Interkingdom interactions on the denture surface: implications for oral hygiene

Background: Evidence to support the role of Candida species in oral disease is limited. Often considered a commensal, this opportunistic yeast has been shown to play a role in denture related disease, though whether it is an active participant or innocent bystander remains to be determined. This study sought to understand the role of Candida species alongside the bacterial microbiome in a denture patient cohort, exploring how the microbiology of the denture was affected by oral hygiene practices. Materials and methods: In vitro denture cleansing studies were performed on a complex 9-species interkingdom denture biofilm model, with quantitative assessment of retained bacterial and fungal viable bioburdens. Patient hygiene measures were also collected from 131 patients, including OHIP, frequency of denture cleansing, oral hygiene measure and patient demographics. The bacterial microbiome was analysed from each patient, alongside quantitative PCR assessment of ITS (fungal) and 16S (bacterial) bioburden from denture, mucosa and intact dentition. Results: It was shown that following in vitro denture cleansing C. albicans were unresponsive to treatment, whereas bacterial biofilms could repopulate 100-fold, but were susceptible to subsequent treatment. Within the patient cohort, oral hygiene did not impact candidal or bacterial composition, nor diversity. The levels of Candida did not significantly influence the bacterial microbiome, though an observed gradient was suggestive of a microbial composition change in response to Candida load, indicating interkingdom interaction rather than an oral hygiene effect. Indeed, correlation analysis was able to show significant correlations between Candida species and key genera (Lactobacillus, Scardovia, Fusobacterium). Conclusions: Overall, this study has shown that the denture microbiome/mycobiome is relatively resilient to oral hygiene challenges, but that Candida species have potential interactions with key oral genera. These interactions may have a bearing on shaping community structure and a shift from health to disease when the opportunity arises

Fractional flow reserve vs. angiography in guiding management to optimize outcomes in non-ST-segment elevation myocardial infarction: the British Heart Foundation FAMOUS-NSTEMI randomized trial

Aim: We assessed the management and outcomes of non-ST segment elevation myocardial infarction (NSTEMI) patients randomly assigned to fractional flow reserve (FFR)-guided management or angiography-guided standard care. Methods and results: We conducted a prospective, multicentre, parallel group, 1 : 1 randomized, controlled trial in 350 NSTEMI patients with ≥ coronary stenosis ≥30% of the lumen diameter assessed visually (threshold for FFR measurement) (NCT01764334). Enrolment took place in six UK hospitals from October 2011 to May 2013. Fractional flow reserve was disclosed to the operator in the FFR-guided group (n = 176). Fractional flow reserve was measured but not disclosed in the angiography-guided group (n = 174). Fractional flow reserve ≤0.80 was an indication for revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). The median (IQR) time from the index episode of myocardial ischaemia to angiography was 3 (2, 5) days. For the primary outcome, the proportion of patients treated initially by medical therapy was higher in the FFR-guided group than in the angiography-guided group [40 (22.7%) vs. 23 (13.2%), difference 95% (95% CI: 1.4%, 17.7%), P = 0.022]. Fractional flow reserve disclosure resulted in a change in treatment between medical therapy, PCI or CABG in 38 (21.6%) patients. At 12 months, revascularization remained lower in the FFR-guided group [79.0 vs. 86.8%, difference 7.8% (−0.2%, 15.8%), P = 0.054]. There were no statistically significant differences in health outcomes and quality of life between the groups. Conclusion: In NSTEMI patients, angiography-guided management was associated with higher rates of coronary revascularization compared with FFR-guided management. A larger trial is necessary to assess health outcomes and cost-effectiveness

Mechanisms of Orthopnoea in Patients with Advanced COPD.

Many patients with severe chronic obstructive pulmonary disease (COPD) report unpleasant respiratory sensation at rest, further amplified by adoption of supine position (orthopnoea). The mechanisms of this acute symptomatic deterioration are poorly understood.16 patients with advanced COPD and history of orthopnoea and 16 age- and sex-matched healthy controls (CTRL) underwent pulmonary function tests and detailed sensory-mechanical measurements including inspiratory neural drive (IND, diaphragm electromyography), oesophageal and gastric pressures in sitting and supine positions.Patients had severe airflow obstruction (FEV1: 40±18%predicted) and lung hyperinflation. Regardless of the position, patients had lower inspiratory capacity (IC) and higher IND for a given tidal volume (i.e. greater neuromechanical dissociation (NMD)), higher intensity of breathing discomfort, minute ventilation (⩒E) and breathing frequency (Fb) compared with CTRL (all p<0.05). In supine position in CTRL (versus sitting erect): IC increased (by 0.48L) with a small drop in ⩒E mainly due to reduced Fb (all p<0.05). By contrast, patients' IC remained unaltered, but dynamic lung compliance decreased (p<0.05) in the supine position. Breathing discomfort, inspiratory work of breathing, inspiratory effort, IND, NMD and neuro-ventilatory uncoupling all increased in COPD in the supine position (p<0.05), but not in CTRL. Orthopnoea was associated with acute changes in IND (r=0.65, p=0.01), neuro-ventilatory uncoupling (r=0.76, p=0.001) and NMD (r=0.73, p=0.002).In COPD, onset of orthopnoea coincided with an abrupt increase in elastic loading of the inspiratory muscles in recumbency in association with increased IND and greater neuromechanical dissociation of the respiratory system

Vegetation management with fire modifies peatland soil thermal regime

Vegetation removal with fire can alter the thermal regime of the land surface, leading to significant changes in biogeochemistry (e.g. carbon cycling) and soil hydrology. In the UK, large expanses of carbon-rich upland environments are managed to encourage increased abundance of red grouse (Lagopus lagopus scotica) by rotational burning of shrub vegetation. To date, though, there has not been any consideration of whether prescribed vegetation burning on peatlands modifies the thermal regime of the soil mass in the years after fire. In this study thermal regime was monitored across 12 burned peatland soil plots over an 18-month period, with the aim of (i) quantifying thermal dynamics between burned plots of different ages (from <2 to 15+years post burning), and (ii) developing statistical models to determine the magnitude of thermal change caused by vegetation management. Compared to plots burned 15+years previously, plots recently burned (<2-4 years) showed higher mean, maximum and range of soil temperatures, and lower minima. Statistical models (generalised least square regression) were developed to predict daily mean and maximum soil temperature in plots burned 15+years prior to the study. These models were then applied to predict temperatures of plots burned 2, 4 and 7 years previously, with significant deviations from predicted temperatures illustrating the magnitude of burn management effects. Temperatures measured in soil plots burned <2 years previously showed significant statistical disturbances from model predictions, reaching+6.2°C for daily mean temperatures and+19.6°C for daily maxima. Soil temperatures in plots burnt 7 years previously were most similar to plots burned 15+years ago indicating the potential for soil temperatures to recover as vegetation regrows. Our findings that prescribed peatland vegetation burning alters soil thermal regime should provide an impetus for further research to understand the consequences of thermal regime change for carbon processing and release, and hydrological processes, in these peatlands

Critical Assessment of Analytical Methods for the Harmonized and Cost-Efficient Analysis of Microplastics

Microplastics are of major concerns for society and is currently in the focus of legislators and administrations. A small number of measures to reduce or remove primary sources of microplastics to the environment are currently coming into effect. At the moment, they have not yet tackled important topics such as food safety. However, recent developments such as the 2018 bill in California are requesting the analysis of microplastics in drinking water by standardized operational protocols. Administrations and analytical labs are facing an emerging field of methods for sampling, extraction, and analysis of microplastics, which complicate the establishment of standardized operational protocols. In this review, the state of the currently applied identification and quantification tools for microplastics are evaluated providing a harmonized guideline for future standardized operational protocols to cover these types of bills. The main focus is on the naked eye detection, general optical microscopy, the application of dye staining, flow cytometry, Fourier transform infrared spectroscopy (FT-Ir) and microscopy, Raman spectroscopy and microscopy, thermal degradation by pyrolysis–gas chromatography–mass spectrometry (py-GC-MS) as well as thermo-extraction and desorption gas chromatography–mass spectrometry (TED-GC-MS). Additional techniques are highlighted as well as the combined application of the analytical techniques suggested. An outlook is given on the emerging aspect of nanoplastic analysis. In all cases, the methods were screened for limitations, field work abilities and, if possible, estimated costs and summarized into a recommendation for a workflow covering the demands of society, legislation, and administration in cost efficient but still detailed manner

End-stage heart failure in congenitally corrected transposition of the great arteries:a multicentre study

BACKGROUND AND AIMS: For patients with congenitally corrected transposition of the great arteries (ccTGA), factors associated with progression to end-stage congestive heart failure (CHF) remain largely unclear. METHODS: This multicentre, retrospective cohort study included adults with ccTGA seen at a congenital heart disease centre. Clinical data from initial and most recent visits were obtained. The composite primary outcome was mechanical circulatory support, heart transplantation, or death. RESULTS: From 558 patients (48% female, age at first visit 36 ± 14.2 years, median follow-up 8.7 years), the event rate of the primary outcome was 15.4 per 1000 person-years (11 mechanical circulatory support implantations, 12 transplantations, and 52 deaths). Patients experiencing the primary outcome were older and more likely to have a history of atrial arrhythmia. The primary outcome was highest in those with both moderate/severe right ventricular (RV) dysfunction and tricuspid regurgitation (n = 110, 31 events) and uncommon in those with mild/less RV dysfunction and tricuspid regurgitation (n = 181, 13 events, P &lt; .001). Outcomes were not different based on anatomic complexity and history of tricuspid valve surgery or of subpulmonic obstruction. New CHF admission or ventricular arrhythmia was associated with the primary outcome. Individuals who underwent childhood surgery had more adverse outcomes than age- and sex-matched controls. Multivariable Cox regression analysis identified older age, prior CHF admission, and severe RV dysfunction as independent predictors for the primary outcome. CONCLUSIONS: Patients with ccTGA have variable deterioration to end-stage heart failure or death over time, commonly between their fifth and sixth decades. Predictors include arrhythmic and CHF events and severe RV dysfunction but not anatomy or need for tricuspid valve surgery.</p

Exposure to secondhand and thirdhand smoke in private vehicles: Measurements in air and dust samples

Background: This study aimed to estimate airborne nicotine concentrations and nicotine, cotinine, and tobaccospecific nitrosamines (TSNAs) in settled dust from private cars in Spain and the UK. Methods: We measured vapor-phase nicotine concentrations in a convenience sample of 45 private cars from Spain (N = 30) and the UK (N = 15) in 2017-2018. We recruited non-smoking drivers (n = 20), smoking drivers who do not smoke inside the car (n = 15), and smoking drivers who smoke inside (n = 10). Nicotine, cotinine, and three TSNAs (NNK, NNN, NNA) were also measured in settled dust in a random subsample (n = 20). We computed medians and interquartile ranges (IQR) of secondhand smoke (SHS) and thirdhand smoke (THS) compounds according to the drivers' profile. Results: 24-h samples yielded median airborne nicotine concentrations below the limit of quantification (LOQ) (IQR

A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points

SU5416 (Z-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone; semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR)2. A Phase I dose escalation study was performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic assessment tool. In all, 27 patients were recruited. SU5416 was administered twice weekly by fixed rate intravenous infusion. Patients were treated in sequential cohorts of three patients at 48, 65, 85 110 and 145 mg m−2. A further dose level of 190 mg m−2 after a 2-week lead in period at a lower dose was completed; thereafter, the cohort at 145 mg m−2 was expanded. SU5416 showed linear pharmacokinetics to 145 mg m−2 with a large volume of distribution and rapid clearance. A significant degree of interpatient variability was seen. SU5416 was well tolerated, by definition a maximum-tolerated dose was not defined. No reproducible changes were seen in DCE-MRI end points. Serial assessments of VEGF in a cohort of patients treated at 145 mg m−2 did not show a statistically significant treatment-related change. Parallel assessments of the impact of SU5416 on coagulation profiles in six patients showed a transient effect within the fibrinolytic pathway. Clinical experience showed that patients who had breaks of therapy longer than a week could not have treatment reinitiated at a dose of 190 mg m−2 without unacceptable toxicity. The 145 mg m−2 dose level is thus the recommended dose for future study

Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis.

IMPORTANCE: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. OBJECTIVE: To identify novel genetic loci and pathways associated with AS. DESIGN, SETTING, AND PARTICIPANTS: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. EXPOSURES: Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. MAIN OUTCOMES AND MEASURES: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. RESULTS: The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]). CONCLUSIONS AND RELEVANCE: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target