Epithelial-derived interleukin-23 promotes oral mucosal immunopathology.

At mucosal surfaces, epithelial cells provide a structural barrier and an immune defense system. However, dysregulated epithelial responses can contribute to disease states. Here, we demonstrated that epithelial cell-intrinsic production of interleukin-23 (IL-23) triggers an inflammatory loop in the prevalent oral disease periodontitis. Epithelial IL-23 expression localized to areas proximal to the disease-associated microbiome and was evident in experimental models and patients with common and genetic forms of disease. Mechanistically, flagellated microbial species of the periodontitis microbiome triggered epithelial IL-23 induction in a TLR5 receptor-dependent manner. Therefore, unlike other Th17-driven diseases, non-hematopoietic-cell-derived IL-23 served as an initiator of pathogenic inflammation in periodontitis. Beyond periodontitis, analysis of publicly available datasets revealed the expression of epithelial IL-23 in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human disease. Collectively, this work highlights an important role for the barrier epithelium in the induction of IL-23-mediated inflammation.

The socio-ecological determinants of help-seeking practices and healthcare access among young men: a systematic review.

Delayed engagement with health services is a key contributor to poorer health outcomes experienced by men. Patterns of health service usage which reduce the opportunity for disease prevention and health promotion appear to be especially prominent amongst young men. To identify the multiple and intersecting determinants of young men's help-seeking practices and health services usage, this review uses the social ecological model (SEM) to guide a critical synthesis of the literature on barriers and facilitators experienced by young men in accessing health services. A systematic review was conducted across five databases (MEDLINE, Embase, PsychINFO, CINAHL and Scopus). Included studies presented primary data regarding young men's (12-24 years) barriers and/or facilitators to seeking and accessing health care. Thirty-one studies (24 qualitative and 7 quantitative) underwent data extraction, quality appraisal and thematic analysis under the guiding framework of the SEM. Seven key themes were constructed, encapsulating the perceived barriers and facilitators to help-seeking and accessing health care experienced by young men, including masculine attitudes, health literacy, social pressure, service accessibility, economic factors, service characteristics and cultural attitudes. These findings highlight the complex interplay between the individual, interpersonal, organizational and societal factors impacting young men's healthcare engagement. They also illuminate avenues for multifaceted, context-specific interventions to enhance healthcare accessibility for this group, including addressing health literacy gaps, providing culturally sensitive care and reducing cost barriers.

A comparison between liquid group A plasma and thawed group A plasma for massive transfusion activation in trauma patients.

BACKGROUND AND OBJECTIVES: The use of group A thawed 24-h plasma when resuscitating haemorrhagic shock patients has become more common; however, limited data exist on the clinical use of liquid plasma (LP). Our aim is to determine whether LP is of clinical benefit to patients requiring massive transfusion. MATERIALS AND METHODS: The objective of this retrospective study was to detect any difference in 24-h survival between patients receiving liquid or thawed plasma (TP) during their massive transfusion activation. Other objectives were to report any difference in hospital length of stay (LOS), intensive care unit (ICU) LOS and in-hospital survival. Data collected included gender, age, mechanism of injury, Injury Severity Score, Revised Trauma Score and Trauma Injury Severity Score. RESULTS: A total of 178 patients received 1283 units of LP, median 4 and range (1-56), whereas 270 patients received 2031 units of TP, median 5 and range (1-87). The two study groups were comparable in terms of gender, age, mechanism of injury, whole blood, red blood cells, platelets and cryoprecipitate transfused. The use of LP during the massive transfusion activation in traumatically injured patients was not associated with increased 24-h survival compared to when using TP, p = 0.553. CONCLUSION: Our study did not show a difference in 24-h or 30-day survival between the use of LP compared to TP in trauma patients. LP should be considered an alternative to TP in trauma patients requiring immediate plasma resuscitation.

A Phase 2a, Double-Blind, Placebo-controlled Randomized Trial of Inhaled TLR9 Agonist AZD1419 in Asthma.

Rationale: To examine the potential of TLR9 (Toll-like receptor 9) activation to modulate the type 2 immune response in asthma.Objectives: To evaluate efficacy and safety of AZD1419, an inhaled TLR9 agonist, in a phase 2a, randomized, double-blind trial.Methods: Adult patients with asthma with a history of elevated eosinophils (>250 cells/µl) were randomized 1:1 to receive 13 once-weekly doses of inhaled AZD1419 (1, 4, or 8 mg; n = 40) or placebo (n = 41). Inhaled corticosteroids and long-acting ß2-agonist were tapered down and then discontinued. The last four doses of AZD1419 were given without maintenance medication, followed by a 40-week observation period. Primary endpoint was time to loss of asthma control (LOC).Measurements and Main Results: AZD1419 induced a T-helper cell type 1-type IFN response with a sustained reduction in markers of type 2 inflammation. However, there were no statistically significant differences between AZD1419 and placebo for time to LOC, proportion of patients with LOC, changes in Asthma Control Questionnaire-five-item version, exacerbations, reliever use, FEV1, peak expiratory flow, or fractional exhaled nitric oxide (FeNO). LOC was predicted by an early rise in FeNO in 63% of patients. Despite withdrawal of maintenance treatment, 24 patients completed the study without LOC; AZD1419 n = 11, placebo n = 13. Adverse events were balanced across groups, with no deaths or serious adverse events judged as causally related to AZD1419.Conclusions: AZD1419 was safe and well tolerated but did not lead to improved asthma control, despite reducing markers of type 2 inflammation. Results suggest that a novel accelerated step-down approach based on FeNO is possible for patients with well-controlled asthma.

Adverse Events Related to Accidental Unintentional Ingestions From Cough and Cold Medications in Children.

OBJECTIVES: Previous research has demonstrated that accidental unsupervised ingestions (AUIs) were responsible for the majority of cough and cold medication (CCM) ingestions leading to significant adverse events (AEs) in children. The objective of this analysis was to characterize the role of AUIs in the morbidity associated with CCM exposure in children. METHODS: This surveillance study collected data from 5 United States data sources from 2009 to 2016, in children younger than 6 years with an AE from an AUI involving at least 1 CCM over-the-counter pharmaceutical ingredient. An expert panel reviewed each case to determine causality. RESULTS: From 4756 total cases reviewed, 3134 (65.9%) had an AE from an AUI determined to be at least potentially related to a CCM ingredient. The majority (61.3%) of cases occurred in children aged 2 to younger than 4 years. Most exposures occurred in the child's own residence (94.9%), and 43.8% were admitted to a health care facility (22.0% to a critical care unit). Dextromethorphan and diphenhydramine, when packaged alone or in combination products, contributed to 96.0% of AUIs. The most common specific products involved were single-ingredient pediatric liquid diphenhydramine (30.1%) and single-ingredient pediatric liquid dextromethorphan (21.4%). There were 3 deaths from solid diphenhydramine formulations. CONCLUSIONS: There continues to be opportunities for the implementation of interventions to prevent AUIs of CCM in children. Additional emphasis on engineering controls, such as flow restrictors for liquid formulations targeting diphenhydramine and dextromethorphan products, represent additional opportunities to further reduce AEs from AUIs of CCM.

First steps in PROMs and PREMs collection in Wales as part of the prudent and value-based healthcare agenda.

PURPOSE: Patients are experts in their own health and should be treated as equal partners in their care. Patient-reported outcome measures (PROMs) are an effective way of gathering patient feedback and can facilitate effectiveness and cost-effectiveness analysis to improve decision making and service improvement. The PROMs, PREMs & Effectiveness Programme was initiated in 2016 and aimed to develop an electronic platform to facilitate collection of PROMs and Patient-reported experience measures (PREMs) from secondary care patients across Wales. METHODS: We worked with all Health Boards in Wales, the NHS Wales Informatics Service (NWIS), and Cedar (a healthcare technology research centre) to identify and meet technical requirements to develop a platform which is fit for purpose. Patient groups were included throughout the development to gather feedback and for extensive testing. Clinical teams helped identify the most appropriate tools, with licences, translations and electronic formatting issues being managed centrally. RESULTS: The developed platform is integrated with patient administration systems minimising the need for manual input, with processes in place to allow automatic collection triggers according to nationally agreed schedules. We have over 30 nationally agreed PROMs 'pathways' with over 110,000 PROMs collected to date. Responses are fed back to clinicians via the electronic patient record and to each health board via feeds to the national data warehouse, making data easily accessible to different teams, maximising use and application. DISCUSSION: The national platform has provided a co-ordinated approach to PROMs collection in Wales, offering an effective means of communicating with patients outside the traditional clinic visit.

Hospital Charges Associated with Central Venous Stenosis in Pediatric Patients Requiring Long-Term Central Venous Access.

OBJECTIVE: To evaluate the hospital charges associated with central venous stenosis in pediatric patients requiring long-term central venous catheters, via associated charges and hospital length of stay (LOS). STUDY DESIGN: This institutional review board-approved retrospective review identified pediatric patients with central venous catheters and either short bowel syndrome (SBS) or end-stage renal disease (ESRD) diagnosed between 2008 and 2015 using the Pediatric Health Information System. These 2 cohorts were selected because long-term central venous access is commonly required for survival. Prevalence of central venous stenosis, total number of admissions, procedures, LOS, and associated charges were recorded. Statistical analysis performed with Wilcoxon nonparametric and 2-sample t test with a significance of P < .05. RESULTS: Of 4952 patients with SBS and 4665 patients with ESRD, 169 (3.4%) patients with SBS and 191 (4.1%) patients with ESRD were diagnosed with central venous stenosis (360 patients total [3.7%]). The cumulative median admissions and LOS was higher in patients with SBS with central venous stenosis (15 admissions and 156 days) vs those without central venous stenosis (5 admissions and 110 days) (P < .001). The cumulative median number of admissions and LOS was higher in patients with ESRD with central venous stenosis (13 admissions and 72 days) vs those without central venous stenosis (7 admissions and 42 days) (P < .001). The mean cumulative charges for patients with SBS with central venous stenosis were higher than for those without central venous stenosis ($1.89 million vs $1.11 million, respectively) (P < .001). Similarly, the mean cumulative charges for patients with ESRD with central venous stenosis were higher than for those without central venous stenosis ($1.17 millions vs $702 000, respectively) (P < .001). CONCLUSIONS: Pediatric patients with central venous stenosis have significantly higher total charges, imaging charges, number of admissions, and longer LOS. Attention to mitigate the incidence of central venous stenosis in pediatric patients requiring long-term central venous access is warranted.

Improving the evaluation of COPD exacerbation treatment effects by accounting for early treatment discontinuations: a post-hoc analysis of randomized clinical trials.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) clinical trials aimed at evaluating treatment effects on exacerbations often suffer from early discontinuations of randomized treatment. Treatment discontinuations imply a loss of information and should ideally be considered in the statistical analysis of trial results, particularly if the discontinuations are related to the disease or treatment itself. Here, we explore this issue by investigating (1) whether there exists an association between the risks of exacerbation and treatment discontinuation in COPD clinical trials and (2) whether disregarding this association can cause bias in exacerbation treatment effect estimates. We focus on the hypothetical estimand, i.e. the treatment effect that would have been observed had all subjects completed the trial as planned. METHODS: The association between exacerbation and discontinuation risks was analysed by applying a joint frailty (random effect) model - allowing for the simultaneous analysis of multiple types of correlated events - to data from five Phase III-IV COPD clinical trials. Specifically, the impact of the association on exacerbation treatment effect estimates was assessed by comparing the treatment hazard ratios of the joint frailty model to the rate/hazard ratios of two related statistical models (the negative binomial and shared frailty models), which both assume discontinuations to be unrelated to the trial outcome. The models were also compared using simulated data. RESULTS: A statistically significant (p < 0.0001), positive association between exacerbation and discontinuation risks was found in all trials. Importantly, simulations confirmed that - with such an association - models disregarding the association risk producing biased results (> 5 percentage point difference in hazard/rate ratio). For some treatment comparisons in the clinical trials, the difference in treatment effect estimates between the joint frailty and the other models was as high as 10-15 percentage points. The difference was affected by the strength of the exacerbation-discontinuation association, the population heterogeneity in exacerbation risk, and the difference in discontinuation rates between treatment arms. CONCLUSIONS: We have identified an association between the risks of exacerbation and treatment discontinuation in five COPD clinical trials. We recommend using the joint frailty model to account for this association when estimating exacerbation treatment effects, particularly when targeting the hypothetical estimand.

Pharmacokinetics, pharmacodynamics and safety of the inverse retinoic acid-related orphan receptor γ agonist AZD0284.

AIMS: Retinoic acid-related orphan receptor γ (RORγ), a master regulator of T-helper 17 (Th17) cell function and differentiation, is an attractive target for treatment of Th17-driven diseases. This first-in-human study aimed to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of the inverse RORγ agonist AZD0284. METHODS: We conducted a phase I, randomized, single-blind, placebo-controlled, two-part, first-in-human study with healthy subjects receiving single (4-238 mg) or multiple (12-100 mg) oral doses of AZD0284 or placebo after overnight fasting. Subjects in the one single dose cohort additionally received a single dose of AZD0284 after a high-calorie meal. AZD0284 plasma concentrations, as well as inhibition of ex vivo-stimulated interleukin (IL)-17A release in whole blood, were frequently measured after both single and multiple dosing. RESULTS: Eighty-three men participated in the study. AZD0284 was absorbed rapidly into plasma after oral dosing and exhibited a terminal half-life of 13-16 hours. Both the area under the concentration-time curve (AUC) and maximum concentration (Cmax ) increased subproportionally with increasing dose (95% confidence intervals of slope parameter were 0.71-0.84 and 0.72-0.88 for AUC and Cmax , respectively). Food intake delayed the absorption of AZD0284 but did not affect the overall exposure or half-life. AZD0284 showed dose-dependent reduction of ex vivo-stimulated IL-17A release after both single and multiple doses. No significant safety concerns were identified in the study. CONCLUSIONS: AZD0284 was well tolerated, rapidly and dose-dependently absorbed, and reduced stimulated IL-17A release after single and multiple dosing. The results of this study support further clinical development of AZD0284.

Moving towards a Network of Autonomous UAS Atmospheric Profiling Stations for Observations in the Earth's Lower Atmosphere: The 3D Mesonet Concept.

The deployment of small unmanned aircraft systems (UAS) to collect routine in situ vertical profiles of the thermodynamic and kinematic state of the atmosphere in conjunction with other weather observations could significantly improve weather forecasting skill and resolution. High-resolution vertical measurements of pressure, temperature, humidity, wind speed and wind direction are critical to the understanding of atmospheric boundary layer processes integral to air-surface (land, ocean and sea ice) exchanges of energy, momentum, and moisture; how these are affected by climate variability; and how they impact weather forecasts and air quality simulations. We explore the potential value of collecting coordinated atmospheric profiles at fixed surface observing sites at designated times using instrumented UAS. We refer to such a network of autonomous weather UAS designed for atmospheric profiling and capable of operating in most weather conditions as a 3D Mesonet. We outline some of the fundamental and high-impact science questions and sampling needs driving the development of the 3D Mesonet and offer an overview of the general concept of operations. Preliminary measurements from profiling UAS are presented and we discuss how measurements from an operational network could be realized to better characterize the atmospheric boundary layer, improve weather forecasts, and help to identify threats of severe weather.

The influence of febuxostat on coronary artery endothelial dysfunction in patients with coronary artery disease: A phase 4 randomized, placebo-controlled, double-blind, crossover trial.

BACKGROUND: The xanthine oxidase (XO) system is a significant source of vascular oxidative stress, which is believed to impair endothelial function, an important contributor to atherosclerotic disease. We tested whether febuxostat, a potent XO inhibitor, improves coronary endothelial function (CEF) in patients with stable coronary artery disease (CAD) in a single-center, randomized, placebo-controlled, double-blind crossover trial. METHODS: CEF was measured using noninvasive magnetic resonance imaging (MRI) assessment of changes in 30 patients with stable CAD and baseline impaired CEF. Patients received either febuxostat or placebo for 6 weeks and then were crossed over to the alternative for an additional 6 weeks. MRI-detected changes in coronary flow and in coronary cross-sectional area from rest to isometric handgrip exercise, a known endothelial-dependent stressor, were measured at the end of each 6 week period. RESULTS: Mean serum urate levels were lower at the end of the 6-week febuxostat period (2.9±0.8mg/dL) than at the end of the 6-week placebo period (5.9±0.04, P<.001). However, there were no significant differences in any of the CEF parameters measured at the end of the febuxostat and placebo periods. CONCLUSIONS: In summary, although XO inhibition with febuxostat was well tolerated and lowered serum urate, it did not improve the primary end point of the study, CEF measured using MRI after 6 weeks of treatment. In conclusion, these findings suggest that short-term inhibition of XO does not significantly improve impaired CEF in patients with stable CAD.

Evaluation of the quality and value of data sources for postmarket surveillance of the safety of cough and cold medications in children.

BACKGROUND: The purpose of this report is to evaluate the quality of data sources used to study cough and cold medication (CCM) safety in children via the Pediatric Cough and Cold Safety Surveillance System. METHODS: The System utilized the National Poison Data System (NPDS), FDA Adverse Event Reporting System (FAERS), English-language medical literature, manufacturer postmarket safety databases, and news/media reports to identify cases from January 2008 through September 2016. Each data source was evaluated by the proportion of detected cases determined to be eligible (met case criteria) and the proportion determined to be evaluable (able to determine causal relationship between adverse event and exposure). RESULTS: A total of 7184 unique cases were identified from 27,597 detected reports. Of these, 6447 (89.7%) were evaluable. The data source with the highest volume of detected cases was news/media; however, only 0.3% of those cases were eligible for panel review and only 0.2% (24 out of 13,450 cases) were evaluable. The data source with the highest proportion of eligible and evaluable cases was NPDS with 7691 detected cases, 6113 (79.5%) eligible cases, and 5587 (72.6%) evaluable cases. CONCLUSIONS: The data sources utilized to evaluate the safety profile of pediatric CCMs yielded variable detection and evaluation rates, but overall provided a comprehensive look at exposures that otherwise cannot be studied in clinical trials. While this study suggests that each source made a valuable contribution and that evaluable cases are generalizable, improvements are needed in case completeness and accuracy to enhance the quality of postmarket safety evaluations.

Interbacterial Adhesion Networks within Early Oral Biofilms of Single Human Hosts.

Specific interbacterial adhesion, termed coaggregation, is well established for three early colonizers of the plaque biofilm: streptococci, actinomyces, and veillonellae. However, little is known about interactions of other early colonizers and about the extent of interactions within the bacterial community from a single host. To address these gaps, subject-specific culture collections from two individuals were established using an intraoral biofilm retrieval device. Molecular taxonomy (Human Oral Microbe Identification Microarray [HOMIM]) analysis of biofilm samples confirmed the integrity and completeness of the collections. HOMIM analysis verified the isolation of Streptococcus gordonii and S. anginosus from only one subject, as well as isolation of a previously uncultivated streptococcal phylotype from the other subject. Strains representative of clonal diversity within each collection were further characterized. Greater than 70% of these streptococcal strains from each subject coaggregated with at least one other coisolate. One-third of the strains carry a known coaggregation mediator: receptor polysaccharide (RPS). Almost all nonstreptococcal isolates coaggregated with other coisolates. Importantly, certain Rothia strains demonstrated more coaggregations with their coisolated bacteria than did any Streptococcus or Actinomyces strain, and certain Haemophilus isolates participated in twice as many. Confocal microscopy of undisturbed biofilms showed that Rothia and Haemophilus each occur in small multispecies microcolonies. However, in confluent high-biomass regions, Rothia occurred in islands whereas Haemophilus was distributed throughout. Together, the data demonstrate that coaggregation networks within an individual's oral microflora are extensive and that Rothia and Haemophilus can be important initiators of cell-cell interactions in the early biofilm.IMPORTANCE Extensive involvement of specific interbacterial adhesion in dental plaque biofilm formation has been postulated based on in vitro coaggregation between oral bacteria from culture collections that are not subject specific. In the present study, subject-specific culture collections were obtained from early plaque biofilm of two volunteers, and coaggregations within each culture collection were assayed. Coaggregations, several of which involved a coaggregation-mediating cell surface molecule known from well-studied streptococci, were widespread. Unexpectedly, the little-studied organisms Haemophilus and Rothia participated in the greatest numbers of interactions with community members; these two organisms showed different distributions within the undisturbed biofilm. The data show that coaggregation networks encompass most organisms within the biofilm community of each individual, and they indicate prominent participation of organisms such as Haemophilus and Rothia in early plaque biofilm formation.

An Airway Risk Assessment Score for Unplanned Extubation in Intensive Care Pediatric Patients.

OBJECTIVE: As a result of a workshop to identify common causes of unplanned extubation, Children's Healthcare of Atlanta developed a scoring tool (Risk Assessment Score) to stratify patients into groups of low, moderate, high, and extreme risk. This tool could be used to institute appropriate monitoring or interventions for patients with high risks of unplanned extubation to enhance safety. The objective of this study is to test the hypothesis that the Risk Assessment Score will correlate with the occurrence rate of unplanned extubation in pediatric patients. DESIGN: Retrospective review of 2,811 patients at five ICUs conducted between December 2012 and July 2014. SETTING: Five ICUs at two freestanding pediatric hospitals within a large children's healthcare system in the United States. PATIENTS: All intubated pediatric patients. INTERVENTIONS: Data of intubations and Risk Assessment Score were collected. Extubation outcomes and severity levels were compared across demographic groups and with the maximum Risk Assessment Score of each intubation. MEASUREMENTS AND MAIN RESULTS: Out of 4,566 intubations, 244 were unplanned extubations (5.3%). The occurrence rates of unplanned extubations in those less than 1, 1-6, and more than 6 years old were 6.7%, 3.6%, and 2.7%, respectively, corresponding to a rate of 0.59, 0.53, and 0.58 unplanned extubation every 100 ventilator days. The occurrence rates were 13.6% for patients weighing less than 1 kg (0.59 unplanned extubation per 100 ventilation days) and 3.8% for patients weighing greater than or equal to 1 kg (0.58 unplanned extubation per 100 ventilation days). For intubations with maximum risk score falling in risk categories of low, moderate, high, and extreme, the occurrence rates were 4.7%, 7.7%, 12.0%, and 8.3%, respectively, which corresponded to rates of 0.54, 0.62, 0.95, and 0.92 unplanned extubation per 100 ventilator days. CONCLUSIONS: Higher Risk Assessment Scores are associated with occurrence rates of unplanned extubation.

The Recognition, Incidence, and Management of Spinal Cord Monitoring Alerts in Early-onset Scoliosis Surgery.

BACKGROUND: The objective of the research was to study the relevance of intraoperative neuromonitoring throughout all stages of surgical management in patients with progressive early-onset scoliosis (EOS).The routine monitoring of spinal cord potentials has gradually become standard of practice among spinal surgeons. However, there is not a consensus that the added expense of this technique necessitates monitoring in all stages of surgical management. METHODS: A retrospective review of 180 surgical cases of 30 patients with EOS from July 2003 to July 2012 was performed. All monitoring alerts as judged by the neuromonitoring team were identified. Both somatosensory-evoked potentials and transcranial electric motor-evoked potentials were studied and no limiting thresholds for reporting electrophysiological changes were deemed appropriate. RESULTS: Of 150 monitored cases there were 18 (12%) monitoring alerts. This represented 40% of the patient cohort over the 9-year study period. CONCLUSIONS: Index versus routine lengthening rate of alerts showed no significant difference in incidence of monitoring alerts. Conversely, several patients whose primary implantation surgeries were uneventful had monitoring alerts later in their treatment course. Intraoperative neuromonitoring is warranted throughout all stages of surgical management of EOS. LEVEL OF EVIDENCE: Level IV. This study is a retrospective review of surgical cases of 30 patients with EOS.

Differential Utilization of Basic Proline-Rich Glycoproteins during Growth of Oral Bacteria in Saliva.

UNLABELLED: Although saliva is widely recognized as a primary source of carbon and nitrogen for growth of the dental plaque biofilm community, little is known about how different oral bacteria utilize specific salivary components. To address this question, 32 strains representing 16 genera commonly isolated from early plaque biofilms were compared for growth over two transfers in stimulated (by chewing Parafilm) whole saliva that was stabilized by heat treatment and dialysis. The cell densities, measured by quantitative PCR (qPCR), ranged from ∼1 × 10(6) to 1 × 10(7)/ml for strains of Streptococcus gordonii, Streptococcus oralis, and Streptococcus mitis and one strain of Streptococcus sanguinis Strains of Streptococcus mutans, Gemella haemolysans, and Granulicatella adiacens reached ∼1 × 10(5) to 1 × 10(6)/ml. In contrast, little or no growth was noted for three other strains of S. sanguinis, as well as for strains of Streptococcus parasanguinis, Streptococcus salivarius, Streptococcus vestibularis, Streptococcus sobrinus, Actinomyces spp., Abiotrophia defectiva, and Rothia dentocariosa SDS-PAGE, lectin blotting, and two-dimensional gel electrophoresis of saliva from cultures of S. gordonii, S. oralis, and S. mitis revealed species-specific differences in the degradation of basic proline-rich glycoproteins (PRG). In contrast, saliva from cultures of other bacteria was indistinguishable from control saliva. Species-dependent differences in the utilization of individual host sugars were minor. Thus, differences in salivary glycan foraging between oral species may be important to cross-feeding and cooperation between organisms in dental plaque biofilm development. IMPORTANCE: Bacteria in the mouth use saliva for nutrition. How each of the many types of bacteria uses saliva is not clear. We show that a major protein in saliva, called PRG, is an important nutrition source for certain bacteria but not for others. PRG has many sugar molecules linked in chains, but the sugar is not available for bacteria until the chains are degraded. The bacteria that can grow by digesting this protein break the sugar chains into parts which not only support their own growth but could also be available to support the growth of those bacteria that cannot use the intact protein.

Cell Surface Glycoside Hydrolases of Streptococcus gordonii Promote Growth in Saliva.

UNLABELLED: The growth of the oral commensal Streptococcus gordonii in saliva may depend on a number of glycoside hydrolases (GHs), including three cell wall-anchored proteins that are homologs of pneumococcal ß-galactosidase (BgaA), ß-N-acetylglucosaminidase (StrH), and endo-ß-N-acetylglucosaminidase D (EndoD). In the present study, we introduced unmarked in-frame deletions into the corresponding genes of S. gordonii DL1, verified the presence (or absence) of the encoded proteins on the resulting mutant strains, and compared these strains with wild-type strain DL1 for growth and glycan foraging in saliva. The overnight growth of wild-type DL1 was reduced 3- to 10-fold by the deletion of any one or two genes and approximately 20-fold by the deletion of all three genes. The only notable change in the salivary proteome associated with this reduction of growth was a downward shift in the apparent molecular masses of basic proline-rich glycoproteins (PRG), which was accompanied by the loss of lectin binding sites for galactose-specific Erythrina cristagalli agglutinin (ECA) and mannose-specific Galanthus nivalis agglutinin (GNA). The binding of ECA to PRG was also abolished in saliva cultures of mutants that expressed cell surface BgaA alone or together with either StrH or EndoD. However, the subsequent loss of GNA binding was seen only in saliva cocultures of different mutants that together expressed all three cell surface GHs. The findings indicate that the growth of S. gordonii DL1 in saliva depends to a significant extent on the sequential actions of first BgaA and then StrH and EndoD on N-linked glycans of PRG. IMPORTANCE: The ability of oral bacteria to grow on salivary glycoproteins is critical for dental plaque biofilm development. Little is known, however, about how specific salivary components are attacked and utilized by different members of the biofilm community, such as Streptococcus gordonii. Streptococcus gordonii DL1 has three cell wall-anchored glycoside hydrolases that are predicted to act on host glycans. In the present study, we introduced unmarked in-frame deletions in the corresponding genes, verified the presence (or absence) of encoded proteins on the resulting mutant strains, and compared these strains with wild-type DL1 for growth and glycan foraging in saliva. The results indicate that the growth of S. gordonii DL1 depends to a significant extent on sequential action of these cell surface GHs on N-linked glycans of basic proline-rich salivary glycoproteins, which appears to be an essential first step in salivary glycan foraging.

The Reliability and Validity of the Clinical Perfectionism Questionnaire in Eating Disorder and Community Samples.

BACKGROUND: Clinical perfectionism is a risk and maintaining factor for anxiety disorders, depression and eating disorders. AIMS: The aim was to examine the psychometric properties of the 12-item Clinical Perfectionism Questionnaire (CPQ). METHOD: The research involved two samples. Study 1 comprised a nonclinical sample (n = 206) recruited via the internet. Study 2 comprised individuals in treatment for an eating disorder (n = 129) and a community sample (n = 80). RESULTS: Study 1 factor analysis results indicated a two-factor structure. The CPQ had strong correlations with measures of perfectionism and psychopathology, acceptable internal consistency, and discriminative and incremental validity. The results of Study 2 suggested the same two-factor structure, acceptable internal consistency, and construct validity, with the CPQ discriminating between the eating disorder and control groups. Readability was assessed as a US grade 4 reading level (student age range 9-10 years). CONCLUSIONS: The findings provide evidence for the reliability and validity of the CPQ in a clinical eating disorder and two separate community samples. Although further research is required the CPQ has promising evidence as a reliable and valid measure of clinical perfectionism.

Composition and development of oral bacterial communities.

The oral bacterial microbiome encompasses approximately 700 commonly occurring phylotypes, approximately half of which can be present at any time in any individual. These bacteria are largely indigenous to the oral cavity; this limited habitat range suggests that interactions between the various phylotypes, and between the phylotypes and their environment, are crucial for their existence. Molecular cataloging has confirmed many basic observations on the composition of the oral microbiome that were formulated well before ribosomal RNA-based systematics, but the power and the scope of molecular taxonomy have resulted in the discovery of new phylotypes and, more importantly, have made possible a level of bacterial community analysis that was unachievable with classical methods. Bacterial community structure varies with location within the mouth, and changes in community structure are related to disease initiation and disease progression. Factors that influence the formation and the evolution of communities include selective adherence to epithelial or tooth surfaces, specific cell-to-cell binding as a driver of early community composition, and interorganismal interaction leading to alteration of the local environment, which represents the first step on the road to oral disease. A comprehensive understanding of how these factors interact to drive changes in the composition of the oral microbial community can lead to new strategies for the inhibition of periodontal diseases and dental caries.