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Supplementary Figure from The Antitumor Effects of Vaccine-Activated CD8+ T Cells Associate with Weak TCR Signaling and Induction of Stem-Like Memory T Cells

To understand why vaccine-activated tumor-specific T cells often fail to generate antitumor effects, we studied two α-fetoprotein–specific CD8+ T cells (Tet499 and Tet212) that had different antitumor effects. We found that Tet499 required high antigen doses for reactivation, but could survive persistent antigen stimulation and maintain their effector functions. In contrast, Tet212 had a low threshold of reactivation, but underwent exhaustion and apoptosis in the presence of persistent antigen. In vivo, Tet499 cells expanded more than Tet212 upon reencountering antigen and generated stronger antitumor effects. The different antigen responsiveness and antitumor effects of Tet212 and Tet499 cells correlated with their activation and differentiation states. Compared with Tet212, the population of Tet499 cells was less activated and contained more stem-like memory T cells (Tscm) that could undergo expansion in vivo. The TCR signaling strength on Tet499 was weaker than Tet212, correlating with more severe Tet499 TCR downregulation. Weak TCR signaling may halt T-cell differentiation at the Tscm stage during immune priming and also explains why Tet499 reactivation requires a high antigen dose. Weak TCR signaling of Tet499 cells in the effector stage will also protect them from exhaustion and apoptosis when they reencounter persistent antigen in tumor lesion, which generates antitumor effects. Further investigation of TCR downregulation and manipulation of TCR signaling strength may help design cancer vaccines to elicit a mix of tumor-specific CD8+ T cells, including Tscm, capable of surviving antigen restimulation to generate antitumor effects. Cancer Immunol Res; 5(10); 908–19. ©2017 AACR.

Preferential activation of regulatory T (Treg) cells limits autoimmune tissue damage during chronic immune responses but can also facilitate tumor growth. Here, we show that tissue-produced inflammatory mediators prime maturing dendritic cells (DC) for the differential ability of attracting anti-inflammatory Treg cells. Our data show that prostaglandin E2 (PGE2), a factor overproduced in chronic inflammation and cancer, induces stable Treg-attracting properties in maturing DC, mediated by CCL22. The elevated production of CCL22 by PGE2-matured DC persists after the removal of PGE2 and is further elevated after secondary stimulation of DC in a neutral environment. This PGE2-induced overproduction of CCL22 and the resulting attraction of FOXP3+ Tregs are counteracted by IFNα, a mediator of acute inflammation, which also restores the ability of the PGE2-exposed DC to secrete the Th1-attracting chemokines: CXCL9, CXCL10, CXCL11, and CCL5. In accordance with these observations, different DCs clinically used as cancer vaccines show different Treg-recruiting abilities, with PGE2-matured DC, but not type 1–polarized DC, generated in the presence of type I and type II IFNs, showing high Treg-attracting activity. The current data, showing that the ability of mature DC to interact with Treg cells is predetermined at the stage of DC maturation, pave the way to preferentially target the regulatory versus proinflammatory T cells in autoimmunity and transplantation, as opposed to intracellular infections and cancer. [Cancer Res 2008;68(14):5972–8]

Supplementary Table 1, Figures 1-5 from Ability of Mature Dendritic Cells to Interact with Regulatory T Cells Is Imprinted during Maturation

Background Although laparoscopic hepatectomy (LH) is associated with improved short-term outcomes compared to open hepatectomy (OH), it is unknown whether frail patients also benefit from LH. The aim of this study was to evaluate the impact of frailty on postoperative outcomes after LH and OH. Methods Consecutive patients who underwent LH and OH between January 2011 and December 2018 were identified from a prospective database. Frailty was assessed using the modified Frailty Index (mFI), with patients scoring mFI ≥ 1 deemed to be frail. Results Of 1826 patients, 34.7% (N=634) were frail and 18.6% (N=340) were elderly (≥ 75 years). Frail patients had significantly higher 90-day mortality (6.6% vs. 2.9%, p Conclusions Frailty is independently associated with inferior postoperative outcomes in patients undergoing hepatectomy. However, the benefits of laparoscopic (compared to open) hepatectomy are similar for frail and non-frail patients. Frailty should not be a contraindication to laparoscopic minor hepatectomy in carefully selected patients.

Background Lymph node ratio (LNR) is a strong prognostic marker in pancreatic cancer (PDAC). In recent years, use of neoadjuvant chemotherapy (NAT) has increased, where it is associated with a higher rate of N0 resections, compared with a surgery first approach. The prognostic accuracy of the LNR after NAT has not been assessed. Methods Retrospective review of prospectively collected data from 2008–2020 of all patients undergoing pancreaticoduodenectomy (PD) for PDAC. Basic demographics, pathological and clinical outcomes were analysed using standard statistical tests. Cox regression and Kaplan-Meier analyses were performed. Results Retrospective review of prospectively collected data from 2008–2020 of all patients undergoing pancreaticoduodenectomy (PD) for PDAC. Basic demographics, pathological and clinical outcomes were analysed using standard statistical tests. Cox regression and Kaplan-Meier analyses were performed. Conclusions NAT reduces the predictive accuracy of the LNR in resected pancreatic cancer; alternative prognostic models will require development.

Background Survival following pancreatic cancer resection remains poor despite advances in adjuvant and neoadjuvant therapy. The incidence of positive margin status (R1) is high and an R1 resection is associated with poorer survival. The most commonly positive margin is the SMA, accounting for between 47–77% of R1 resections. Periadventitial dissection of the SMA includes the lymphoneural tissue around the adventitia in addition to the ‘mesopancreas’ in the resection specimen and is used to varying extent across different centres. Theoretically this technique should reduce R1 resection rate, however, there is a lack of prospective evidence in the published literature. Methods The DISSECT trial is a single centre, randomised control trial. All patients with a resectable as per NCCN staging criteria head of pancreas tumour are randomised to either ‘periadventitial SMA dissection’ or ‘no periadventitial SMA dissection’ (1:1 block randomisation, sealed envelope system). A standardised technique for length and circumference of dissection is used and intra-operative photography with blinded assessment of dissection status ensures quality control. This safety and feasibility stage assesses recruitment, technique and complications and will be followed by a study powered to detect the primary outcome of reduction in positive SMA margin status. Primary outcomes to be assessed in the fully powered study will be the SMA margin status as detailed by the AJCC 8th edition. Secondary outcomes are status of other margins, length of stay, complications, overall and disease-free survival, complications, and adjuvant treatment details. These are assessed prospectively by an investigator blinded to the study arm. Results For the feasibility stage, the following criteria were set to proceed: recruitment of 20 patients in 6 months, at least 80% of recruited patients to undergo correct arm of randomisation, and an increase in complication rate of no more than 10%. Within the first 6 months, 32 patients were successfully recruited and randomised. 6 were excluded post-randomisation but before SMA approach (N=2 cancelled and not re-booked, N=2 abandoned after opening, N=2 converted to total pancreatectomy). N=3 were eligible but not recruited, (2 refused after approach and 1 was missed due to research team capacity). N=25 (96.2%) underwent their allocated study arm (confirmed by blinded photo assessment). For potentially procedure related complications (SMA bleed, post-operative haemorrhage, chyle leak, collection, and anastomotic leak) there was an overall rate of 38.5%, with no significant difference between the 2 arms (42.9% in No SMA dissection arm and 33.3% in the SMA dissection arm). There were no incidences of SMA branch bleed in the SMA dissection arm and a single post-operative haemorrhage in the SMA dissection arm that was due to a mesenteric venous bleed. Conclusions The DISSECT trial is a randomised controlled trial that aims to evaluate the use of a standardised technique of periadventitial SMA dissection to reduce the rate of R1 resection in early stages of pancreatic cancer. The feasibility and safety pilot is complete and demonstrates successful recruitment and randomisation, excellent adherence to randomisation arm and no operative concerns from the surgical team. The study will now proceed to full recruitment with complications and blinded photo reviews for quality control assessed contemporaneously. Primary and secondary outcomes will be recorded prospectively by a member of the research team blinded to randomisation arm.

No conclusive recommendations exist regarding use of abdominal drainage in hepatectomy. The practice of abdominal drainage remains commonplace despite unfavorable outcomes reported by randomized controlled trials. We aimed to compare the impact of abdominal drainage on outcomes of hepatectomy.A systematic search of electronic information sources and bibliographic reference lists was conducted. A combination of free text and controlled vocabulary search adapted to thesaurus headings, search operators, and limits in each of the above databases was applied. Overall perioperative and wound-related complications, bile leak, intra-abdominal collections (including those requiring an intervention), and the length of hospital stay were the evaluated outcome parameters.Seven randomized controlled trials reporting 1,064 patients undergoing hepatectomy with (n = 533) or without (n = 531) placement of abdominal drain were included. Patients in both groups were of comparable age (P = .23), sex (P = .49), proportion of major hepatectomy (P = .93), minor hepatectomy (P = .96), cirrhosis (P = .78), and malignant pathologies (P = .61). Drainage after hepatectomy was associated with significantly higher overall complications (RR: 1.37, P = .0003) and wound-related complications (risk ratio: 2.29, P = .01) compared to no drainage. Moreover, there was no significant difference in bile leak (risk ratio: 2.15, P = .19), intra-abdominal collections (risk ratio: 1.13, P = .70), intra-abdominal collections requiring interventions (risk ratio: 1.19, P = .71), or length of hospital stay (mean difference: 0.37, P = .67) between the 2 groups. The trial sequential analysis confirmed conclusiveness of the findings.Abdominal drainage after hepatectomy increases overall and wound-related complications, without any reduction in the risk of intra-abdominal collections needing an intervention. Routine drainage after an uncomplicated hepatectomy should be avoided, with the possible exception of the presence of a bilioenteric anastomosis.

Appendiceal mucinous neoplasms (AMNs) with disseminated disease are a heterogeneous group of tumors with variable clinicopathologic behavior. Despite the development of prognostic systems, objective biomarkers are needed to accurately stratify patients. With the advent of next-generation sequencing (NGS), it remains unclear if molecular testing can improve the evaluation of disseminated AMN patients with respect to currently used prognostic systems. Therefore, targeted NGS was performed for 183 patients and correlated with patient demographics, AJCC/WHO histologic grade, lymphovascular and perineural invasion, regional lymph node metastasis, peritoneal cancer index (PCI), completeness of cytoreduction (CC) score, and overall survival (OS). Genomic alterations were identified for 179 (98%) disseminated AMNs and consisted of KRAS (84%), GNAS (59%), TP53 (24%), SMAD4 (19%), PIK3CA (4%), ATM (4%), PTEN (2%), NRAS (2%), BRAF (2%), and CDKN2A (1%). Excluding mitogen activated protein kinase (MAPK) genes and GNAS due to their ubiquitous nature among AMNs, collective genomic alterations in TP53, SMAD4, CDKN2A, and the mTOR genes were associated with older mean age (p = 0.019), higher AJCC/WHO histologic grade (p TP53, SMAD4, ATM, CDKN2A, and/or mTOR gene alterations were found to have lower OS rates of 55% at 5 years and 14% at 10 years, as compared to 88% at 5 years and 88% at 10 years for patients without the aforementioned genomic alterations (p TP53, SMAD4, ATM, CDKN2A, and/or the mTOR genes in disseminated AMNs were a negative prognostic factor for OS and independent of AJCC/WHO histologic grade, PCI, CC score, and hyperthermic intraperitoneal chemotherapy treatment (p = 0.006). In summary, targeted NGS improves the prognostic assessment of patients with disseminated AMNs and identifies patients that may require increased surveillance and/or more aggressive management.

Eye-tracking techniques can be used to understand the visual search process in diagnostic radiology. Nonetheless, most prior eye-tracking studies in CT only involved single cross-sectional images or video playback of the reconstructed volume and meanwhile applied strong constraints to reader-image interactivity, yielding a disconnection between the corresponding experimental setup and clinical reality. To overcome this limitation, we developed an eye-tracking system that integrates eye-tracking hardware with in-house-built image viewing software. This system enabled recording of radiologists’ real-time eye-movement and interactivity with the displayed images in clinically relevant tasks. In this work, the system implementation was demonstrated, and the spatial accuracy of eye-tracking data was evaluated using digital phantom images and patient CT angiography exam. The measured offset between targets and gaze points was comparable to that of many prior eye-tracking systems (The median offset: phantom – visual angle ~0.8°; patient CTA – visual angle ~0.7 – 1.3°). Further, the eye-tracking system was used to record radiologists’ visual search in a liver lesion detection task with contrast-enhanced abdominal CT. From the measured data, several variables were found to correlate with radiologists’ sensitivity, e.g., mean sensitivity of readers with longer interpretation time was higher than that of the others (88 ± 3% vs 78 ± 10%; p < 0.001). In summary, the proposed eye-tracking system has the potential of providing high-quality data to characterize radiologists’ visual-search process in clinical CT tasks.

The aim of this study was to determine predictors of erosive tooth wear (ETW) progression, using novel primary-care quantitative analysis techniques.In a single-centre, prospective, observational cohort longitudinal study, adolescents, aged 11-18 years, underwent a baseline BEWE examination, validated risk factors questionnaire and baseline intraoral scan (IOS, TRIOS 3.0, 3Shape, Copenhagen, Denmark). One year later a repeat scan was taken. Quantitative analysis of wear progression (volume loss) on first permanent molars and upper central incisors was performed using previously published protocols. Multilevel linear regression was used to investigate the associations between baseline predictors and volume loss per mmA total of 295 dental surfaces (131 incisors and 164 molars) in 70 patients were analysed for this study. The mean age of participants at baseline was 15.0 years (SD: 0.79), and the average time between scans was 11.8 months (1.61 SD; range 10-13). The mean volume loss per mmThe findings help to characterise groups at greater risk of ETW and would indicate that improved screening and upstream preventative measures should form the basis of a preventative program.Intra-orals scans and registration software might improve the ability to diagnose, monitor and prevent the early loss of dental hard tissue.

ObjectivesTo determine if superimposition of sequential scans can discriminate between different fluorides at step heights less than 5 μm on natural human enamel surfaces.Materials and methodsNatural, unpolished, human enamel specimens (n = 60) were randomly assigned to one of three pre-treatment toothpaste slurries with a calcium silicate/fluoride, fluoride-only and a control. Baseline and post treatment scans, from a non-contacting profilometer with a 0.01 μm z-axis and ResultsConfidence and resolution of superimposition and subtraction of repeated profiles from unpolished enamel revealed accuracy within 1–2 μm. The technique was able to discriminate between the fluorides demonstrating statistical differences in mean (SD) 3D step height (μm) of 1.96 (0.40) and 2.75 (0.49) (p = 0.0024). There was a statistically significant increase in surface roughness for all groups after 15 min erosion compared to baseline. But no statistically significant difference between the interventions after 15 min erosion but there was compared to no fluoride (p = 0.006).ConclusionSuperimposition and subtraction of profiles could discriminate between fluoride interventions, which showed statistical differences in enamel loss differences less than 3 μm.Clinical significanceThis erosion model and data analysis workflow was able to distinguish differences between scans of 3 μm on unpolished enamel following the interaction with fluoride.

Background Traumatic injuries are of global health concern and significant contributors to Emergency Department (ED) and hospital workload. Aim To compare patterns of traumatic injuries among patient presentations to the ED across different modes of arrival (ambulance, police, or private transport) and to examine the predictors of an ED length of stay (LOS) exceeding 4 hours and hospital admission requirement. Methods A retrospective observational study using 6 months of health data (8th October 2012–7th April 2013) of ED patient presentations made to one large, regional ED in Queensland, Australia, with a diagnosis code related to trauma. Findings Over 6 months, 24.2% (n = 6,668) of adult patient presentations were trauma-related; most (60.9%) arrived via privately arranged transport (PAT); 38.7% were brought in by ambulance (BIBA) and 0.4% were brought in by police (BIBP). Demographics, clinical profile and patient outcomes differed based on mode of arrival. One in four patient presentations required hospital admission and 25% had an ED length of stay of >4 hours. Factors influencing hospital admission included older age, night shift, more emergent priority, and being BIBA. An ED length of stay of >4 hours was associated with older age, being BIBA, emergent nature of presentation, and hospital admission. Conclusion The profile and outcomes of ED patient presentations with traumatic injury differs based on their mode of arrival to the ED. People BIBA were more likely to require hospital admission and have longer ED LOS, compared with those BIBP or PAT, even when controlling for covariates. Our findings may be used to inform nursing resource allocation when considering mode of arrival, especially for older people and people BIBA.

This paper explains how to screen tooth wear in general practice using the Basic Erosive Wear Examination (BEWE) index. It explains how stakeholders in the UK acknowledged the convenience of the BEWE and that it could be recorded at the same time as the Basic Periodontal Examination (BPE). The article contains examples of anterior and posterior tooth wear for each BEWE score to help dentists in their evaluation.

Objectives To determine the detection threshold of non-contacting laser profilometry (NCLP) measuring surface form and surface roughness change in natural human enamel in vitro, characterise how ambient scanning thermal variation affects NCLP measurement, and calculate bulk enamel loss in natural human enamel. Methods NCLP repeatability and reproducibility accuracy was determined by consecutively scanning natural human enamel samples with/without sample repositioning. Ambient thermal variation and NCLP sensor displacement over short (30 s), medium (20 min), and long (2 h) scanning periods were evaluated for their standard deviation. Natural human enamel specimens (n = 12) were eroded using citric acid (0.3% w/w pH3.2) for 5, 10, and 15 min and characterised using surface profilometry, tandem scanning confocal microscopy (TSM), and optical coherence tomography (OCT). Results Repeatability and reproducibility error of NCLP for surface form was 0.28 μm and 0.43 μm, and for surface roughness 0.07 μm and 0.08 μm. Ambient thermal variation resulted in NCLP sensor displacement of 0.56 μm and 1.05 μm over medium and long scanning periods. Wear scar depth (μm) was calculated between 0.72–1.61 at 5 min, 1.72–3.06 at 10 min, and 3.40–7.06 at 15 min. Mean (SD) surface roughness (μm) was 1.13 (0.13), 1.52 (0.23), 1.44 (0.19), and 1.43 (0.21) at baseline, 5, 10, and 15 min. Qualitative image analysis indicated erosive change at the surface level, progressing after increasing erosion time. Significance Minimum detectable limits for NCLP measuring surface form and surface roughness changes were characterised. Ambient thermal variation, subsequent sensor displacement, and its impact on NCLP performance were characterised. Dental erosion lesions in natural human enamel could be characterised using surface profilometry, surface roughness, OCT, and TSM. Step height formation could be calculated within NCLP and temperature operating limits using profile superimposition and profile subtraction techniques. Natural enamel samples can now be used in in-vitro studies to investigate the formation and development of early acid erosive tooth wear, as well as the assessment of methods for enamel lesion remineralisation and repair.

To estimate the prevalence and distribution of tooth wear among groups of adolescents and adults in Shanghai, China through an epidemiological survey, and explore the associated factors.Multistage, stratified, constant volume and cluster sampling methods were used in an epidemiological survey conducted in Shanghai in 2014. The basic erosive wear examination (BEWE) index was used to screen for tooth wear in different age groups: 12 years, 15 years, 18 to 35 years, 36 to 49 years and 50 to 74 years. A previously published questionnaire collected information including dietary habits, oral hygiene habits and general conditions.This survey reports the results for 1806 participants in Shanghai. The prevalence of tooth wear was 59.7% in adolescents (BEWE ≥ 1) and 93.1% in adults (BEWE ≥ 2). The prevalence and severity of disease increased with age (P0.01). The teeth most susceptible to wear were the central incisors and first molars. Multivariate analysis of covariance (ANCOVA) results showed that soft drinks, alcoholic drinks, pickled vegetables and hard food, gastroesophageal reflux disease (GERD), xerostomia and poor tooth brushing habits were statistically correlated with tooth wear in different age groups.The prevalence of tooth wear appears to be high in adolescents and adults in Shanghai. Frequent consumption of soft or alcoholic drinks, GERD, xerostomia and poor tooth brushing habits were positively associated with tooth wear in different age groups.

Digital microscopy offers the ability to scan surfaces to produce 3D reconstructions, allowing step height measurements with high accuracy. The aims of this study were to compare the step heights from the gold standard, non-contact profilometry, to digital microscopy in an erosion/abrasion model.Dentine specimens (n = 60) were immersed in deionised water, 1450 ppm and 5000 ppm fluoride as sodium fluoride for 3 min, eroded for a total of 25 min in a cycled protocol in 0.3% citric acid (pH 2.7) and abraded with 120 and 240 brushing strokes. Samples were scanned by a non-contacting profilometer with a 0.1 μm vertical resolution and then the same samples imaged with a digital microscope and the step heights compared. Data were analysed in GraphPad Prism 7.00. Data were normally distributed and a 3 way ANOVA with post hoc analysis used to assess for differences between groups. Agreement between the measurement method was assessed using IntraClass Correlations and Bland Altmans plots.The mean step heights from the profilometry and the digital microscope on the same samples were not statistically significant different. The magnitude of the differences was less than 0.5 μm. The results of the ANOVA demonstrated that the individual factors fluoride concentration and number of strokes were significant (P0.05), however, the method of analysis was not (p = 0.74). ICC's between the two methods of analysis were excellent (0.996, p0.001) with no proportional bias.This study reports that step height on dentine from a digital microscopy and non-contact profilometry were not significantly different. The digital microscope, although slower, allows visual inspection of the samples as well as measurement.Digital microscope's offer the ability to scan, 2D or 3D images and perform meteorological analysis of samples. In this investigation both showed that 5000 ppm fluoride prevents erosive tooth wear in vitro.

BackgroundOral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact are the four oral health-related quality of life (OHRQoL) dimensions (4D) or areas in which oral disorders impact pediatric patients. Using their dentists' assessment, the study aimed to evaluate whether pediatric dental patients' oral health concerns fit into the 4D of the Oral Health-Related Quality of Life (OHRQoL) construct.MethodsDentists who treat children from 32 countries and all WHO regions were selected from a web-based survey of 1580 international dentists. Dentists were asked if their pediatric patients with current or future oral health concerns fit into the 4D of the Oral Health-Related Quality of Life (OHRQoL) construct. Proportions of all pediatric patients’ oral health problems and prevention needs were computed.FindingsData from 101 dentists treating children only and 523 dentists treating children and adults were included. For 90% of pediatric patients, their current oral health problems fit well in the four OHRQoL dimensions. For 91% of oral health problems they intended to prevent in the future were related to these dimensions as well. Both numbers increased to at least 96% when experts analyzed dentists´ explanations of why some oral health problems would not fit these four categories.ConclusionsThe study revealed the four fundamental components of dental patients, i.e., the four OHRQoL dimensions (Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact) are also applicable for pediatric patients, regardless of whether they have current or future oral health concerns, and should be considered when measuring OHRQoL in the pediatric dental patient population.

Natural human enamel (NHE) is a complex freeform surface which has presented significant difficulties in measuring surface form change using non-contacting laser profilometry (NCLP). Measuring surface form change on NHE is a metrology proxy for measuring dental tooth structure loss, and characterising this using non-ISO parameters (volume, surface area, and normalised lesion depth) has been seldom studied due surface complexity and undetermined measurement errors. This study determines NCLP measurement errors (instrument repeatability and method reproducibility) for non-ISO parameters, characterises change in surface form on NHE following a dietary pH-cycling model. NHE (n = 1) was scanned consecutively twenty-times using NCLP with/without sample replacement producing consecutive surface profile data. Residual data was created after subtracting consecutive filtered profile data (80 μm, Gaussian filter), and mean (SD) volume, surface area, and normalised lesion depth was determined within a 1.5 mm circular region of interest (ROI). Volume error (expressed as height variation across ROI surface area) was 0.022 μm (instrument repeatability) and 0.149 μm (method reproducibility), whilst surface area error (expressed as percentage change of the surface area deviation across the entire surface area) was 0.034% (repeatability error) and 0.081% (reproducibility error). Sixty-four natural enamel surfaces taped with polyvinyl-chloride tape leaving 1.5 mm exposed ROI underwent dietary erosion cycling (three 5-min cycles, 0.3% citric acid w/v, pH 3.2) generating artificial erosion lesions. Samples were scanned with NCLP before/after each erosion cycle, scans filtered for microtexture, and after-erosion scans were subtracted from before-erosion scans. NCLP results show mean (SD) volume, surface area, normalised depth, and 3D step-height of the eroded area increased significantly after each erosion cycle, with no significant difference in calcium and phosphate release after each cycle. We demonstrate a robust and valid dental model with analysis workflow to measure surface form change in NHE using NCLP, improving understanding of measuring surface form change in complex freeform surfaces.

To compare the frequency of patients' oral health problems and prevention needs among Slovenian and international dentists with the aim to validate the four oral health-related quality of life (OHRQoL) dimensions across six clinical dental fields in all World Health Organization (WHO) regions.An anonymous electronic survey in the English language was designed using Qualtrics software. A probability sampling for Slovenia and a convenience sampling strategy for dentist recruitment was applied for 31 countries. Dentists engaged in six dental fields were asked to categorize their patients' oral health problems and prevention needs into the four OHRQoL dimensions (Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact). Proportions of patients' problems and prevention needs were calculated together with the significance of Slovenian and international dentists' differences based on dental fields and WHO regions.Dentists (n=1,580) from 32 countries completed the survey. There were 223 Slovenian dentists (females: 68%) with a mean age (SD) of 41 (10.6) years and 1,358 international dentists (females: 51%) with a mean age (SD) of 38 (10.4). Pain-related problems and prevention needs were the most prevalent among all six dental fields reported by dentists; Slovenian (37%) and 31 countries (45%). According to Cohen, differences between Slovenia, the broader European Region, and 31 countries were considered non-significant (0.1).According to the dentists' responses, the frequency of patients' oral health problems and prevention needs are proportionate between Slovenia and 31 countries, regionally and globally. The four OHRQoL dimensions can be considered universal across all dental fields.V raziskavi smo želeli primerjati pogostost ustno-obraznih težav in potreb po preventivnem zdravju zobozdravstvenih pacientov med slovenskimi in mednarodnimi zobozdravniki s pomočjo spletne ankete, ki bi potrdila veljavnost štirih dimenzij oralnega zdravja v šestih kliničnih zobozdravstvenih specialnostih iz vseh svetovnih regij, kot jih določa Svetovna zdravstvena organizacija.V programski opremi Qualtrics smo v angleškem jeziku izdelali anonimno spletno anketo z namenom kategorizirati ustno-obrazne težave in preventivne ukrepe zobozdravstvenih pacientov v štiri dimenzije oralnega zdravja (funkcionalna, bolečinska, estetska in psihosocialna) na osnovi šestih stomatoloških specialnosti. Naključno vzorčenje smo uporabili za slovenske zobozdravnike, medtem ko smo za zobozdravnike iz 31 držav uporabili priložnostno vzorčenje. Za preverjanje pacientovih ustno-obraznih težav ter njihove potrebe po zdravljenju na osnovi zobozdravnikove ocene smo uporabili razmerja v odstotkih. Velikost učinka smo računali za preverjanje razlik med slovenskimi in tujimi zobozdravniki iz vseh regij po razdelitvi Svetovne zdravstvene organizacije in na osnovi šestih zobozdravstvenih specialnosti.Tisoč petsto osemdeset zobozdravnikov iz 32 držav je izpolnilo spletno anketo. Od tega je bilo 223 slovenskih (68 % žensk) s povprečno starostjo (SD) 41 (10,6) let in 1.358 tujih zobozdravnikov (51 % žensk) s povprečno starostjo (SD) 38 (10,4) let. Slovenski (37 %) in tuji (45 %) zobozdravniki so izbrali ustnoobrazno bolečino kot najpogostejšo težavo in preventivni ukrep pri zobozdravstvenih pacientih v vseh šestih zobozdravstvenih specialnostih. Po Cohenu so bile razlike med slovenskimi in pacienti iz drugih držav z ustnoobraznimi težavami in pri preventivnih ukrepih zelo majhne (0,1).Ustno-obrazne težave zobozdravstvenih pacientov in njihove potrebe po zdravljenju znotraj vseh šestih zobozdravstvenih specialnosti so v Sloveniji in drugih 31 državah, regionalno in globalno, primerljive. Vse štiri dimenzije podpirajo zobozdravnikov celostni pogled na oralno zdravje in preventivne ukrepe zobozdravstvenih pacientov po svetu in zobozdravstvenih specialnostih.

Las lesiones dentales no cariosas, como los defectos de desarrollo del esmalte (DDE) y el desgaste dental erosivo (ETW), son objeto de una intensa investigación. Este artículo tiene como objetivo brindar perspectivas sobre DDE, incluida la fluorosis dental y la hipomineralización de incisivos molares (MIH), y ETW, presentando datos epidemiológicos de las Américas y aspectos de diagnóstico asociados. Además, es importante presentar evidencia para guiar el proceso de evaluación clínica, apoyando las decisiones de manejo de los clínicos hacia una mejor salud bucal de sus pacientes. El aumento general en la prevalencia mundial de lesiones no cariosas discutidas en este documento puede reflejar la necesidad de cambios en la percepción. Aunque el número de publicaciones relacionadas con estas condiciones ha ido en aumento en los últimos años, todavía existe la necesidad de concienciación sobre el diagnóstico clínico y el manejo para incluir estas condiciones en la práctica odontológica de rutina. Además, es importante brindar recomendaciones para criterios de evaluación clínica estandarizados, mejorando el proceso y ayudando a la adherencia de los clínicos. En este sentido, este trabajo discute los índices más comúnmente implementados para cada condición. Así, a pesar de la amplia gama de índices diagnósticos, se propone que BEWE sea el índice recomendado para la evaluación de ETW, los índices de Dean o Thylstrup & Fejerskov para fluorosis y preferiblemente los criterios EAPD (o índice DDE modificado) para MIH. En general, las lesiones no cariosas son una preocupación creciente, y es importante implementar medidas preventivas que controlen su gravedad y progresión, y un diagnóstico preciso por parte del odontólogo. Non-carious dental lesions such as developmental defects of enamel (DDE) and erosive tooth wear (ETW) are the subject of intensive research. This paper aims to give perspectives on both DDE, including dental fluorosis and molar incisor hypomineralization (MIH), and ETW, presenting epidemiological data from the Americas and associated diagnostic aspects. Besides, it is important to present evidence to guide the clinical assessment process, supporting the clinicians' management decisions towards better oral health of their patients. The overall increase in the worldwide prevalence of non-carious lesions discussed in this this paper may reflect the need of perceptual changes. Although the number of publications related to these conditions has been increasing in the last years, there is still a need for clinical diagnostic and management awareness to include these conditions in routine dental practice. Besides, it is important to provide recommendations for standardized clinical assessment criteria, improving the process and helping clinicians' adherence. In this sense, this paper discusses the most commonly implemented indices for each condition. Thus, despite the wide range of diagnostic indices, BEWE is proposed to be the index recommended for ETW assessment, Dean or Thylstrup & Fejerskov indices for fluorosis and preferably the EAPD criteria (or modified DDE index) for MIH. Overall, non-carious lesions are a growing concern, and it is important to implement preventive measures that control their severity and progression, and accurate diagnosis by the dental clinician.

BACKGROUND: The Clinical Oral Disorder in Elders (CODE) index was proposed in 1999 to assess the oral health status and treatment needs of older people who typically were edentate or had few natural teeth. Since then, more people are retaining natural teeth into old age and have oral disorders similar to younger adults. In addition, there has been further guidance on screening for disease that includes changes to the clinical indicators of several oral disorders and greater sensitivity to people's concerns about their oral health and care needs. METHODS: Experts in dental geriatrics assembled at a satellite symposium of the International Association of Dental Research in June 2019 to revise the objectives and content of the CODE index. Before the symposium, 139 registrants were asked for comments on the CODE index, and 11 content experts summarised current evidence and assembled reference lists of relevant information on each indicator. The reference lists provided the base for a narrative review of relevant evidence supplemented by reference tracking and direct searches of selected literature for additional evidence. RESULTS: Analysis of the evidence by consensus of the experts produced the Clinical Oral Disorders in Adults Screening Protocol (CODA-SP). CONCLUSIONS: The CODA-SP encompasses multiple domains of physical and subjective indicators with weighted severity scores. Field tests are required now to validate its effectiveness and utility in oral healthcare services, outcomes and infrastructure. ispartof: GERODONTOLOGY vol:38 issue:1 pages:5-16 ispartof: location:England status: published

Government and public concern about corporate wrongdoing in Australia is arguably at an all-time high. However, the extent and nature of corporate crime is largely unknown; it is concealed by regulatory agency reporting practices and the absence of a single data source which combines data across all regulators. This study addresses the problem by examining corporate offending by 33 of the country’s top companies, and their wholly owned subsidiaries, over a five-year period. The results indicate that corporate offending is patterned and unevenly distributed across the business community. Drawing on the findings and on their experience of conducting the research, the authors make recommendations for improving policy and practice, including the establishment of a national database of corporate offending.

Background Three-dimensional scans are increasingly used to quantify biological topographical changes and clinical health outcomes. Traditionally, the use of 3D scans has been limited to specialized centers owing to the high cost of the scanning equipment and the necessity for complex analysis software. Technological advances have made cheaper, more accessible methods of data capture and analysis available in the field of dentistry, potentially facilitating a primary care system to quantify disease progression. However, this system has yet to be compared with previous high-precision methods in university hospital settings. Objective The aim of this study was to compare a dental primary care method of data capture (intraoral scanner) with a precision hospital-based method (laser profilometer) in addition to comparing open source and commercial software available for data analysis. Methods Longitudinal dental wear data from 30 patients were analyzed using a two-factor factorial experimental design. Bimaxillary intraoral digital scans (TrueDefinition, 3M, UK) and conventional silicone impressions, poured in type-4 dental stone, were made at both baseline and follow-up appointments (mean 36 months, SD 10.9). Stone models were scanned using precision laser profilometry (Taicaan, Southampton, UK). Three-dimensional changes in both forms of digital scans of the first molars (n=76) were quantitatively analyzed using the engineering software Geomagic Control (3D Systems, Germany) and freeware WearCompare (Leeds Digital Dentistry, UK). Volume change (mm3) was the primary measurement outcome. The maximum point loss (μm) and the average profile loss (μm) were also recorded. Data were paired and skewed, and were therefore compared using Wilcoxon signed-rank tests with Bonferroni correction. Results The median (IQR) volume change for Geomagic using profilometry and using the intraoral scan was –0.37 mm3 (–3.75-2.30) and +0.51 mm3 (–2.17-4.26), respectively (P Conclusions As expected, the method of data capture, software used, and measurement metric all significantly influenced the measurement outcome. However, when appropriate analysis was used, the primary care system was able to quantify the degree of change and can be recommended depending on the accuracy needed to diagnose a condition. Lower-resolution scanners may underestimate complex changes when measuring at the micron level.

Objectives: The aim of this study was to investigate variations in the interaction between enamel, that is, the acquired enamel pellicle (AEP) and citric or hydrochloric acid. Materials and Methods: A 24-h AEP was formed on natural enamel specimens (n = 40) from pooled whole mouth human saliva. Samples were randomly allocated to citric (0.3%, pH 3.2) or hydrochloric (HCl) acid (0.01 M, pH 2.38) exposure for 30 or 300 s. The total protein concentration (TPC), and phosphorous and calcium concentrations of the pellicle were determined before and after acid exposure, and again after re-immersion in saliva. Surface roughness and tandem scanning confocal microscopy imaging were used to assess enamel changes. Results: After 300 s of citric acid exposure, the mean ± SD TPC reduced from 5.1 ± 1.1 to 3.5 ± 1.1 mg/mL (p < 0.05). In contrast, after 300 s of HCl exposure, the mean TPC did not reduce significantly from baseline (6.6 ± 1.1 to 5.7 ± 0.7 mg/mL) but was significantly reduced in the reformed pellicle to 4.9 ± 1.2 mg/mL (p < 0.001). This reduction occurred after significant release of calcium and phosphorous from the enamel surface (p < 0.001). Thirty seconds of exposure to either acid had no obvious effect on the AEP. The surface roughness of the enamel decreased after acid exposure but no differences between groups was observed. Conclusions: These findings indicate that citric acid interacted with proteins in the AEP upon contact, offering enamel protection. In contrast, HCl appeared to bypass the pellicle, and reduced protein was observed only after changes in the enamel chemical composition.

Objective The dimensions of oral health–related quality of life (OHRQoL) Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact are the major areas where patients are impacted by oral diseases and dental interventions. The aim of this study was to evaluate whether dental patients' reasons to visit the dentist fit the 4 OHRQoL dimensions. Methods Dentists (N = 1580) from 32 countries participated in a web-based survey. For their patients with current oral health problems, dentists were asked whether these problems were related to teeth, mouth, and jaws' function, pain, appearance, or psychosocial impact or whether they do not fit the aforementioned 4 categories. Dentists were also asked about their patients who intended to prevent future oral health problems. For both patient groups, the proportions of oral health problems falling into the 4 OHRQoL dimensions were calculated. Results For every 100 dental patients with current oral health problems, 96 had problems related to teeth, mouth, and jaws' function, pain, appearance, or psychosocial impact. For every 100 dental patients who wanted to prevent future oral health problems, 92 wanted to prevent problems related to these 4 OHRQoL dimensions. Both numbers increased to at least 98 of 100 patients when experts analyzed dentists' explanations of why some oral health problems would not fit the four dimension. For the remaining 2 of 100 patients, none of the dentist-provided explanations suggested evidence against the OHRQoL dimensions as the concepts that capture dental patients' suffering. Conclusion Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact capture dental patients' oral health problems worldwide. These 4 OHRQoL dimensions offer a psychometrically sound and practical framework for patient care and research, identifying what is important to dental patients.

Goblet cell carcinoids (GCC) are an aggressive, albeit rare, subtype of appendiceal tumors that exhibit distinct histologic features and lack clear treatment guidelines. We aimed to ascertain the impact of adjuvant chemotherapy (AC) for GCC in a national cohort of patients.Patients who underwent a right hemicolectomy for stage I-III GCC of the appendix between 2006 and 2016 were selected from the National Cancer Database (NCDB). Stratification based on AC receipt was performed. Kaplan-Meier survival estimates and Cox proportional hazard regression were used to identify predictors of overall survival (OS).A total of 867 patients were identified, of whom 124 (14%) received AC. Patients in the AC group were significantly younger (54 vs. 57 years; p = 0.006) and were predominantly of male sex (60 vs. 48%; p = 0.012). On histopathology, patients in the AC group had a higher proportion of poorly/undifferentiated grade (27 vs. 5%; p 0.001), T4 disease (35 vs. 11%; p 0.001), and lymph node-positive disease (45 vs. 7%; p 0.001) than patients who did not receive AC. After excluding patients diagnosed in 2016 due to a lack of follow-up data (n = 162), a survival advantage for the AC group was detected only after stratification for lymph node-positive disease (p = 0.007). On Cox proportional hazard regression, AC demonstrated an independent association with improved OS (hazard ratio 0.24, 95% confidence interval 0.084-0.683; p = 0.007).The current analysis from the NCDB supports the role of AC for GCC of the appendix, chiefly for patients with lymph node metastatic disease.

Objective To investigate the measurement threshold of an intra-oral scanner (IOS) on polished human enamel. Methods The optical performance of an IOS was compared to a gold-standard non contacting laser profilometer (NCLP), on a painted microscope slide, compared to increasing particle size of silicon-carbide papers (21.8–269.0 μm) and separately on polished human enamel with increasing step-heights. The enamel samples were randomised (n = 80) and scanned using the IOS and NCLP at increasing step-height depths (μm) (1.87–86.46 μm) and quantified according to ISO:5436-1. The measurement threshold of the IOS was determined using a custom designed automated lesion localisation algorithm, corroborated by Gaussian skewness (Ssk) and kurtosis (Sku) analysis, to assess the minimum step-height measured on each enamel sample. Results The NCLP showed statistically increased Sq surface roughness for all silicon carbide particle sizes compared to the microscope slide, whereas, the IOS Sq roughness discriminated silicon-carbide particles above 68.0 μm compared to the glass slide (p ≤ 0.02). On polished enamel, the automated minimum detectable step-height measurable on each sample was 44 μm. No statistically significantly different step-height enamel lesion measurements were observed between NCLP and IOS above this threshold (p > 0.05). Significance This study revealed the fundamental optical metrological parameters for the IOS, was step-heights above 44 μm and this reflects the data acquisition of the system. These results highlight the limitations of IOS used in this study, mandating further research to optimise the performance of other IOS systems, for measuring wear of materials or tooth wear on human unpolished natural enamel surfaces.

This paper discusses the presence of, and interplay between, erosion, abrasion and attrition as risk factors of tooth wear progression. The Basic Erosive Wear Examination is recommended as a simple practice-based screening tool to integrate into a risk assessment. Finally, the risk indicators are summarized and categorized using a high, medium or low risk classification system to facilitate practical risk assessment.CPD/Clinical Relevance: This paper provides a practical guide for oral health providers to screen and risk assess tooth wear.

Objectives: to investigate how the composition of the acquired enamel pellicle (AEP) affected a laboratory model of erosive tooth wear (ETW) on human enamel by comparing whole mouth saliva (WMS) to parotid saliva (PS). Methods: 60 enamel specimens were prepared from extracted human teeth and were randomly assigned to 4 experimental groups: WMS (n = 20), PS (n = 20), artificial saliva (AS, n = 10) and deionised water (DW, n = 10). Following incubation, a subset of WMS (n = 5) and PS (n = 5) groups were used to collect the AEP before the erosive challenge. The rest of the blocks, had their AEP collected after five cycles of acid, wash and saliva and were then assessed for mean step height changes using a non-contacting profilometer (n = 10 each). AEP samples were collected from the enamel specimens by rubbing with filter papers soaked in sodium dodecyl sulfate. Total protein in AEP was quantified using BCA assay, individual protein components of AEP were separated and analysed using SDS-PAGE and western blot for [mucin 5b, albumin, carbonic anhydrase VI (CA VI), statherin]. Specific antibody binding was quantified using purified protein standards of known concentration. Samples of AEP were also analysed by LC/MS/MS sequencing. Results: WMS group had significantly (p < 0.0001) less acid-induced erosion (step height [4.16 (0.9) μm]) than PS group [6.41 (0.3) μm]. The amount of total protein, mucin 5b and albumin were more dominant in WMS pellicles than PS (p < 0.0001) whereas CA VI and statherin were dominant in PS pellicles (p < 0.0001). Conclusion: The composition of the acquired enamel pellicle influences the degree of protection from acid attack, possibly by altering the mechanism of protection. The in-vitro model used in this study was severe enough to cause tissue loss as opposed to just softening of the surface structure. AEP from WMS was more protective than that of PS, and its likely mechanisms of protection seem to be as a physical barrier rather than stabilising the crystal structure. Significance: The protective salivary proteins against in-vitro erosion models differ from in-vivo studies. Therfore, it can be recommended that in-vitro laboratory models of ETW need to be assessed carefully to represent the clinical environment more closely.

BACKGROUND.l-Carnitine, an abundant nutrient in red meat, accelerates atherosclerosis in mice via gut microbiota–dependent formation of trimethylamine (TMA) and trimethylamine N-oxide (TMAO) via a multistep pathway involving an atherogenic intermediate, γ-butyrobetaine (γBB). The contribution of γBB in gut microbiota–dependent l-carnitine metabolism in humans is unknown. METHODS. Omnivores and vegans/vegetarians ingested deuterium-labeled l-carnitine (d3-l-carnitine) or γBB (d9-γBB), and both plasma metabolites and fecal polymicrobial transformations were examined at baseline, following oral antibiotics, or following chronic (≥2 months) l-carnitine supplementation. Human fecal commensals capable of performing each step of the l-carnitine→γBB→TMA transformation were identified. RESULTS. Studies with oral d3-l-carnitine or d9-γBB before versus after antibiotic exposure revealed gut microbiota contribution to the initial 2 steps in a metaorganismal l-carnitine→γBB→TMA→TMAO pathway in subjects. Moreover, a striking increase in d3-TMAO generation was observed in omnivores over vegans/vegetarians (>20-fold; P = 0.001) following oral d3-l-carnitine ingestion, whereas fasting endogenous plasma l-carnitine and γBB levels were similar in vegans/vegetarians (n = 32) versus omnivores (n = 40). Fecal metabolic transformation studies, and oral isotope tracer studies before versus after chronic l-carnitine supplementation, revealed that omnivores and vegans/vegetarians alike rapidly converted carnitine to γBB, whereas the second gut microbial transformation, γBB→TMA, was diet inducible (l-carnitine, omnivorous). Extensive anaerobic subculturing of human feces identified no single commensal capable of l-carnitine→TMA transformation, multiple community members that converted l-carnitine to γBB, and only 1 Clostridiales bacterium, Emergencia timonensis, that converted γBB to TMA. In coculture, E. timonensis promoted the complete l-carnitine→TMA transformation. CONCLUSION. In humans, dietary l-carnitine is converted into the atherosclerosis- and thrombosis-promoting metabolite TMAO via 2 sequential gut microbiota–dependent transformations: (a) initial rapid generation of the atherogenic intermediate γBB, followed by (b) transformation into TMA via low-abundance microbiota in omnivores, and to a markedly lower extent, in vegans/vegetarians. Gut microbiota γBB→TMA/TMAO transformation is induced by omnivorous dietary patterns and chronic l-carnitine exposure. TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01731236","term_id":"NCT01731236"}}NCT01731236. FUNDING. NIH and Office of Dietary Supplements grants HL103866, {"type":"entrez-nucleotide","attrs":{"text":"HL126827","term_id":"1051905411","term_text":"HL126827"}}HL126827, and {"type":"entrez-nucleotide","attrs":{"text":"DK106000","term_id":"187625904","term_text":"DK106000"}}DK106000, and the Leducq Foundation.

This manuscript summarises the reasons behind choosing indirect restorations in the treatment of tooth wear. The purpose of this article is to discuss the use of crowns as a restorative treatment option for tooth wear. There are also challenges with the use of composites as they can repeatedly fail and in these situations the indications for crowns for treatment of tooth wear is worthy of consideration. This article is part of a themed issue discussing the management of tooth wear.

Persons with rheumatoid arthritis (RA) have poor cardiorespiratory fitness and accelerated biological aging driven by systemic impairments in metabolism and inflammation. In this study of older RA participants, our goal was to identify the effects of a high-intensity interval training (HIIT) program on cardiorespiratory fitness and peripheral CD4+ T cell metabolism. We isolated CD4+ T cells from peripheral blood mononuclear cells in sedentary female RA participants (n=6; age=64.0+/-6.3 years) who underwent cardiopulmonary exercise testing and phlebotomy before and after 10 weeks of HIIT. HIIT improved RA cardiorespiratory fitness by 6.5+/-6.0% (pre-HIIT VO2 peak=25.1+/-5.1 ml/kg/min, post-HIIT VO2 peak=26.7+/-5.0; p=0.05). As measured by Seahorse XF Mito Stress Test, there were no significant mean changes in CD4+ T cell oxidative (oxygen consumption rate (OCR); pmol/min) or glycolytic (extracellular acidification rate (ECAR); mpH/min) metabolism, however there was large interindividual variability. RA peripheral CD4+ T cells preferred glycolytic metabolism (pre-HIIT mean basal OCR/ECAR ratio=0.78+/-0.13 pmol/mpH), while HIIT non-significantly shifted cellular preference toward oxidative metabolism (post-HIIT mean basal OCR/ECAR ratio=0.86+/-0.16; p=0.30). Increases in RA cardiorespiratory fitness following HIIT were significantly associated with increases in RA peripheral CD4+ T cell OCR/ECAR ratio (Spearman’s rho=1.0, p