Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids.

Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood1. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex whereby glucocorticoids provoke an increase in activity and enable an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA-cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. By contrast, artificial blocking of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, interferes with the anti-inflammatory effects of glucocorticoids and, accordingly, abrogates their beneficial effects during a diverse range of preclinical models of immune-mediated inflammatory diseases. Our findings provide important insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs.

Shared decision-making in scaling and root planing.

INTRODUCTION: Estimate proportion of various approaches used by dental hygienists for engaging patients in decisions commonly arising during scaling and root planing. Distribution of approaches was compared across various task components in this procedure, practice experience of dental hygienists and patient compliance. MATERIALS AND METHODS: Survey of graduates from and students in a baccalaureate dental hygiene program. RESULTS: Paternalism (tell then do) and informed consent (give choices and reasons and ask for permission) were more common than shared decision-making (discuss alternatives, solicit patient input and arrive at a mutual decision) and disengagement (patient refusing offered service or avoiding further involvement) by a ratio of 4 to 1 for the first 2 compared with the latter 2. This relationship was held across selecting treatment, procedural adjuncts, homecare instructions and financial arrangements. Dental hygienists exhibited a range of personal preferences for engagement approaches. No-show rate, patient disengagement outside the office, was high (20%). CONCLUSION: Dental hygienists reported using 'more controlled' approaches to engaging patients in decisions regarding treatment. Patients may prefer to engage in more shared decisions and choose this approach by staying away from the office. This may underestimate patients' decisions to stay away from treatment, for example by not showing for completion of the treatment or disregarding homecare routines.

Vitamin E Acetate in Bronchoalveolar-Lavage Fluid Associated with EVALI.

BACKGROUND: The causative agents for the current national outbreak of electronic-cigarette, or vaping, product use-associated lung injury (EVALI) have not been established. Detection of toxicants in bronchoalveolar-lavage (BAL) fluid from patients with EVALI can provide direct information on exposure within the lung. METHODS: BAL fluids were collected from 51 patients with EVALI in 16 states and from 99 healthy participants who were part of an ongoing study of smoking involving nonsmokers, exclusive users of e-cigarettes or vaping products, and exclusive cigarette smokers that was initiated in 2015. Using the BAL fluid, we performed isotope dilution mass spectrometry to measure several priority toxicants: vitamin E acetate, plant oils, medium-chain triglyceride oil, coconut oil, petroleum distillates, and diluent terpenes. RESULTS: State and local health departments assigned EVALI case status as confirmed for 25 patients and as probable for 26 patients. Vitamin E acetate was identified in BAL fluid obtained from 48 of 51 case patients (94%) in 16 states but not in such fluid obtained from the healthy comparator group. No other priority toxicants were found in BAL fluid from the case patients or the comparator group, except for coconut oil and limonene, which were found in 1 patient each. Among the case patients for whom laboratory or epidemiologic data were available, 47 of 50 (94%) had detectable tetrahydrocannabinol (THC) or its metabolites in BAL fluid or had reported vaping THC products in the 90 days before the onset of illness. Nicotine or its metabolites were detected in 30 of 47 of the case patients (64%). CONCLUSIONS: Vitamin E acetate was associated with EVALI in a convenience sample of 51 patients in 16 states across the United States. (Funded by the National Cancer Institute and others.).

Efficacy of sustained knowledge translation (KT) interventions in chronic disease management in older adults: systematic review and meta-analysis of complex interventions.

BACKGROUND: Chronic disease management (CDM) through sustained knowledge translation (KT) interventions ensures long-term, high-quality care. We assessed implementation of KT interventions for supporting CDM and their efficacy when sustained in older adults. METHODS: Design: Systematic review with meta-analysis engaging 17 knowledge users using integrated KT. ELIGIBILITY CRITERIA: Randomized controlled trials (RCTs) including adults (> 65 years old) with chronic disease(s), their caregivers, health and/or policy-decision makers receiving a KT intervention to carry out a CDM intervention for at least 12 months (versus other KT interventions or usual care). INFORMATION SOURCES: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from each database's inception to March 2020. OUTCOME MEASURES: Sustainability, fidelity, adherence of KT interventions for CDM practice, quality of life (QOL) and quality of care (QOC). Data extraction, risk of bias (ROB) assessment: We screened, abstracted and appraised articles (Effective Practice and Organisation of Care ROB tool) independently and in duplicate. DATA SYNTHESIS: We performed both random-effects and fixed-effect meta-analyses and estimated mean differences (MDs) for continuous and odds ratios (ORs) for dichotomous data. RESULTS: We included 158 RCTs (973,074 participants [961,745 patients, 5540 caregivers, 5789 providers]) and 39 companion reports comprising 329 KT interventions, involving patients (43.2%), healthcare providers (20.7%) or both (10.9%). We identified 16 studies described as assessing sustainability in 8.1% interventions, 67 studies as assessing adherence in 35.6% interventions and 20 studies as assessing fidelity in 8.7% of the interventions. Most meta-analyses suggested that KT interventions improved QOL, but imprecisely (36 item Short-Form mental [SF-36 mental]: MD 1.11, 95% confidence interval [CI] [- 1.25, 3.47], 14 RCTs, 5876 participants, I2 = 96%; European QOL-5 dimensions: MD 0.01, 95% CI [- 0.01, 0.02], 15 RCTs, 6628 participants, I2 = 25%; St George's Respiratory Questionnaire: MD - 2.12, 95% CI [- 3.72, - 0.51] 44 12 RCTs, 2893 participants, I2 = 44%). KT interventions improved QOC (OR 1.55, 95% CI [1.29, 1.85], 12 RCTS, 5271 participants, I2 = 21%). CONCLUSIONS: KT intervention sustainability was infrequently defined and assessed. Sustained KT interventions have the potential to improve QOL and QOC in older adults with CDM. However, their overall efficacy remains uncertain and it varies by effect modifiers, including intervention type, chronic disease number, comorbidities, and participant age. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018084810.

Twenty years of collaborative research to enhance community practice for cancer prevention and control.

The Cancer Prevention and Control Research Network (CPCRN) was established in 2002 to conduct applied research and undertake related activities to translate evidence into practice, with a special focus on the unmet needs of populations at higher risk of getting cancer and dying from it. A network of academic, public health and community partners, CPCRN is a thematic research network of the Prevention Research Centers Program at the Centers for Disease Control and Prevention (CDC). The National Cancer Institute's Division of Cancer Control and Population Sciences (DCCPS) has been a consistent collaborator. The CPCRN has fostered research on geographically dispersed populations through cross-institution partnerships across the network. Since its inception, the CPCRN has applied rigorous scientific methods to fill knowledge gaps in the application and implementation of evidence-based interventions, and it has developed a generation of leading investigators in the dissemination and implementation of effective public health practices. This article reflects on how CPCRN addressed national priorities, contributed to CDC's programs, emphasized health equity and impacted science over the past twenty years and potential future directions.

Siglec-15 on Osteoclasts Is Crucial for Bone Erosion in Serum-Transfer Arthritis.

Siglec-15 is a conserved sialic acid-binding Ig-like lectin, which is expressed on osteoclasts. Deficiency of Siglec-15 leads to an impaired osteoclast development, resulting in a mild osteopetrotic phenotype. The role of Siglec-15 in arthritis is still largely unclear. To address this, we generated Siglec-15 knockout mice and analyzed them in a mouse arthritis model. We could show that Siglec-15 is directly involved in pathologic bone erosion in the K/BxN serum-transfer arthritis model. Histological analyses of joint destruction provided evidence for a significant reduction in bone erosion area and osteoclast numbers in Siglec-15-/- mice, whereas the inflammation area and cartilage destruction was comparable to wild-type mice. Thus, Siglec-15 on osteoclasts has a crucial function for bone erosion during arthritis. In addition, we generated a new monoclonal anti-Siglec-15 Ab to clarify its expression pattern on immune cells. Whereas this Ab demonstrated an almost exclusive Siglec-15 expression on murine osteoclasts and hardly any other expression on various other immune cell types, human Siglec-15 was more broadly expressed on human myeloid cells, including human osteoclasts. Taken together, our findings show a role of Siglec-15 as a regulator of pathologic bone resorption in arthritis and highlight its potential as a target for future therapies, as Siglec-15 blocking Abs are available.

Transcription Profile and Pathway Analysis of the Endocannabinoid Receptor Inverse Agonist AM630 in the Core and Infiltrative Boundary of Human Glioblastoma Cells.

BACKGROUND: We have previously reported that the endocannabinoid receptor inverse agonist AM630 is a potent inhibitor of isocitrade dehydrogenase-1 wild-type glioblastoma (GBM) core tumour cell proliferation. To uncover the mechanism behind the anti-tumour effects we have performed a transcriptional analysis of AM630 activity both in the tumour core cells (U87) and the invasive margin cells (GIN-8), the latter representing a better proxy of post-surgical residual disease. RESULTS: The core and invasive margin cells exhibited markedly different gene expression profiles and only the core cells had high expression of a potential AM630 target, the CB1 receptor. Both cell types had moderate expression of the HTR2B serotonin receptor, a reported AM630 target. We found that the AM630 driven transcriptional response was substantially higher in the central cells than in the invasive margin cells, with the former driving the up regulation of immune response and the down regulation of cell cycle and metastatic pathways and correlating with transcriptional responses driven by established anti-neoplastics as well as serotonin receptor antagonists. CONCLUSION: Our results highlight the different gene sets involved in the core and invasive margin cell lines derived from GBM and an associated marked difference in responsiveness to AM630. Our findings identify AM630 as an anti-neoplastic drug in the context of the core cells, showing a high correlation with the activity of known antiproliferative drugs. However, we reveal a key set of similarities between the two cell lines that may inform therapeutic intervention.

Consistency of orthodontists' clinical decisions: A systematic review, meta-analysis, and theory development.

INTRODUCTION: The purpose of this systematic review and meta-analysis is to provide a literature-based estimate of the consistency of orthodontists' clinical decisions. METHODS: A systematic review of the literature using a modified Reporting Items for Systematic Reviews and Meta-Analyses approach identified 20 articles, representing 53 unique datasets, reporting kappa statistics and standard errors for situations allowing intrarater or interrater comparison on decisions such as the need for treatment, extraction, surgery, and various specific treatment approaches. Meta-regression based on random effect models was used to explore the shape of the underlying distribution, the prevalence of the target condition in the data set, and the professional experience of raters as covariables. RESULTS: No evidence of publication bias was found. Common patient records accounted for approximately 25% of the variance between orthodontists and 33% of the variance within orthodontists making the same decision from the same records. Random and representative samples were judged more consistently than were samples chosen to contain borderline cases. (P <0.001). Raters were in greater agreement on the presence of target conditions than their absence (P <0.001). Residents were more consistent than were practicing orthodontists or dental students (P <0.006). CONCLUSIONS: Low consistency was found among orthodontists making clinical decisions from common records. Factors associated with samples and raters suggest an underlying pattern of orthodontists viewing cases through personal mental frameworks.

Cellular stressors may alter islet hormone cell proportions by moderation of alternative splicing patterns.

Changes to islet cell identity in response to type 2 diabetes (T2D) have been reported in rodent models, but are less well characterized in humans. We assessed the effects of aspects of the diabetic microenvironment on hormone staining, total gene expression, splicing regulation and the alternative splicing patterns of key genes in EndoC-ßH1 human beta cells. Genes encoding islet hormones [somatostatin (SST), insulin (INS), Glucagon (GCG)], differentiation markers [Forkhead box O1 (FOXO1), Paired box 6, SRY box 9, NK6 Homeobox 1, NK6 Homeobox 2] and cell stress markers (DNA damage inducible transcript 3, FOXO1) were dysregulated in stressed EndoC-ßH1 cells, as were some serine arginine rich splicing factor splicing activator and heterogeneous ribonucleoprotein particle inhibitor genes. Whole transcriptome analysis of primary T2D islets and matched controls demonstrated dysregulated splicing for ~25% of splicing events, of which genes themselves involved in messenger ribonucleic acid processing and regulation of gene expression comprised the largest group. Approximately 5% of EndoC-ßH1 cells exposed to these factors gained SST positivity in vitro. An increased area of SST staining was also observed ex vivo in pancreas sections recovered at autopsy from donors with type 1 diabetes (T1D) or T2D (9.3% for T1D and 3% for T2D, respectively compared with 1% in controls). Removal of the stressful stimulus or treatment with the AKT Serine/Threonine kinase inhibitor SH-6 restored splicing factor expression and reversed both hormone staining effects and patterns of gene expression. This suggests that reversible changes in hormone expression may occur during exposure to diabetomimetic cellular stressors, which may be mediated by changes in splicing regulation.

Revisiting time to translation: implementation of evidence-based practices (EBPs) in cancer control.

PURPOSE: Previous studies estimate translation of research evidence into practice takes 17 years. However, this estimate is not specific to cancer control evidence-based practices (EBPs), nor do these studies evaluate variation in the translational process. We examined the translational pathway of cancer control EBPs. METHODS: We selected five cancer control EBPs where data on uptake were readily available. Years from landmark publication to clinical guideline issuance to implementation, defined as 50% uptake, were measured. The translational pathway for each EBP was mapped and an average total time across EBPs was calculated. RESULTS: Five cancer control EBPs were included: mammography, clinicians' advice to quit smoking, colorectal cancer screening, HPV co-testing, and HPV vaccination. Time from publication to implementation ranged from 13 to 21 years, averaging 15 years. Time from publication to guideline issuance ranged from 3 to 17 years, and from guideline issuance to implementation, - 4 to 12 years. Clinician's advice to quit smoking, HPV co-testing, and HPV vaccination were most rapidly implemented; colorectal cancer screening and mammography were slowest to implement. CONCLUSION: The average time to implementation was 15 years for the five EBPs we evaluated, a marginal improvement from prior findings. Although newer EBPs such as HPV vaccination and HPV co-testing were faster to implement than other EBPs, continued efforts in implementation science to speed research to practice are needed.

Improvement Science and Implementation Science in Cancer Care: Identifying Areas of Synergy and Opportunities for Further Integration.

Efforts to improve cancer care primarily come from two fields: improvement science and implementation science. The two fields have developed independently, yet they have potential for synergy. Leveraging that synergy to enhance alignment could both reduce duplication and, more importantly, enhance the potential of both fields to improve care. To better understand potential for alignment, we examined 20 highly cited cancer-related improvement science and implementation science studies published in the past 5 years, characterizing and comparing their objectives, methods, and approaches to practice change. We categorized studies as improvement science or implementation science based on authors' descriptions when possible; otherwise, we categorized studies as improvement science if they evaluated efforts to improve the quality, value, or safety of care, or implementation science if they evaluated efforts to promote the implementation of evidence-based interventions into practice. All implementation studies (10/10) and most improvement science studies (6/10) sought to improve uptake of evidence-based interventions. Improvement science and implementation science studies employed similar approaches to change practice. For example, training was employed in 8/10 implementation science studies and 4/10 improvement science studies. However, improvement science and implementation science studies used different terminology to describe similar concepts and emphasized different methodological aspects in reporting. Only 4/20 studies (2 from each category) described using a formal theory or conceptual framework to guide program development. Most studies were multi-site (10/10 implementation science and 6/10 improvement science) and a minority (2 from each category) used a randomized design. Based on our review, cancer-related improvement science and implementation science studies use different terminology and emphasize different methodological aspects in reporting but share similarities in purpose, scope, and methods, and are at similar levels of scientific development. The fields are well-positioned for alignment. We propose that next steps include harmonizing language and cross-fertilizing methods of program development and evaluation.

Ras-ERK-ETS inhibition alleviates neuronal mitochondrial dysfunction by reprogramming mitochondrial retrograde signaling.

Mitochondrial dysfunction activates the mitochondrial retrograde signaling pathway, resulting in large scale changes in gene expression. Mitochondrial retrograde signaling in neurons is poorly understood and whether retrograde signaling contributes to cellular dysfunction or is protective is unknown. We show that inhibition of Ras-ERK-ETS signaling partially reverses the retrograde transcriptional response to alleviate neuronal mitochondrial dysfunction. We have developed a novel genetic screen to identify genes that modify mitochondrial dysfunction in Drosophila. Knock-down of one of the genes identified in this screen, the Ras-ERK-ETS pathway transcription factor Aop, alleviates the damaging effects of mitochondrial dysfunction in the nervous system. Inhibition of Ras-ERK-ETS signaling also restores function in Drosophila models of human diseases associated with mitochondrial dysfunction. Importantly, Ras-ERK-ETS pathway inhibition partially reverses the mitochondrial retrograde transcriptional response. Therefore, mitochondrial retrograde signaling likely contributes to neuronal dysfunction through mis-regulation of gene expression.

Evaluation of the Cancer Control P.L.A.N.E.T. Web Portal.

CONTEXT: The Cancer Control P.L.A.N.E.T. (P.L.A.N.E.T.) Web portal was designed to ease access to data and evidence-based resources for cancer control practitioners and researchers focused on developing, implementing, and evaluating cancer control programs. OBJECTIVES: To determine usability, applicability, and opportunities to improve the P.L.A.N.E.T. Web portal after significant changes to the portal over time. DESIGN: The National Cancer Institute surveyed and interviewed cancer control professionals to assess factors influencing utilization of P.L.A.N.E.T. Data were collected from May 2017 to June 2018 via partner agencies, electronic publications, and online links. OUTCOME MEASURES: Descriptive statistics with χ test were used to analyze the quantitative data and examine the relationship among variables. Qualitative interviews further informed the quantitative analysis. RESULTS: Of the 724 participants surveyed, 51% were users of P.L.A.N.E.T., with the majority accessing P.L.A.N.E.T. within the last 6 months. Most users felt that P.L.A.N.E.T. effectively met their needs for accessing specific cancer data, identifying evidenced-based programs, and ascertaining details on various cancer topics. There were statistically significant differences in demographic characteristics between users and nonusers of P.L.A.N.E.T., where users were more likely to have more experience in the cancer field, were older in age, and located in southern states. CONCLUSION: Results indicate that P.L.A.N.E.T. is seen as a viable and credible source for cancer control program planning and delivery. A reassessment of P.L.A.N.E.T.'s goals is warranted, which may support reaching out to new audiences, amplifying or removing underutilized resources, and adding additional resources and topics. Consideration for training and tutorials on P.L.A.N.E.T. would benefit partner agencies and build capacity for evidence-based program development.

Measuring orthodontic treatment impact: Description or judgment, challenge or result.

INTRODUCTION: Determination of improvement in orthodontic treatment may depend on the measurement method used and the purpose. METHODS: Improvement after orthodontic treatment (from T1 to T2 [beginning to end of treatment]) was assessed 3 ways from a set of 98 patient records: (1) calculated by subtracting judges' assessments at T2 from T1 for records presented in random order, (2) judged as a holistic impression viewing T1 and T2 records side by side, and (3) determined from proxies (American Board of Orthodontics Discrepancy Index, the American Board of Orthodontics Objective Grading System, and the Peer Assessment Rating index). RESULTS: High levels of intramethod consistency were observed, with intraclass correlation coefficient clustering around an intraclass correlation coefficient of 0.900, and distributions were normal. Calculated and judged improvements correlated at r = 0.606. Calculated or judged improvements were correlated at a lower level with proxies. Calculated improvement was significantly associated with "challenge" (T1) scores and judged improvement associated with "results" (T2) scores. Common method bias was observed, with higher correlations among similar indexes than among indexes at the same time that used various methods. Relative to differences in Peer Assessment Rating scores, calculated improvement overestimated low scores and underestimated high ones. The same effect, but statistically greater, was observed using direct judgment of improvement. CONCLUSIONS: These findings are consistent with decision science and measurement theory. In some circumstances, such as third-party reimbursement and research, operationally defined measures of occlusion are appropriate. In practice, the determination of occlusion and improvement are best performed by judgment that naturally corrects for biases in proxies and incorporates background information.

[Protective macrophages : New insights into the role of synovial macrophages in inflammatory joint diseases]. / Protektive Makrophagen : Neue Einblicke zur Rolle von Synovialmakrophagen bei entzündlichen Gelenkerkrankungen.

Macrophages are among the phylogenetically oldest cells of the immune system and are found in all tissues and organs. In addition to playing an important role in immune response against pathogenic microorganisms, these cells were previously described to play a vital role in chronic inflammatory diseases such as rheumatoid arthritis. Using novel techniques such as single-cell sequencing and advanced microscopy techniques it has now been shown that macrophages are far more versatile. Thus, these cells contribute considerably to tissue homeostasis and tissue regeneration. As each tissue has to fulfill special requirements, macrophages vary in their phenotype and function between organs. New data have now identified a specialised population of epithelioid macrophages that exert a protective and anti-inflammatory function in synovial tissue and prevent the initial onset as well as episodes of joint inflammation in rheumatoid arthritis.

Local myostatin inhibition improves skeletal muscle glucose uptake in insulin-resistant high-fat diet-fed mice.

Myostatin inhibition is thought to improve whole body insulin sensitivity and mitigate the development of insulin resistance in models of obesity. However, although myostatin is known to be a major regulator of skeletal muscle mass, the direct effects of myostatin inhibition in muscle on glucose uptake and the mechanisms that may underlie this are still unclear. We investigated the effect of local myostatin inhibition by adeno-associated virus-mediated overexpression of the myostatin propeptide on insulin-stimulated skeletal muscle glucose disposal in chow-fed or high fat diet-fed mice and evaluated the molecular pathways that might mediate this. We found that myostatin inhibition improved glucose disposal in obese high fat diet-fed mice alongside the induction of muscle hypertrophy but did not have an impact in chow-fed mice. This improvement was not associated with greater glucose transporter or peroxisome proliferator-activated receptor-γ coactivator-1α expression or 5' AMP-activated protein kinase activation as previously suggested. Instead, transcriptomic analysis suggested that the improvement in glucose disposal was associated with significant enrichment in genes involved in fatty acid metabolism and translation of mitochondrial genes. Thus, myostatin inhibition improves muscle insulin-stimulated glucose disposal in obese high fat diet-fed mice independent of muscle hypertrophy, potentially involving previously unidentified pathways.

Novel methods for the analysis of toxicants in bronchoalveolar lavage fluid samples from e-cigarette, or vaping, product use-associated lung injury cases: Selected petroleum distillates.

RATIONALE: Over 2700 e-cigarette, or vaping, product use-associated lung injury (EVALI) cases were reported to the Centers for Disease Control and Prevention (CDC) during August 2019-February 2020. Bronchoalveolar lavage (BAL) fluid samples from 51 EVALI and 99 non-EVALI cases were analyzed for toxicants including petroleum distillates. We describe a novel method to measure petroleum distillates in BAL fluid using gas chromatography-mass spectrometry (GC/MS). METHODS: n-Hexane, n-heptane, n-octane, methylcyclopentane, and cyclohexane were measured in BAL fluid specimens by headspace solid-phase microextraction/GC/MS. We created and characterized BAL fluid pools from non-EVALI individuals to determine assay accuracy, precision, linearity, limits of detection (LODs), and analytical specificity. All measurements were conducted in accordance with the rigorous method validation procedures of CDC's Division of Laboratory Sciences. RESULTS: Matrix validation experiments showed that calibration curves in BAL fluid and saline had similar slopes, with differences less than 5%. Assay precision ranged from 1.98% to 18%. In addition, the LODs for the five analytes ranged from 0.05 to 0.10 µg/L, and their linearity was confirmed with R2 values >0.99. The analysis of selected petroleum distillates in BAL fluid analysis was shown to be comparable with their analysis in blood in which the 95th percentiles are below detection. CONCLUSIONS: We developed and validated a method to quantify petroleum distillates in BAL fluid specimens using GC/MS. The assay provided precise and accurate analyses of EVALI and non-EVALI BAL fluid specimens in support of CDC's EVALI response. This method is applicable to the determination of a broad range of volatile organic compounds in BAL fluid specimens.

The "secret sauce" for a mentored training program: qualitative perspectives of trainees in implementation research for cancer control.

BACKGROUND: Mentored training approaches help build capacity for research through mentoring networks and skill building activities. Capacity for dissemination and implementation (D&I) research in cancer is needed and mentored training programs have been developed. Evaluation of mentored training programs through quantitative approaches often provides us with information on "what" improved for participants. Qualitative approaches provide a deeper understanding of "how" programs work best. METHODS: Qualitative interviews were conducted with 21 fellows of the National Cancer Institute-funded Mentored Training for Dissemination and Implementation in Cancer to gain understanding of their experiences with mentoring received during the program. Fellows were selected from all 55 trained participants based upon their gain in D&I research skills (highest and lowest) and number of collaborative connections in the program network (highest and lowest) reported in previous quantitative surveys. Phone interviews were recorded with permission, transcribed verbatim, and de-identified for analysis. Codes were developed a priori to reflect interview guide concepts followed by further development and iterative coding of three common themes that emerged: 1) program and mentoring structure, 2) importance of mentor attributes, and 3) enhanced capacity: credentials, confidence, credibility and connections. RESULTS: Interviews provided valuable information about program components that worked best and impacts attributed to participation in the program. Fellows reported that regular monthly check-in calls with mentors helped to keep their research moving forward and that group mentoring structures aided in their learning of basic D&I research concepts and their application. Accessible, responsive, and knowledgeable mentors were commonly mentioned by fellows as a key to their success in the program. Fellows mentioned various forms of impact that they attributed to their participation in the program including gaining credibility in the field, a network of peers and experts, and career developments (e.g., collaborative publications and grant funding). CONCLUSIONS: These findings suggest that mentored training works best when mentoring is structured and coupled with applied learning and when respected and dedicated mentors are on board. Increased scientific collaborations and credibility within a recognized network are important trainee experiences that should be considered when designing, implementing, and sustaining mentored training programs.

Diagnostic paths for a mouth-breathing patient.

INTRODUCTION: The clinical choice of diagnostic tests or treatment options is determined by the probability that the value of their execution (called the warrant for the test) exceeds their cost, and by their usefulness. The purpose of this study was to determine the warrant and usefulness of STOP-Bang, an obstructive sleep apnea screening questionnaire, and cone-beam computed tomography (CBCT) information about the minimal cross-sectional area for referring a mouth-breathing patient to a sleep specialist and for modifying planned orthodontic treatment. METHODS: A branching survey was used to identify the prominence of paths between the presenting situation, 2 diagnostic tests, and 2 referral and/or treatment options. A description was given of a hypothetical patient: an overweight, mouth-breathing female teenager. Path analysis was used as a method for quantifying diagnostic warrant and usefulness. RESULTS: There was a wide variation among the 125 orthodontists who responded to the survey. All paths were chosen. The use of tests altered the referral (χ2 = 8.039; P = 0.03) and/or treatment decisions (χ2 = 12.636; P = 0.005). Ownership of a CBCT system significantly influenced the use of this diagnostic test, with owning a CBCT system resulting in greater use in-office (χ2 = 50.416; P <0.001) and greater use in the study (χ2 = 22.959; P <0.001). The usefulness of the diagnostic tests could not be determined directly because common values were used for each test, but the variation in the use of this standard stimulus was very large, indicating personal differences in the interpretation of actual data. CONCLUSIONS: Wide variation in the choice and interpretation of diagnostic tests for referral and orthodontic treatment modification relative to airway condition exists among orthodontists. Diagnostic path analysis is a potentially useful model for studying how practitioners make decisions independent of research evidence.

The three-dimensional stable mandibular landmarks in patients between the ages of 12.5 and 17.1 years.

BACKGROUND: With the aid of implants, Björk identified two-dimensional mandibular stable structures in cephalograms during facial growth. However, we do not know what the three-dimensional stable structures are with certainty. The purpose of this study was to identify the most stable mandibular landmarks in growing patients using three-dimensional images. METHODS: The sample was comprised of two cone-beam computed tomography (CBCT) scans taken about 4.6 years apart in 20 growing patients between the ages of 12.5 (T1) and 17.1 years (T2). After head orientation, landmarks were located on the chin (Pog), internal symphysis (Points C, D and E), and mandibular canals, which included the mental foramina (MF and MFA) and mandibular foramina (MdF). The linear distance change between Point C and these landmarks was measured on each CBCT to test stability through time. The reliability of the suggested stable landmarks was also evaluated. RESULTS: The total distance changes between Point C and points D, E, Pog, MF, and MFA were all less than 1.0 mm from T1 to T2. The reliability measures of these landmarks, which were measured by the Cronbach alpha, were above 0.94 in all three dimensions for each landmark. From T1 to T2, the distance changes from Point C to the right and left mandibular foramina were 3.39 ± 3.29 mm and 3.03 ± 2.83 mm, respectively. CONCLUSIONS: During a growth period that averaged 4.6 years, ranging from 11.2 to 19.8 years old, the structures that appeared relatively stable and could be used in mandibular regional superimpositions included Pog, landmarks on the inferior part of the internal symphysis, and the mental foramen. The centers of the mandibular foramina and the starting points of the mandibular canal underwent significant changes in the transverse and sagittal dimensions.