A mathematical model of biofilm growth and spread within plant xylem: Case study of Xylella fastidiosa in olive trees.

Xylem-limited bacterial pathogens cause some of the most destructive plant diseases. Though imposed measures to control these pathogens are generally ineffective, even among susceptible taxa, some hosts can limit bacterial loads and symptom expression. Mechanisms by which this resistance is achieved are poorly understood. In particular, it is still unknown how differences in vascular structure may influence biofilm growth and spread within a host. To address this, we developed a novel theoretical framework to describe biofilm behaviour within xylem vessels, adopting a polymer-based modelling approach. We then parameterised the model to investigate the relevance of xylem vessel diameters on Xylella fastidiosa resistance among olive cultivars. The functionality of all vessels was severely reduced under infection, with hydraulic flow reductions of 2-3 orders of magnitude. However, results suggest wider vessels act as biofilm incubators; allowing biofilms to develop over a long time while still transporting them through the vasculature. By contrast, thinner vessels become blocked much earlier, limiting biofilm spread. Using experimental data on vessel diameter distributions, we were able to determine that a mechanism of resistance in the olive cultivar Leccino is a relatively low abundance of the widest vessels, limiting X. fastidiosa spread.

Non-opioid analgesics in adults after major surgery: systematic review with network meta-analysis of randomized trials.

BACKGROUND: Morphine, and analgesics other than morphine (AOM), are commonly used to treat postoperative pain after major surgery. However, which AOM provides the best efficacy-safety profile remains unclear. METHODS: Randomized trials of any AOM alone or any combination of AOM compared with placebo or another AOM in adults undergoing major surgery and receiving morphine patient-controlled analgesia were included in a network meta-analysis. The outcomes were morphine consumption, pain, incidence of nausea, vomiting at 24 h and severe adverse effects. RESULTS: 135 trials (13,287 patients) assessing 14 AOM alone or in combination were included. For all outcomes, comparisons with placebo were over-represented. Few trials assessed combinations of two AOM and none the combination of three or more. Network meta-analysis found morphine consumption reduction was greatest with the combination of two AOM (acetaminophen + nefopam, acetaminophen + NSAID, and tramadol + metamizol): -23.9 (95% CI -40;-7.7), -22.8 (-31.5;-14) and -19.8 (35.4;-4.2) mg per 24 h, respectively. For AOM used alone, morphine consumption reduction was greatest with α-2 agonists, NSAIDs, and COX-2 inhibitors. When considering the risk of nausea, NSAIDs, corticosteroids and α-2 agonists used alone were the most efficacious (OR 0.7 [95% CI: 0.6-0.8], 0.36 [0.18-0.79], 0.41 [0.15-.64], respectively). The paucity of severe adverse effects data did not allow assessment of efficacy-safety balance. CONCLUSIONS: A combination of aetaminophen with either an NSAID or nefopam was superior to most AOM used alone, in reducing morphine consumption. Efficacy was best with three AOM used alone (α-2 agonists, NSAIDs and COX-2 inhibitors) and least with tramadol and acetaminophen. There is insufficient trial data reporting adverse events. CLINICAL TRIAL REGISTRATION: PROSPERO: CRD42013003912.

Organizational stressors and basic psychological needs: The mediating role of athletes' appraisal mechanisms.

This article reports the first study to quantitatively examine the relationships between the demands encountered by athletes that are associated with the organization within which they are operating, cognitive appraisals, and basic psychological need experiences. Three hundred and fifteen high-level British athletes completed a multisection questionnaire which assessed each of the aforementioned constructs. A series of path analyses provided valuable insight into the way in which the three dimensions (ie, frequency, intensity, and duration) of five organizational stressor categories were evaluated by athletes and, in turn, how such threat or challenge appraisals predicted feelings of need satisfaction and need frustration. Moreover, cognitive stress appraisals were found to mediate the relationship between organizational stressors and psychological need experiences. The role of secondary control appraisals was also explored and found to mediate the relationship between primary cognitive appraisals and basic psychological need experiences. Study limitations, proposed future research directions, and the implications of the findings for applied practitioners are discussed.

Novel porcine model of cutaneous myiasis: a training tool for healthcare workers.

Cutaneous myiasis is a well-described problem in travellers to endemic regions including military personnel. Realistic training is important to ensure that healthcare workers have the confidence and expertise to recognise cutaneous myiasis and safely remove larvae if required. A model is described here that is simple, reproducible and realistic, and will allow for training of military healthcare workers in safe surgical removal of larvae when required.

Patterns of Multi-Antibiotic-Resistant Escherichia Coli from Streams with No History of Antimicrobial Inputs.

A growing body of evidence suggests that contaminated environments may harbor a greater proportion of antibiotic-resistant microorganisms than unpolluted reference sites. Here, we report the screening of 427 Escherichia coli strains isolated from 11 locations on nine streams draining the US Department of Energy's Savannah River Site against a panel of five antibiotics. Streams were chosen to capture a wide range of watersheds from minimally disturbed to highly impacted. Overall, higher levels of resistance were found in waterborne E. coli that also generally exhibited low spatial variability. However, 3 of 11 locations also demonstrated elevated resistance levels in sediments. Two of these occurred in highly disturbed tributaries with no obvious sources of antimicrobials. To further investigate these patterns, we screened a subset of isolates obtained from three streams against 23 antibiotics or antibiotic combinations. A large proportion of these isolates (>40 %) demonstrated resistance to 10 or more antimicrobials, suggesting that environmental multi-antibiotic resistance may be prevalent in this bacterial commensal. Only 4 of 87 viable isolates were tested susceptible to all 23 antibiotics and combinations. Among these multi-antibiotic-resistant isolates, several demonstrated resistance to all structural classes of antimicrobial agents tested, including frontline antibiotics such as gatifloxacin and ciprofloxacin.

Demographic differences in sport performers' experiences of organizational stressors.

Organizational stressors are particularly prevalent across sport performers' experiences and can influence their performance, health, and well-being. Research has been conducted to identify which organizational stressors are encountered by sport performers, but little is known about how these experiences vary from athlete to athlete. The purpose of this study was to examine if the frequency, intensity, and duration of the organizational stressors that sport performers encounter vary as a function of gender, sport type, and performance level. Participants (n = 1277) completed the Organizational Stressor Indicator for Sport Performers (OSI-SP; Arnold et al., 2013), and the resultant data were analyzed using multivariate analyses of covariance. The findings show that demographic differences are apparent in the dimensions of the goals and development, logistics and operations, team and culture, coaching, and selection organizational stressors that sport performers encounter. More specifically, significant differences were found between males and females, between team and individual-based performers, and between performers competing at national or international, regional or university, and county or club levels. These findings have important implications for theory and research on organizational stress, and for the development of stress management interventions with sport performers.

Effect of combining tramadol and morphine in adult surgical patients: a systematic review and meta-analysis of randomized trials.

The role for tramadol in multimodal postsurgical analgesic strategies remains unclear. We undertook a systematic review to evaluate the utility of combining tramadol with morphine after surgery. We searched the MEDLINE, EMBASE, LILAC, Cochrane, and Clinical Trial Register databases for randomized, controlled studies comparing tramadol with placebo or active control in patients undergoing surgery. Fourteen studies (713 patients) were included. There was a limited but significant postoperative morphine-sparing effect, with a weighted mean difference (WMD) of -6.9 (95% confidence interval -11.3 to -2.5) mg. This effect was not associated with a decrease in morphine-related adverse effects. No difference in the incidence of nausea, vomiting, sedation, or shivering was observed. There was no decrease in pain intensity at 24 h; the WMD was -0.9 (-7.2; 5.2) on a 100 mm visual analogue scale at 24 h. We found no significant clinical benefit from the combination of i.v. tramadol and morphine after surgery.

Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis.

BACKGROUND: Opioids can increase sensitivity to noxious stimuli and cause opioid-induced hyperalgesia. We performed a systematic review to evaluate the clinical consequences of intra-operative doses of opioid. METHODS: We identified randomized controlled trials which compared intra-operative opioid to lower doses or placebo in adult patients undergoing surgery from MEDLINE, EMBASE, LILAC, Cochrane, and hand searches of trial registries. We pooled data of postoperative pain intensity, morphine consumption, incidence of opioid-related side-effects, primary and secondary hyperalgesia. For dichotomous outcomes relative risks [95% confidence intervals (CIs)] and for continuous outcomes mean differences (MDs) or standardized mean difference (SMD; 95% CI) were calculated. RESULTS: Twenty-seven studies involving 1494 patients were included in the analysis. Patients treated with high intra-operative doses of opioid reported higher postoperative pain intensity than the reference groups (MD: 9.4 cm; 95% CI: 4.4, 14.5) at 1 h, (MD: 7.1 cm; 95% CI: 2.8, 11.3) at 4 h, and (MD: 3 cm; 95% CI: 0.4, 5.6) at 24 h on a 100 cm visual analogue scale. They also showed higher postoperative morphine use after 24 h (SMD: 0.7; 95% CI: 0.37, 1.02). There was no difference in the incidences of nausea, vomiting, and drowsiness. These results were mainly associated with the use of remifentanil. The impact of other opioids is less clear because of limited data. DISCUSSION: This review suggests that high intra-operative doses of remifentanil are associated with small but significant increases in acute pain after surgery.

The analgesic efficiency of combined pregabalin and ketamine for total hip arthroplasty: a randomised, double-blind, controlled study.

Ketamine and pregabalin each provide postoperative analgesia, although the combination has yet to be evaluated. One hundred and forty-two patients undergoing total hip arthroplasty were randomly assigned to receive ketamine alone, pregabalin alone, ketamine and pregabalin combined, or placebo. Pain scores at rest and on movement, morphine consumption, side-effects, pressure pain thresholds and secondary hyperalgesia were evaluated. Mean (SD) total 48-h morphine use was reduced in patients given ketamine alone (52 (22) mg) and pregabalin alone (44 (20) mg) compared with placebo (77 (36) mg) p < 0.001. Morphine use was further reduced in patients given both ketamine and pregabalin (38 (19) mg) with an interaction between ketamine and pregabalin (ANOVA factorial; p = 0.028). Secondary hyperalgesia was reduced by ketamine. There were no differences between groups in pain scores after surgery, pressure pain thresholds or side-effects. The combination of pregabalin and ketamine has a small, beneficial clinical effect.

The effect of high-level chlorine carcass drench on the recovery of Salmonella and enumeration of bacteria from broiler carcasses.

A study was conducted to determine the bacteriological effect of exposing processed broiler carcasses to a high (10-fold increase) concentration chlorinated drench. During each of 6 replicate trials, eviscerated prechill carcasses were obtained from a commercial processing plant and chlorine-treated carcasses were subjected to a 1-min drench in 500 mL of a 500 mg/kg chlorine solution (sodium hypochlorite). Water-drenched carcasses were treated the same way except water was used in place of chlorinated water drench. Control carcasses were not drenched. All carcasses were then subjected to a whole carcass rinse (WCR) in 450 mL of buffered peptone water, from which 50 mL of the rinsate was removed for enumeration of total aerobic bacteria (APC), Escherichia coli, and total coliforms (TC). The entire carcass was then incubated 24 h at 37°C (whole carcass enrichment, WCE) for recovery of Salmonella. Levels of bacteria recovered from WCR were lower by 0.6 log10 cfu/mL for APC, 0.8 for E. coli, and 0.9 for TC when carcasses were drenched with water compared with undrenched control levels. Similarly, the levels of bacteria recovered from WCR were further lower by 1.0 log10 cfu/mL for APC, 0.5 for E. coli, and 0.5 for TC, when carcasses were drenched with 500 mg/kg of chlorine compared with water. However, there was no significant difference (P > 0.05) in prevalence of Salmonella among the treatments (29% positive for control, 26% positive for water, 38% positive for chlorinated). These results indicate that drenching eviscerated carcasses with water or chlorinated water at 500 mg/kg significantly, but minimally, reduces the numbers of APC, E. coli, and TC bacteria recovered compared with undrenched carcasses. However, neither drenching carcasses with water or high chlorine had an effect on the prevalence of Salmonella that remain with the carcass as determined by WCE. The results of this study confirms the importance of maintaining and replenishing free chlorine for optimal antimicrobial activity, because chlorine at 500 mg/kg was rapidly used within 1 min of exposure to the carcass to <10 mg/kg.

Fluid-structure interactions of peripheral arteries using a coupled in silico and in vitro approach.

Vascular compliance is considered both a cause and a consequence of cardiovascular disease and a significant factor in the mid- and long-term patency of vascular grafts. However, the biomechanical effects of localised changes in compliance cannot be satisfactorily studied with the available medical imaging technologies or surgical simulation materials. To address this unmet need, we developed a coupled silico-vitro platform which allows for the validation of numerical fluid-structure interaction results as a numerical model and physical prototype. This numerical one-way and two-way fluid-structure interaction study is based on a three-dimensional computer model of an idealised femoral artery which is validated against patient measurements derived from the literature. The numerical results are then compared with experimental values collected from compliant arterial phantoms via direct pressurisation and ring tensile testing. Phantoms within a compliance range of 1.4-68.0%/100 mmHg were fabricated via additive manufacturing and silicone casting, then mechanically characterised via ring tensile testing and optical analysis under direct pressurisation with moderately statistically significant differences in measured compliance ranging between 10 and 20% for the two methods. One-way fluid-structure interaction coupling underestimated arterial wall compliance by up to 14.7% compared with two-way coupled models. Overall, Solaris™ (Smooth-On) matched the compliance range of the numerical and in vivo patient models most closely out of the tested silicone materials. Our approach is promising for vascular applications where mechanical compliance is especially important, such as the study of diseases which commonly affect arterial wall stiffness, such as atherosclerosis, and the model-based design, surgical training, and optimisation of vascular prostheses.

Identification of novel coding mutation in C1qA gene in an African-American pedigree with lupus and C1q deficiency.

OBJECTIVES: Homozygous C1q deficiency is an extremely rare condition and strongly associated with systemic lupus erythematosus. To assess and characterize C1q deficiency in an African-American lupus pedigree, C1q genomic region was evaluated in the lupus cases and family members. METHODS: Genomic DNA from patient was obtained and C1q A, B and C gene cluster was sequenced using next generation sequencing method. The identified mutation was further confirmed by direct Sanger sequencing method in the patient and all blood relatives. C1q levels in serum were measured using sandwich ELISA method. RESULTS: In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid methionine to arginine at position 1. The Met1Arg mutation prevents protein translation (Met1Arg). Mutation analyses of the patient's family members also revealed the Met1Arg homozygote mutation in her deceased brother who also had lupus with absence of total complement activity consistent with a recessive pattern of inheritance. CONCLUSION: The identification of new mutation in C1qA gene that disrupts the start codon (ATG to AGG (Met1Arg)) has not been reported previously and it expands the knowledge and importance of the C1q gene in the pathogenesis of lupus especially in the high-risk African-American population.

A conceptual framework of organizational stressors in sport performers.

In the study reported here, 12 sport performers (six elite and six non-elite) were interviewed with regard to organizational-related issues they had experienced in preparation for competition. Grounded theory procedures facilitated the development of a conceptual framework of organizational stressors consisting of five general dimensions: factors intrinsic to the sport, roles in the sport organization, sport relationships and interpersonal demands, athletic career and performance development issues, and organizational structure and climate of the sport. The data indicate that the stressors were encountered proportionately more by elite performers (#EPOS=315) than non-elite performers (#NPOS=228) with some demands being in common and some unique to each group. The results are discussed in relation to previous research and regarding their implications for professional practice.

Caffeine ingestion and antigen-stimulated human lymphocyte activation after prolonged cycling.

This study investigated the effect of caffeine ingestion on antigen-stimulated T- (CD4(+) and CD8(+) ) and natural killer (NK)- (CD3(-) CD56(+) ) cell activation after prolonged, strenuous cycling. In a randomized cross-over design, nine male endurance cyclists (age: 22 ± 3 years, VO(2peak) : 62 ± 4 mL/kg/min, mean ± SD) cycled for 90 min at 70% VO(2peak) 60 min after ingesting 6 mg/kg body mass of caffeine (CAF) or placebo (PLA). Venous blood samples were obtained before supplementation, pre-exercise, immediately post-exercise and 1 h post-exercise. Whole blood was stimulated with Pediacel (five in one) vaccine. At 1 h post-exercise the number of antigen-stimulated CD4(+) cells expressing CD69 decreased on CAF compared with PLA [15 (17) × 10(6) vs 23 (22) × 10(6) cells/L, P<0.05]. In addition, the geometric mean fluorescence intensity (GMFI) of CD69 expression on antigen-stimulated CD8(+) cells decreased on CAF compared with PLA 1 h post-exercise [78 (10)% vs 102 (24)%, P<0.05]. At the same time-point GMFI of CD69 expression on antigen-stimulated CD3(-) CD56(+) cells was increased on CAF compared with PLA [103 (9)% vs 87 (8)%, P<0.05]. These findings suggest that caffeine reduces antigen-stimulated CD69 expression on T cells while at the same time increases NK-cell activation 1 h after intensive cycling.

A 3D image-based modelling approach for understanding spatiotemporal processes in phosphorus fertiliser dissolution, soil buffering and uptake by plant roots.

Phosphorus (P) is a key yield-limiting nutrient for crops, but the main source of P fertiliser is finite. Therefore, efficient fertilisation is crucial. Optimal P application requires understanding of the dynamic processes affecting P availability to plants, including fertiliser dissolution rate and soil buffer power. However, standard soil testing methods sample at fixed time points, preventing a mechanistic understanding of P uptake variability. We used image-based modelling to investigate the effects of fertiliser dissolution rate and soil buffer power on P uptake by wheat roots imaged using X-ray CT. We modelled uptake based on 1-day, 1-week, and 14-week dissolution of a fixed quantity of total P for two common soil buffer powers. We found rapid fertiliser dissolution increased short-term root uptake, but total uptake from 1-week matched 1-day dissolution. We quantified the large effects root system architecture had on P uptake, finding that there were trade-offs between total P uptake and uptake per unit root length, representing a carbon investment/phosphorus uptake balance. These results provide a starting point for predictive modelling of uptake from different P fertilisers in different soils. With the addition of further X-ray CT image datasets and a wider range of conditions, our simulation approach could be developed further for rapid trialling of fertiliser-soil combinations to inform field-scale trials or management.

Combining experimental and computational techniques to understand and improve dry powder inhalers.

INTRODUCTION: Dry Powder Inhalers (DPIs) continue to be developed to deliver an expanding range of drugs to treat an ever-increasing range of medical conditions; with each drug and device combination needing a specifically designed inhaler. Fast regulatory approval is essential to be first to market, ensuring commercial profitability. AREAS COVERED: In vitro deposition, particle image velocimetry, and computational modeling using the physiological geometry and representative anatomy can be combined to give complementary information to determine the suitability of a proposed inhaler design and to optimize its formulation performance. In combination, they allow the entire range of questions to be addressed cost-effectively and rapidly. EXPERT OPINION: Experimental techniques and computational methods are improving rapidly, but each needs a skilled user to maximize results obtained from these techniques. Multidisciplinary teams are therefore key to making optimal use of these methods and such qualified teams can provide enormous benefits to pharmaceutical companies to improve device efficacy and thus time to market. There is already a move to integrate the benefits of Industry 4.0 into inhaler design and usage, a trend that will accelerate.

Quantifying citrate-enhanced phosphate root uptake using microdialysis.

AIMS: Organic acid exudation by plant roots is thought to promote phosphate (P) solubilisation and bioavailability in soils with poorly available nutrients. Here we describe a new combined experimental (microdialysis) and modelling approach to quantify citrate-enhanced P desorption and its importance for root P uptake. METHODS: To mimic the rhizosphere, microdialysis probes were placed in soil and perfused with citrate solutions (0.1, 1.0 and 10 mM) and the amount of P recovered from soil used to quantify rhizosphere P availability. Parameters in a mathematical model describing probe P uptake, citrate exudation, P movement and citrate-enhanced desorption were fit to the experimental data. These parameters were used in a model of a root which exuded citrate and absorbed P. The importance of soil citrate-P mobilisation for root P uptake was then quantified using this model. RESULTS: A plant needs to exude citrate at a rate of 0.73 µmol cm-1 of root h-1 to see a significant increase in P absorption. Microdialysis probes with citrate in the perfusate were shown to absorb similar quantities of P to an exuding root. CONCLUSION: A single root exuding citrate at a typical rate (4.3 × 10-5 µmol m-1 of root h-1) did not contribute significantly to P uptake. Microdialysis probes show promise for measuring rhizosphere processes when calibration experiments and mathematical modelling are used to decouple microdialysis and rhizosphere mechanisms.

Precipitation-optimised targeting of nitrogen fertilisers in a model maize cropping system.

Typically, half of the nitrogen (N) fertiliser applied to agricultural fields is lost to the wider environment. This inefficiency is driven by soil processes such as denitrification, volatilisation, surface run-off and leaching. Rainfall plays an important role in regulating these processes, ultimately governing when and where N fertiliser moves in soil and its susceptibility to gaseous loss. The interaction between rainfall, plant N uptake and N losses, however, remains poorly understood. In this study we use numerical modelling to predict the optimal N fertilisation strategy with respect to rainfall patterns and offer mechanistic explanations to the resultant differences in optimal times of fertiliser application. We developed a modelling framework that describes water and N transport in soil over a growing season and assesses nitrogen use efficiency (NUE) of split fertilisations within the context of different rainfall patterns. We used ninety rainfall patterns to determine their impact on optimal N fertilisation times. We considered the effects of root growth, root N uptake, microbial transformation of N and the effect of soil water saturation and flow on N movement in the soil profile. On average, we show that weather-optimised fertilisation strategies could improve crop N uptake by 20% compared to the mean uptake. In drier years, weather-optimising N applications improved the efficiency of crop N recovery by 35%. Further analysis shows that maximum plant N uptake is greatest under drier conditions due to reduced leaching, but it is harder to find the maximum due to low N mobility. The model could capture contrasting trends in NUE seen in previous arable cropping field trials. Furthermore, the model predicted that the variability in NUE seen in the field could be associated with precipitation-driven differences in N leaching and mobility. In conclusion, our results show that NUE in cropping systems could be significantly enhanced by synchronising fertiliser timings with both crop N demand and local weather patterns.

Verification and Validation of Digital Pathology (Whole Slide Imaging) for Primary Histopathological Diagnosis: All Wales Experience.

AIMS: The study is aimed to verify Aperio AT2 scanner for reporting on the digital pathology platform (DP) and to validate the cohort of pathologists in the interpretation of DP for routine diagnostic histopathological services in Wales, United Kingdom. MATERIALS METHODS AND RESULTS: This was a large multicenter study involving seven hospitals across Wales and unique with 22 (largest number) pathologists participating. 7491 slides from 3001 cases were scanned on Leica Aperio AT2 scanner and reported on digital workstations with Leica software of e-slide manager. A senior pathology fellow compared DP reports with authorized reports on glass slide (GS). A panel of expert pathologists reviewed the discrepant cases under multiheader microscope to establish ground truth. 2745 out of 3001 (91%) cases showed complete concordance between DP and GS reports. Two hundred and fifty-six cases showed discrepancies in diagnosis, of which 170 (5.6%) were deemed of no clinical significance by the review panel. There were 86 (2.9%) clinically significant discrepancies in the diagnosis between DP and GS. The concordance was raised to 97.1% after discounting clinically insignificant discrepancies. Ground truth lay with DP in 28 out of 86 clinically significant discrepancies and with GS in 58 cases. Sensitivity of DP was 98.07% (confidence interval [CI] 97.57-98.56%); for GS was 99.07% (CI 98.72-99.41%). CONCLUSIONS: We concluded that Leica Aperio AT2 scanner produces adequate quality of images for routine histopathologic diagnosis. Pathologists were able to diagnose in DP with good concordance as with GS. STRENGTHS AND LIMITATIONS OF THIS STUDY: Strengths of this study - This was a prospective blind study. Different pathologists reported digital and glass arms at different times giving an ambience of real-time reporting. There was standardized use of software and hardware across Wales. A strong managerial support from efficiency through the technology group was a key factor for the implementation of the study. LIMITATIONS: This study did not include Cytopathology and in situ hybridization slides. Difficulty in achieving surgical pathology practise standardization across the whole country contributed to intra-observer variations.