A multinational, drug utilization study to investigate the use of dexmedetomidine (Dexdor®) in clinical practice in the EU.

AIMS: Dexmedetomidine (dexdor®) is approved in the European Union (EU) for sedation of adults in the intensive care unit (ICU). The present observational, retrospective study was requested by the European Medicines Agency to investigate dexmedetomidine use in clinical practice, with a particular focus on off-label use, including the paediatric population. METHODS: Study countries and sites were chosen from those with highest dexmedetomidine use, based on sales. Site selection (blind) was conducted by a multispecialist, independent group. Anonymized data on demographics, treatment indication, dexmedetomidine dosing, concomitant medications and treatment effectiveness were collected retrospectively from records of all dexmedetomidine-treated patients at the site during the enrolment period. Informed consent was waived, to avoid influencing the prescribing of dexmedetomidine. Recruitment was completed within 18 months of first site initiation. RESULTS: Data from 2000 patients were collected from 16 hospitals in four EU countries (Finland 750, Poland 505, Germany 470, Austria 275). The median age was 62 years, with more males (70.2%) than females. Dexmedetomidine was primarily used in the adult ICU (86.0%) for ICU sedation (78.6%) and mostly dosed according the product label. The intended sedative effect was obtained in 84.9% of administrations. Paediatric use (5.9% of patients, mostly in Austria and Finland) occurred mainly in the adult or paediatric ICU (75.6%) for sedation (67.2%). CONCLUSIONS: Overall, most patients were treated with dexmedetomidine according to the product labelling. Use in children was limited but significant and similar in scope to that in adults. Administrations not fully according to the product labelling usually occurred in an ICU environment and reflected extensively investigated clinical uses of dexmedetomidine.

Antibiotic Guardians: the Role of the Dental Profession.

The increasing emergence of antibiotic resistance is a major international public health problem. As a consequence, it is essential that steps are taken to conserve the effectiveness of existing antimicrobial agents. Consumption of antibiotics is the prime contributor to the development of resistance. General dental practitioners write almost 1 out of 10 prescriptions for antibiotics in primary care within the UK and therefore the prudent prescribing of antibiotics in dentistry has never been more vital. This paper outlines the impact of antimicrobial resistance on modern healthcare, describes the current use of antibiotics in general dental practice, and recommends pragmatic ways in which dental practitioners can evaluate and optimize their prescribing. Clinical relevance: Dental professionals have a responsibility to both their patients and the wider community to prescribe antibiotics appropriately.

Role of bacterial lipopolysaccharide in enhancing host immune response to Candida albicans.

Human infections involving yeast of the genus Candida often occur in the presence of bacteria, and, as such, it is important to understand how these bacteria influence innate host immunity towards Candida. Dectin-1 is a cell receptor of macrophages for Candida albicans recognition. The aim of this study was to examine dectin-1 expression by monocytes after stimulation with bacterial lipopolysaccharide (LPS), followed by heat-killed C. albicans (HKC). Freshly isolated human peripheral blood monocytes (PBMCs) and human monocytes cell line (THP-1) cells expressed low levels of dectin-1. Stimulation with LPS and GM-CSF/IL-4 was found to increase dectin-1 expression in both CD14(+) human PBMC and THP-1 cells. Enhanced dectin-1 expression resulted in increased phagocytosis of Candida. When THP-1 cells were challenged only with HKC, detectable levels of IL-23 were not evident. However, challenge by LPS followed by varying concentrations of HKC resulted in increased IL-23 expression by THP-1 cells in HKC dose-dependent manner. Increased expression of IL-17 by PBMC also occurred after stimulation with Candida and LPS. In conclusion, bacterial LPS induces an enhanced immune response to Candida by immune cells, and this occurs through increasing dectin-1 expression.

'Hubble-bubble leads to trouble'--waterpipe smoking and oral health.

UNLABELLED: Waterpipes are used to smoke tobacco by more than 100 million people worldwide. Use is not restricted to any single racial, ethnic, or cultural group, and dentists are almost certain to encounter waterpipe users amongst their patients. This article describes what the practice involves and seeks to inform members of the dental team of the significantly detrimental impacts of waterpipe smoking on both general and oral health and how'hubble-bubble really can lead to trouble'. Advising patients on ceasing waterpipe use is also discussed. CLINICAL RELEVANCE: This paper explains what smoking a waterpipe involves, the associated misconceptions of safety amongst users and the dangers to health.

Oral ulceration (Part 1).

Ulceration is probably the oral mucosal condition seen most frequently by general dental practitioners. It is almost always painful and therefore sufferers are prompt to seek advice. An important exception to this generalisation is the occurrence of oral squamous cell carcinoma, which is often painless in its early stages. Definitive diagnosis, which requires mucosal biopsy, is mandatory for any persistent area of oral ulceration.

Education of healthcare professionals and the public.

In the winter of 2007-08 a new public-facing antimicrobial campaign was agreed by the Advisory Committee on Antimicrobial Resistance and Healthcare-Associated Infection (ARHAI) Education sub-Group (later divided into subgroups for professional and public education): it comprised posters with a positive message on how the public could help themselves when they had a cold. However, the poster campaign, used in isolation in England, did not improve antibiotic use; therefore, the Public Education sub-Group took forward educational approaches to change the behaviour of the public and health professionals. Professionals have been encouraged to give patients clear information about the likely duration of symptoms, self-care, and benefits and harms of antibiotics, reinforcing the public poster campaigns in surgeries, hospitals and pharmacies. Since 2008, campaigns have been launched in England to coincide with European Antibiotic Awareness Day (EAAD) on 18 November, using Department of Health and EAAD materials. Professional education has been facilitated by the 2008 National Institute for Health and Clinical Excellence respiratory tract infection delayed prescribing guidance for general practitioners. A toolkit of materials for medicines management teams, to facilitate good antimicrobial stewardship in primary care (ASPIC), is being taken forward by the Public Education sub-Group and professional societies. After advice from ARHAI, in 2009 the General Medical Council requested that all postgraduate deans and Royal Colleges ensure infection prevention and control and antimicrobial prescribing become standard practice implemented in all clinical settings, and that they are emphasized strongly in undergraduate and postgraduate medical training. ARHAI has also taken a keen interest in reviewing, advising and leading on a number of European Union initiatives dealing with professional education.

Systemic interventions for recurrent aphthous stomatitis (mouth ulcers).

BACKGROUND: Recurrent aphthous stomatitis (RAS) is the most frequent form of oral ulceration, characterised by recurrent oral mucosal ulceration in an otherwise healthy individual. At its worst RAS can cause significant difficulties in eating and drinking. Treatment is primarily aimed at pain relief and the promotion of healing to reduce the duration of the disease or reduce the rate of recurrence. A variety of topical and systemic therapies have been utilised. OBJECTIVES: To determine the clinical effect of systemic interventions in the reduction of pain associated with RAS, a reduction in episode duration or frequency. SEARCH METHODS: We undertook electronic searches of: Cochrane Oral Health Group and PaPaS Trials Registers (to 6 June 2012); CENTRAL via The Cochrane Library (to Issue 4, 2012); MEDLINE via OVID (1950 to 6 June 2012); EMBASE via OVID (1980 to 6 June 2012); CINAHL via EBSCO (1980 to 6 June 2012); and AMED via PubMed (1950 to 6 June 2012). We searched reference lists from relevant articles and contacted the authors of eligible trials to identify further trials and obtain additional information. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in which the primary outcome measures assess a reduction of pain associated with RAS, a reduction in episode duration or a reduction in episode frequency. Trials were not restricted by outcome alone. We also included RCTs of a cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data in duplicate. We contacted trial authors for details of randomisation, blindness and withdrawals. We carried out risk of bias assessment on six domains. We followed The Cochrane Collaboration statistical guidelines and risk ratio (RR) values were to be calculated using fixed-effect models (if two or three trials in each meta-analysis) or random-effects models (if four or more trials in each meta-analysis). MAIN RESULTS: A total of 25 trials were included, 22 of which were placebo controlled and eight made head-to-head comparisons (five trials had more than two treatment arms). Twenty-one different interventions were assessed. The interventions were grouped into two categories: immunomodulatory/anti-inflammatory and uncertain. Only one study was assessed as being at low risk of bias. There was insufficient evidence to support or refute the use of any intervention. AUTHORS' CONCLUSIONS: No single treatment was found to be effective and therefore the results remain inconclusive in regard to the best systemic intervention for RAS. This is likely to reflect the poor methodological rigour of trials, and lack of studies for certain drugs, rather than the true effect of the intervention. It is also recognised that in clinical practice, individual drugs appear to work for individual patients and so the interventions are likely to be complex in nature. In addition, it is acknowledged that systemic interventions are often reserved for those patients who have been unresponsive to topical treatments, and therefore may represent a select group of patients.

The role of the IL-12 cytokine family in directing T-cell responses in oral candidosis.

Candida albicans is an opportunistic fungal pathogen that normally exists as a harmless commensal in humans. In instances where host debilitation occurs, Candida can cause a range of clinical infections, and whilst these are primarily superficial, effecting mucosal membranes, systemic infections can develop in severely immunocompromised individuals. The mechanism of host immunity during commensal carriage of C. albicans has been intensively studied. In this paper, we present the most recent information concerning host recognition of C. albicans leading to cytokine production and the subsequent T-cell responses generated in response to C. albicans. Particular focus is given to the role of the IL-12 cytokine family including IL-12, IL-23, IL-27, and IL-35, in host immunity to Candida. CD4(+) T-cells are considered crucial in the regulation of immunity and inflammation. In this regard, the role of Th1/2, helper cells, together with the recently identified Th17 and Treg cells in candidosis will be discussed. Understanding the detailed mechanisms that underlie host immunity to Candida not only will be of benefit in terms of the infections caused by this organism but could also be exploited in the development of therapeutic interventions for other diseases.

Beyond the p-value: Bayesian Statistics and Causation.

Statistical paradigms limit the perspective and tools social work researchers use to study the world and answer questions impacting people and policy. Currently, quantitative social work researchers overwhelmingly rely on the frequentist paradigm of statistics. This paper discusses foundational differences between the frequentist and Bayesian statistical paradigms, describes basic concepts of Bayesian analysis, compares Bayesian and frequentist statistical analysis for a sample social work problem, and introduces two types of causal analyses built on Bayesian statistical thinking: counterfactual causality, and causality based on work by computer scientist Judea Pearl. Implications for social work research are discussed.

Droplet Sizes Emitted from Demonstration Electric Toothbrushes.

The COVID-19 pandemic has drawn attention to microbial transmission risk via aerosols in dental practice. Demonstration electric toothbrushes are used intra-orally for education. The aim of this investigation was to measure the size of droplets emitted by the brush head of two demonstration oscillating-rotating electric toothbrushes. Measurement of droplet production and size was recorded in vitro using three methods: (1) Malvern Spraytec (LASER particle size measurement device with detectable particle size of 0.1-2500 µm) and brushes mounted on a 3D-printed, two-shell form-fit fixture with a supply of tap water; (2) a DustTrak aerosol measurement device and toothpaste slurry, with brushing simulated in the oral cavity of a phantom head; (3) high-speed visualization in a simulated-use situation in the oral cavity of a phantom head, with individual evaluation of tap water, water with detergent, 70% ethanol, glycerin and toothpaste slurry. Both brushes showed the size of emitted droplets was consistently between 200 and 1200 µm, categorized as splatter (dental aerosols are <50 µm diameter). No significant incremental aerosol-sized matter was detected during toothbrush operation. The high-speed video visualization confirmed only splatter-sized droplets during operation. These findings indicate that oscillating-rotating toothbrushes do not produce aerosol-sized particles during simulated use.

Macrolides and community-acquired pneumonia: is quorum sensing the key?

Combination therapy with two antimicrobial agents is superior to monotherapy in severe community-acquired pneumonia, and recent data suggest that addition of a macrolide as the second antibiotic might be superior to other combinations. This observation requires confirmation in a randomised control trial, but this group of antibiotics have pleiotropic effects that extend beyond bacterial killing. Macrolides inhibit bacterial cell-to-cell communication or quorum sensing, which not only might be an important mechanism of action for these drugs in severe infections but may also provide a novel target for the development of new anti-infective drugs.

Effects of nutrient pre-exposure on atrazine toxicity to Vallisneria americana Michx. (wild celery).

Accelerated eutrophication is common to many freshwater and marine environments and often co-occurs with the presence of anthropogenic chemicals. However, the toxic effects of common chemical stressors such as herbicides in the presence of elevated nutrients are not well understood for most aquatic flora, particularly vascular species. To provide insight, field-collected Vallisneria americana Michx. (wild celery) were sequentially exposed to three nutrient concentrations for 3 months and then to nominal 11 and 110 microg L(-1) atrazine for 96 h. Nutrient concentrations (combined NH(4)(+), NO(2)(-), NO(3)(-), PO(4)(-)) were based on ambient concentrations in the St. Johns River (FL) and ranged from 0.013 to 0.668 mg L(-1). Nutrient pretreatment potentiated the toxicity of atrazine as determined by chlorophyll fluorescence activity. Electron transport rates (ETR) were significantly less (48-59%) for plants pretreated with low and ambient nutrient levels in the presence of an average of 107.5-128.1 microg L(-1) atrazine. Significant ETR reductions were also observed for plants exposed to an average of 11.4 microg L(-1) atrazine after exposure to nutrients three times the ambient concentration in the St. Johns River. The results indicate the importance of considering the presence of nutrients in chemical hazard assessments, particularly for phytotoxicants and nontarget vascular plants.

Nonnutrient anthropogenic chemicals in seagrass ecosystems: fate and effects.

Impacts of human-related chemicals, either alone or in combination with other stressors, are important to understand to prevent and reverse continuing worldwide seagrass declines. This review summarizes reported concentrations of anthropogenic chemicals in grass bed-associated surface waters, sediments, and plant tissues and phytotoxic concentrations. Fate information in seagrass-rooted sediments and overlying water is most available for trace metals. Toxicity results in aqueous exposures are available for at least 13 species and a variety of trace metals, pesticides, and petrochemicals. In contrast, results for chemical mixtures and chemicals in sediment matrices are uncommon. Contaminant bioaccumulation information is available for at least 23 species. The effects of plant age, tissue type, and time of collection have been commonly reported but not biological significance of the chemical residues. Experimental conditions have varied considerably in seagrass contaminant research and interspecific differences in chemical residues and chemical tolerances are common, which limits generalizations and extrapolations among species and chemicals. The few reported risk assessments have been usually local and limited to a few single chemicals and species representative of the south Australian and Mediterranean floras. Media-specific information describing exposure concentrations, toxic effect levels, and critical body burdens of common near-shore contaminants is needed for most species to support integrated risk assessments at multiple geographical scales and to evaluate the ability of numerical effects-based criteria to protect these marine angiosperms at risk.

Comparison of genotypes, antimicrobial resistance and virulence profiles of oral and non oral Enterococcus faecalis from Brazil, Japan and the United Kingdom.

OBJECTIVES: To determine whether phenotypic and genotypic differences amongst isolates ofEnterococcus faecalis relate to geographical and clinical origin. METHODS: E. faecalis from primary endodontic infections in Brazilian patients (n = 20), oral infections in UK patients (n = 10), and non-oral infections in Japanese patients (n = 9) were studied. In addition, 20 environmental vancomycin resistant Enterococcus faecalis (VRE) isolates from a UK hospital were analysed. For all isolates, polymerase chain reaction (PCR) was used to detect genes associated with antibiotic resistance and virulence, whilst randomly amplified polymorphic DNA-PCR (RAPD-PCR) was used to produce molecular profiles. RESULTS: Gelatinase gene (gelE) was prevalent amongst isolates (77-100%) and for oral isolates, genes of aggregation substances (agg), immune evasion protein (esp), cytolysin (cylB), tetracycline resistance (tetM; tetL) and erythromycin resistance (ermB) were detected to varying extent. Japanese non-oral isolates had a similar genetic profile to oral isolates, but with higher prevalence of ermB and cylB. All VRE isolates were positive for gelE, esp, agg, vanA, ermB and tetM, 95% were positive for cylB and 17% positive for tetL. All isolates were negative for ermA, asa373 vanB, vanC1 and vanC2/3. RAPD-PCR revealed clustering of VRE isolates. CONCLUSIONS: RAPD-PCR analysis revealed extensive genetic variability among the tested isolates. Oral isolates carried antibiotic resistance genes for tetracycline and whilst they possessed genes that could contribute to pathogenicity, these were detected at lower incidence compared with non-oral and VRE isolates. RAPD-PCR proved to be a useful approach to elucidate relatedness of disparate isolates.

Molecular community profiling of the bacterial microbiota associated with denture-related stomatitis.

Denture-associated stomatitis (DS) affects over two-thirds of denture-wearers. DS presents as erythema of the palatal mucosa in areas where denture-surface associated polymicrobial biofilms containing the fungus Candida albicans exist. The contribution of the oral bacterial microbiota toward the infection is unknown. Therefore, this study characterised the bacterial microbiota of sites within the oral cavity to identify potential associations with occurrence of DS. Denture-wearing patients were recruited (denture stomatitis (DS) n = 8; non-denture stomatitis (NoDS) n = 11) and the oral bacterial microbiota of the tongue, palate and denture-fitting surface was characterised using next-generation sequencing. Operational taxonomic units (OTUs) were identified to bacterial genera and species, and presence/absence and relative abundances were examined. A significant (P = 0.007) decrease in the number of OTUs and thus, diversity of the microbiota was observed in tongue samples of DS patients (vs non-DS). The microbiota of denture-fitting surfaces and palatal mucosae were similar. Large differences in the abundance of bacterial genera and species were observed at each sample site, and unique presence/absence of bacteria was noted. Presence/absence and relative abundance of specific bacteria associated with DS warrants further in vitro and in vivo evaluation, particularly as our previous work has shown C. albicans virulence factor modulation by oral bacteria.

Denture-associated biofilm infection in three-dimensional oral mucosal tissue models.

PURPOSE: In vitro analyses of virulence, pathogenicity and associated host cell responses are important components in the study of biofilm infections. The Candida-related infection, denture-associated oral candidosis, affects up to 60 % of denture wearers and manifests as inflammation of palatal tissues contacting the denture-fitting surface. Commercially available three-dimensional tissue models can be used to study infection, but their use is limited for many academic research institutions, primarily because of the substantial purchase costs. The aim of this study was to develop and evaluate the use of in vitro tissue models to assess infections by biofilms on acrylic surfaces through tissue damage and Candida albicans virulence gene expression. METHODOLOGY: In vitro models were compared against commercially available tissue equivalents (keratinocyte-only, SkinEthic; full-thickness, MatTek Corporation). An in vitro keratinocyte-only tissue was produced using a cancer-derived cell line, TR146, and a full-thickness model incorporating primary fibroblasts and immortalised normal oral keratinocytes was also generated. The in vitro full-thickness tissues incorporated keratinocytes and fibroblasts, and have potential for future further development and analysis. RESULTS: Following polymicrobial infection with biofilms on acrylic surfaces, both in-house developed models were shown to provide equivalent results to the SkinEthic and MatTek models in terms of tissue damage: a significant (P<0.05) increase in LDH activity for mixed species biofilms compared to uninfected control, and no significant difference (P>0.05) in the expression of most C. albicans virulence genes when comparing tissue models of the same type. CONCLUSION: Our results confirm the feasibility and suitability of using these alternative in vitro tissue models for such analyses.

A molecular analysis of the bacteria present within oral squamous cell carcinoma.

In order to characterize the bacterial microbiota present within oral cancerous lesions, tumorous and non-tumorous mucosal tissue specimens (approx. 1 cm(3)) were harvested from ten oral squamous cell carcinoma (OSCC) patients at the time of surgery. Any microbial contamination on the surface of the specimens was eliminated by immersion in Betadine and washing with PBS. Bacteria were visualized within sections of the OSCC by performing fluorescent in situ hybridization with the universal oligonucleotide probe, EUB338. DNA was extracted from each aseptically macerated tissue specimen using a commercial kit. This was then used as template for PCR with three sets of primers, targeting the 16S rRNA genes of Spirochaetes, Bacteroidetes and the domain Bacteria. PCR products were differentiated by TA cloning and bacterial species were identified by partial sequencing of the 16S rRNA gene fragments. A total of 70 distinct taxa was detected: 52 different phylotypes isolated from the tumorous tissues, and 37 taxa from within the non-tumorous specimens. Differences between the composition of the microbiotas within the tumorous and non-tumorous mucosae were apparent, possibly indicating selective growth of bacteria within carcinoma tissue. Most taxa isolated from within the tumour tissue represented saccharolytic and aciduric species. Whether the presence of these bacteria within the mucosa has any bearing on the carcinogenic process is a concept worthy of further investigation.

Florida seagrass habitat evaluation: a comparative survey for chemical quality.

Contaminant concentrations were determined for media associated with 13 Florida seagrass beds. Concentrations of 10 trace metals were more commonly detected in surface water, sediment and two seagrass species than PAHs, pesticides and PCBs. Concentrations of copper and arsenic in surface water exceeded Florida aquatic life criteria more frequently than other trace elements. Total organic carbon, mercury, chromium, zinc, total chlordane, total PAHs, total PCBs, DDD and DDE were significantly greater in seagrass-rooted sediments than adjacent non-vegetated sediments. Total DDT, DDD, DDE, total chlordane, arsenic, copper and nickel exceeded proposed sediment quality guidelines at six of 13 grass beds. Pesticides, PAHs, and PCBs were below detection in seagrass tissues. Mercury, cadmium, nickel, lead and silver were detected in 50% or more of the tissues for Thalassia testudinum (turtle grass) and Halodule wrightii (shoal grass). Spatial, interspecific and tissue differences were usually an order of magnitude or less.

Respiratory pathogen colonization of dental plaque, the lower airways, and endotracheal tube biofilms during mechanical ventilation.

PURPOSE: In mechanically ventilated patients, the endotracheal tube is an essential interface between the patient and ventilator, but inadvertently, it also facilitates the development of ventilator-associated pneumonia (VAP) by subverting pulmonary host defenses. A number of investigations suggest that bacteria colonizing the oral cavity may be important in the etiology of VAP. The present study evaluated microbial changes that occurred in dental plaque and lower airways of 107 critically ill mechanically ventilated patients. MATERIALS AND METHODS: Dental plaque and lower airways fluid was collected during the course of mechanical ventilation, with additional samples of dental plaque obtained during the entirety of patients' hospital stay. RESULTS: A "microbial shift" occurred in dental plaque, with colonization by potential VAP pathogens, namely, Staphylococcus aureus and Pseudomonas aeruginosa in 35 patients. Post-extubation analyses revealed that 70% and 55% of patients whose dental plaque included S aureus and P aeruginosa, respectively, reverted back to having a predominantly normal oral microbiota. Respiratory pathogens were also isolated from the lower airways and within the endotracheal tube biofilms. CONCLUSIONS: To the best of our knowledge, this is the largest study to date exploring oral microbial changes during both mechanical ventilation and after recovery from critical illness. Based on these findings, it was apparent that during mechanical ventilation, dental plaque represents a source of potential VAP pathogens.