina-derived cell lines.

Sequence analysis and relationships between meningococcal class 3 serotype proteins and other porins from pathogenic and non-pathogenic Neisseria species.

The presence of highly conserved regions within previously determined porin gene sequences from Neisseria meningitidis and Neisseria gonorrhoeae permitted the construction of oligonucleotide primers for PCR amplification of other neisserial porin genes. Although two separate porin genes (porA and porB) are present in N. meningitidis only a single fragment, corresponding to porB, could be amplified from this species. The amplified porB genes from four different meningococcal serotypes, which express the class 3 outer membrane protein, were sequenced. Amplified fragments corresponding to porin genes from N. lactamica and N. sicca were also sequenced. In common with the known neisserial porins, models of the organisation of the predicted proteins indicated trans-membrane structures with eight surface exposed loops. In the meningococcal class 3 proteins the main regions of sequence variation, which must be responsible for serotype specificity, were located on loops 5 and 7. A phylogenetic analysis of the family of porins from the Neisseria confirmed the close relationship of the meningococcal class 3 protein with the gonococcal PIA protein, while the gonococcal PIB protein was shown to be closely related to the N. lactamica porin. The close relationship seen between porins of the pathogenic and non-pathogenic Neisseriae identified no obvious virulence-associated regions in the proteins, but did suggest that the current nomenclature for neisserial porin genes may need reviewing.

Role of the mother's touch in failure to thrive: a preliminary investigation.

OBJECTIVE: This study investigated the hypothesis that specific types of maternal touch that might promote infant growth are reduced in cases of failure to thrive (FTT) and tested reports that maternal physical interaction and physical affection are diminished in FTT. METHODS: Frequencies of operationally defined maternal touch categories were scored by blinded raters from videotaped mother-child feeding and play interactions of 21 children, aged 9 to 19 months, with FTT and 18 normally growing comparison children. After scoring and statistical analyses were completed, investigators unblinded to group status and clinical data reviewed the videotapes of the dyads with the lowest touch scores. RESULTS: Mothers of children with FTT provided less matter-of-fact touch in feeding (p = .017) and unintentional touch in play (p = .048) than the comparison group, and there was a trend (p = .082) for them to provide less proprioceptive stimulation in play. Unblinded case reviews indicate that, among children with FTT, extremely infrequent touch signals a marked touch aversion by either the mother or child. CONCLUSIONS: Types of maternal touch that may promote growth or facilitate feeding are reduced in FTT, due, in extreme cases, to maternal or child touch aversion. Clinicians evaluating FTT should be alert to very infrequent touch in the mother-child interaction and consider whether it may represent a maternal intolerance of physical contact with her infant or a problem with the infant's feeding competence.