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'.

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.

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].

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.

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.

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.

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.

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.

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.

Guillotine versus dissection tonsillectomy: randomised, controlled trial.

OBJECTIVE: This trial aimed to compare the guillotine technique of tonsillectomy with 'cold steel' dissection, the current 'gold standard'. DESIGN: A single centre, randomised, controlled trial. METHODS: One hundred children aged 3 to 11 years who were listed for bilateral tonsillectomy were recruited. Patients had one tonsil removed by each technique, and were blinded to the side. The operative time, intra-operative blood loss, haemostasis requirement and post-operative pain scores were recorded and compared. RESULTS: Operative time and intra-operative blood loss were both significantly less for the guillotine technique (p < 0.001) and there was a significantly reduced haemostasis requirement (p < 0.001). Pain was also less on the guillotine side (p < 0.001). There were no tonsillar remnants or palatal trauma for either technique. There was no significant difference between techniques in the frequency of secondary haemorrhage. CONCLUSION: This study provides level Ib evidence that guillotine tonsillectomy in children with mobile tonsils is an effective and time-efficient procedure which produces less intra-operative blood loss and post-operative pain than cold steel dissection.

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.

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.

Evaluation of the information needs of patients with chronic obstructive pulmonary disease following pulmonary rehabilitation: a focus group study.

AIMS: This study aimed to understand patient information needs and how best to meet them in order to improve rehabilitation provision and aid disease self-management by exploring experiences of people who had recently completed a pulmonary rehabilitation programme in a community hospital setting. METHODS: Qualitative research using focus groups was undertaken with 23 patients who had completed pulmonary rehabilitation within the previous four months. The focus groups were tape-recorded and contemporaneous notes made. The tapes were transcribed verbatim and template analysis was used to develop themes. FINDINGS: The key information needs were for a full understanding of the disease to be generated for patients, their families and the wider public much earlier in the disease process and preferably at the point of diagnosis. Patients perceived that they needed to come to terms with the condition. In order to improve disease self-management feelings of anxiety and frustration should to be addressed with the suggestion that individual counselling might be made available through the rehabilitation programme. The need for continued support was highlighted with an emphasis on peer group support activities. CONCLUSIONS: The findings have implications for primary care in terms of unmet needs in the early stages of the condition and pulmonary rehabilitation programmes in terms of providing individual counselling and ongoing peer group support to aid disease self-management.

A derivative of the menaquinone precursor 1,4-dihydroxy-2-naphthoate is involved in the reductive transformation of carbon tetrachloride by aerobically grown Shewanella oneidensis MR-1.

Transformation of carbon tetrachloride (CT) by Shewanella oneidensis MR-1 has been proposed to involve the anaerobic respiratory-chain component menaquinone. To investigate this hypothesis a series of menaquinone mutants were constructed. The menF mutant is blocked at the start of the menaquinone biosynthetic pathway. The menB, menA and menG mutants are all blocked towards the end of the pathway, being unable to produce 1,4-dihydroxy-2-naphthoic acid (DHNA), demethyl-menaquinone and menaquinone, respectively. Aerobically grown mutants unable to produce the menaquinone precursor DHNA (menF and menB mutants) showed a distinctly different CT transformation profile than mutants able to produce DHNA but unable to produce menaquinone (menA and menG mutants). While DHNA did not reduce CT in an abiotic assay, the addition of DHNA to the menF and menB mutants restored normal CT transformation activity. We conclude that a derivative of DHNA, that is distinct from menaquinone, is involved in the reduction of CT by aerobically grown S. oneidensis MR-1. When cells were grown anaerobically with trimethylamine-N-oxide as the terminal electron acceptor, all the menaquinone mutants showed wild-type levels of CT reduction. We conclude that S. oneidensis MR-1 produces two different factors capable of dehalogenating CT. The factor produced under anaerobic growth conditions is not a product of the menaquinone biosynthetic pathway.

Bronchiolitis obliterans and organising pneumonia caused by carbamazepine and mimicking community acquired pneumonia.

Bronchiolitis obliterans and organising pneumonia (BOOP) presents with fever, dyspnoea, and other features that may be mistaken for pneumonia. Treatment is, however, very different, requiring corticosteroids. A man was admitted as an emergency with fever, dyspnoea, and non-productive cough. The chest radiograph showed consolidation which, despite antibiotics, progressed to become bilateral. BOOP was considered, and confirmed by transbronchial biopsy. The response to oral prednisolone was rapid with complete resolution of symptoms and radiographic consolidation within three weeks. The cause of BOOP is often never found; it is believed, however, that in this instance it occurred as a result of carbamazepine therapy started seven weeks earlier.