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There is growing recognition across broad sectors of the scientific community that use of genomic biomarkers has the potential to reduce the need for conventional rodent carcinogenicity studies of industrial chemicals, agrochemicals, and pharmaceuticals through a weight-of-evidence approach. These biomarkers fall into 2 major categories: (1) sets of gene transcripts that can identify distinct tumorigenic mechanisms of action; and (2) cancer driver gene mutations indicative of rapidly expanding growth-advantaged clonal cell populations. This call-to-action article describes a collaborative approach launched to develop and qualify biomarker gene expression panels that measure widely accepted molecular pathways linked to tumorigenesis and their activation levels to predict tumorigenic doses of chemicals from short-term exposures. Growing evidence suggests that application of such biomarker panels in short-term exposure rodent studies can identify both tumorigenic hazard and tumorigenic activation levels for chemical-induced carcinogenicity. In the future, this approach will be expanded to include methodologies examining mutations in key cancer driver gene mutation hotspots as biomarkers of both genotoxic and nongenotoxic chemical tumor risk. Analytical, technical, and biological validation studies of these complementary genomic tools are being undertaken by multisector and multidisciplinary collaborative teams within the Health and Environmental Sciences Institute. Success from these efforts will facilitate the transition from current heavy reliance on conventional 2-year rodent carcinogenicity studies to more rapid animal- and resource-sparing approaches for mechanism-based carcinogenicity evaluation supporting internal and regulatory decision-making.

This study evaluated the effect of different protocols for Ca(OH)2 removal on the bond strength (BS) of epoxy resin-based sealer in long oval root canals. Forty-eight mandibular incisors with long oval root canals were selected by CBCT. Biomechanical preparation was performed, the samples were filled with Ca(OH)2 paste and distributed in four groups (n = 12): G-without Ca(OH)2 paste (C); G2-syringe/needle (SN); G3-SN + XP-Endo® Finisher (XPF); G4-SN + passive ultrasonic irrigation (PUI). After 7 days, Ca(OH)2 was removed and teeth were filled using AHPlus and guttapercha. In four samples from each group, the sealer was manipulated with 0.1% rhodamine to assess sealer penetration by fluorescent laser confocal microscopy (FLCM). Samples were sectioned in slices for BS, scanning electron microscopy, and FLCM analysis. The BS data were analyzed by ANOVA and Tukey tests (α = 0.05). The lowest BS values were found for the SN group (12.89 ± 4.36) compared to C (35.55 ± 10.05), while PUI group presented intermediate values (28.57 ± 9.35) and the XPF group (31.34 ± 9.8) showed values that were sometimes similar to C group and sometimes similar to PUI group (p > .05). The analysis of the adhesive interface showed evident gaps, with the presence of residues between the dentin and the filling material for the SN group, and for C, XPF and PUI groups juxtaposed adhesive interface. FLCM images showed sealer penetration in the dentinal tubules along the entire perimeter for C, XPF, and PUI groups. Ca(OH)2 removal with XPF and PUI from long oval root canals resulted in higher bond strength values compared to SN, besides better sealer penetration on dentinal tubules and juxtaposed adhesive interface.

To determine the influence of periapical lesions on the repeatability of two electronic apex locators (EALs), Root ZX II, and RomiApex A-15, in maxillary anterior teeth, in vivo. After approval by the local ethics committee, 43 maxillary anterior teeth scheduled for root canal therapy were assigned to two groups. The periapical lesion (PAL) group included 21 teeth with necrotic pulps and radiographically visible periapical lesion, and the normal periapex (NPA) group consisted of 22 teeth with vital pulps and no periapical lesion. In each canal, Root ZX II and RomiApex A-15 were used to determine working length defined as the “zero” reading on the display. Two consecutive measurements were performed with each EAL on each tooth and a second operator measured the endodontic file with a digital caliper without knowledge of the EAL being used or the tooth diagnosis. The absolute value of the difference between the first and second measurement (measurement pairs) was calculated. Repeatability was evaluated by the Bland-Altman method, and an aligned ranks transformation ANOVA was conducted to compare the EALs. The median absolute difference between measurement pairs was significantly lower (p < 0.001) and the limits of agreement were narrower in the NPA group. Among the EALs, median absolute differences were significantly smaller for Root ZX (p < 0.001). Measurements were more repeatable when no periapical lesion was present. Root ZX showed better repeatability than RomiApex. Periapical lesions seem to influence successive in vivo measurements with EALs.

Under ICH M7, impurities are assessed using the bacterial reverse mutation assay (i.e., Ames test) when predicted positive using in silico methodologies followed by expert review. N-Nitrosamines (NAs) have been of recent concern as impurities in pharmaceuticals, mainly because of their potential to be highly potent mutagenic carcinogens in rodent bioassays. The purpose of this analysis was to determine the sensitivity of the Ames assay to predict the carcinogenic outcome with curated proprietary Vitic (n = 131) and Leadscope (n = 70) databases. NAs were selected if they had corresponding rodent carcinogenicity assays. Overall, the sensitivity/specificity of the Ames assay was 93-97% and 55-86%, respectively. The sensitivity of the Ames assay was not significantly impacted by plate incorporation (84-89%) versus preincubation (82-89%). Sensitivity was not significantly different between use of rat and hamster liver induced S9 (80-93% versus 77-96%). The sensitivity of the Ames is high when using DMSO as a solvent (87-88%). Based on the analysis of these databases, the Ames assay conducted under OECD 471 guidelines is highly sensitive for detecting the carcinogenic hazards of NAs.

La gulupa (Passiflora edulis Sims) es una fruta exótica de sabor dulce y ligeramente ácido, aroma agradable y de gran aceptación principalmente en mercados europeos. En Colombia, una parte de las cosechas producidas está conformada por frutos que no cumplen con los estándares de calidad para la exportación, por lo que se destinan para el consumo nacional, y son comercializados a precios muy bajos; por eso, es necesario proponer alternativas para su aprovechamiento y potencial mercado. El objetivo del presente trabajo fue evaluar la influencia del grado de madurez de gulupa sobre la aceptación sensorial en productos alimenticios. Se elaboraron yogur y barras de cereal endulzados con salsa de gulupa proveniente de frutos con diferentes estados de madurez (T1: 30 %, T2: 50 %, T3: 70 % y T4: 100 %). Estos productos fueron evaluados sensorialmente por un panel de 101 consumidores, de edades entre los 18 y 54 años, por medio de la escala hedónica facial de 5 puntos. Los resultados obtenidos mostraron que el 56.44% de los consumidores mencionaron que les encantó el tratamiento T4 (yogur), y el 51.49% de los consumidores que les gustó el tratamiento T3 (barras de cereal). Lo anterior permite concluir que para el yogur, lo más recomendable es endulzar con frutas maduras, o incluso sobremaduras, mientras que para las barras de cereal lo ideal es usar gulupas con menor estado de maduración (70%).

The metabolic syndrome (MS) is a constellation of related factors that increases the risk of developing cardiovascular diseases. Vaccinium meridionale Swartz contains polyphenols that could modulate some components of MS. Epidemiological and intervention studies have shown differences between men and women in MS components and antioxidant capacity. The objective of this study is to compare between men and women with MS the effects of agraz consumption on insulin resistance, antioxidant capacity, and markers of oxidation and inflammation. Men and women diagnosed with MS according to the Adult Treatment Panel III criteria were recruited in a double-blind, crossover study of 12 weeks. Participants were assigned to consume agraz nectar or placebo over 4 weeks. After 4 weeks of washout, they were switched to the alternative treatment. At the end of each period, the components of the MS, insulin resistance, antioxidant capacity, and some oxidative (oxidized low-density lipoprotein [oxLDL]; thiobarbituric acid reactive substances) and inflammatory (high-sensitive C-reactive protein [hs-CRP]) markers were evaluated. After consuming agraz, there was a tendency to increase the levels of antioxidants and to reduce the levels of hs-CRP in both genders. In addition, women who increased their serum phenols after consuming agraz had a significant reduction in insulin resistance, which was different from the results in men. Regarding men, those who increased their serum antioxidant capacity after consuming agraz had a better effect on the reduction of oxLDL levels that was significant compared to women. There are important differences between genders in the effects of agraz consumption in adults with MS.

Objective:To know the anti-infective effectiveness of ascorbic acid, after a linear incision in the mucosa of the mandibular antero-inferior segment of the oral cavity of the guinea pigs, housed in the vivarium of the Biology Center of the Central University of Ecuador. Materials and methods:This study is experimental in-vivo and longitudinal, where an incision was made in the mucosa of the mandibular anteroinferior segment of the oral cavity in guinea pigs, three groups of 10 guinea pigs were formed, Group C, received mega doses ( 1.42 ml / 214.2 mg) which contained high amounts of ascorbic acid, Group B received normal doses (0.095 ml / 14.25 mg) and group Aor control group did not receive ascorbic acid, this dose was applied one day before, during, and one day after the incision. The clinical evaluation was performed at 24 and 72 hours post incision, a sample was taken by swab from the wounded area at 72 hours for the planting of bacterial cultivation. Results: The clinical examination shows that at 24 hours in group C, 0% bleeding, edema, and erythema, and 100% epithelial junction, while in group B, 30% bleeding, 50% edema, 50% erythema and 100% epithelial junction and in group A50% bleeding, 40% edema, 40% erythema and 20% epithelial junction; at 72 hours the results in group C and B showed better healing percentages in relation to group A, in this group some guinea pigs still showed bleeding edema and erythema in the wounded area. Conclusion: It is determined that the guinea pigs who received mega doses of ascorbic acid presented a better result in the process of healing after clinical examination at 24 and 72 hours and the swab exam shows a lower amount of bacterial colonization, thus demonstrating the effectiveness of ascorbic acid in mega doses of infectious processes.

The in vitro MultiFlow® DNA Damage Assay multiplexes γH2AX, p53, phospho-histone H3, and polyploidization biomarkers into a single flow cytometric analysis. The current report describes a tiered sequential data analysis strategy based on data generated from exposure of human TK6 cells to a previously described 85 chemical training set and a new pharmaceutical-centric test set (n = 40). In each case, exposure was continuous over a range of closely spaced concentrations, and cell aliquots were removed for analysis following 4 and 24 hr of treatment. The first data analysis step focused on chemicals' genotoxic potential, and for this purpose, we evaluated the performance of a machine learning (ML) ensemble, a rubric that considered fold increases in biomarkers against global evaluation factors (GEFs), and a hybrid strategy that considered ML and GEFs. This first tier further used ML output and/or GEFs to classify genotoxic activity as clastogenic and/or aneugenic. Test set results demonstrated the generalizability of the first tier, with particularly good performance from the ML ensemble: 35/40 (88%) concordance with a priori genotoxicity expectations and 21/24 (88%) agreement with expected mode of action (MoA). A second tier applied unsupervised hierarchical clustering to the biomarker response data, and these analyses were found to group certain chemicals, especially aneugens, according to their molecular targets. Finally, a third tier utilized benchmark dose analyses and MultiFlow biomarker responses to rank genotoxic potency. The relevance of these rankings is supported by the strong agreement found between benchmark dose values derived from MultiFlow biomarkers compared to those generated from parallel in vitro micronucleus analyses. Collectively, the results suggest that a tiered MultiFlow data analysis pipeline is capable of rapidly and effectively identifying genotoxic hazards while providing additional information that is useful for modern risk assessments-MoA, molecular targets, and potency. Environ. Mol. Mutagen. 60:513-533, 2019. © 2019 Wiley Periodicals, Inc.

This paper presents the results obtained in the use of the Automated Driving Toolbox of MATLAB to detect moving and static objects in a virtual simulation environment of autonomous driving. The objective of this research is to configure different scenarios related to autonomous driving systems (ADAS - Advanced Driver Assistance Systems), in order to obtain information about the behavior of cameras and radars in the presence of different objects placed on the road. The results obtained show that the best performance is achieved when side cameras and a frontal sensor are placed. In addition, the size of the object under study does not affect the objetcs detection rate on the road.

Resumen La criptococosis meníngea presenta alta mortalidad mundial, especialmente en población VIH/sida. La OMS recomienda detectar el antígeno capsular de Crypto coccus como estrategia para un diagnóstico temprano y poder minimizar complicaciones. Objetivo: realizar antigenemia temprana de Cryptococcus mediante in munocromatografía/ensayo de flujo lateral en pacientes asintomáticos VIH+. Material y método: estudio descriptivo observacional; entre julio-2016 y mayo-2019 se procesaron mediante ensayo de flujo lateral, muestras de suero de 169 pacientes asintomáticos VIH+, con CD4 ≤120 cel/μL en Barranquilla, Colombia. Ante resultado positivo, se indicó profilaxis con fluconazol; se hizo seguimiento a todos los casos. Resultados: la antigenemia fue positiva en cinco pacientes (2,96%); uno falleció, cuatro recibieron profilaxis y la prueba se negativizó en dos. Los pacientes con resultado negativo inicial no desarrollaron durante el estudio sinto matología compatible con esta micosis. Discusión: el ensayo de flujo lateral de Cryptococcus está recomendado para el diagnóstico temprano de la criptococosis en población VIH/sida. Conclusión: detectar tempranamente el antígeno circulante de Cryptococcus mediante ensayo de flujo lateral en pacientes asintomáticos VIH+, permitió instaurar profilaxis oportuna, hacer seguimiento y control para reducir la mortalidad asociada con la criptococosis meníngea. Abstract Meningeal cryptococcosis presents high levels of global mortality, especially in the HIV/AIDS population. The WHO recommends detecting the capsular antigen as an important strategy for early diagnosis and be able to minimize complications. Objective: Perform early cryptococcal antigenemia by immunochromatographic/ lateral flow assay in asymptomatic HIV+ patients. Material and method: descriptive observational study; between July-2016 and May-2019, serum samples from 169 asymptomatic HIV+ patients with CD4 ≤120 cells/μL were processed by lateral flow assay in Barranquilla, Colombia. Given a positive result, prophylaxis with fluconazole was indicated; all cases were followed up. Results: antigenemia was positive in five (2.96%) patients; one died; four received prophylaxis, and the test turned negative in two. The patients with an initial negative result, did not developed symptoms compatible with this mycosis during the study period. Discussion: lateral flow assay for Cryptococcus is recommended for the early diagnosis of cryptococcosis in the HIV/AIDS population. Conclusion: early detection of circulating Cryptococcus antigen by lateral flow assay in HIV+ patients allowed the establishment of timely prophylaxis, follow-up, and control to reduce mortality associated with meningeal cryptococcosis.

COVID-19 morbidity is highest in Black and Latino older adults. These racial and ethnic groups initially had lower vaccination uptake than others, and rates in Black adults continue to lag.To evaluate the effect of outreach via electronic secure messages and mailings from primary care physicians (PCPs) on COVID-19 vaccination uptake among Black and Latino older adults and to compare the effects of culturally tailored and standard PCP messages.This randomized clinical trial was conducted from March 29 to May 20, 2021, with follow-up surveys through July 31, 2021. Latino and Black individuals aged 65 years and older from 4 Kaiser Permanente Northern California (KPNC) service areas were included. Data were analyzed from May 27, 2021, to September 28, 2021.Individuals who had not received COVID-19 vaccination after previous outreach were randomized to electronic secure message and/or mail outreach from their PCP, similar outreach with additional culturally tailored content, or usual care. Outreach groups were sent a secure message or letter in their PCP's name, followed by a postcard to those still unvaccinated after 4 weeks.The primary outcome was time to receipt of COVID-19 vaccination during the 8 weeks after initial study outreach. KPNC data were supplemented with state data from external sources. Intervention effects were evaluated via proportional hazards regression.Of 8287 included individuals (mean [SD] age, 72.6 [7.0] years; 4665 [56.3%] women), 2434 (29.4%) were Black, 3782 (45.6%) were Latino and preferred English-language communications, and 2071 (25.0%) were Latino and preferred Spanish-language communications; 2847 participants (34.4%) had a neighborhood deprivation index at the 75th percentile or higher. A total of 2767 participants were randomized to culturally tailored PCP outreach, 2747 participants were randomized to standard PCP outreach, and 2773 participants were randomized to usual care. Culturally tailored PCP outreach led to higher COVID-19 vaccination rates during follow-up compared with usual care (664 participants [24.0%] vs 603 participants [21.7%]; adjusted hazard ratio (aHR), 1.22; 95% CI, 1.09-1.37), as did standard PCP outreach (635 participants [23.1%]; aHR, 1.17; 95% CI, 1.04-1.31). Individuals who were Black (aHR, 1.19; 95% CI, 1.06-1.33), had high neighborhood deprivation (aHR, 1.17; 95% CI, 1.03-1.33), and had medium to high comorbidity scores (aHR, 1.19; 95% CI, 1.09-1.31) were more likely to be vaccinated during follow-up.This randomized clinical trial found that PCP outreach using electronic and mailed messages increased COVID-19 vaccination rates among Black and Latino older adults.ClinicalTrials.gov Identifier: NCT05096026.

Purple passionfruit (Passiflora edulis Sims) is an exotic, sweet and slighty acid flavored fruit with a pleasant aroma. It is also widely accepted in European markets. In Colombia, a part of the yield crop is comprised of fruit that does not meet quality standards for export and is intended for national consumption, and marketed at very low prices. Therefore, it is necessary to propose alternatives for its use and potential market. The aim of this study was to assess the influence of the degree of ripeness for purple passionfruit on the sensory acceptance in food products. Yogurt and cereal bars sweetened with purple passionfruit sauce from fruit with different stages of ripeness (T1: 30 %, T2: 50 %, T3: 70 % and T4: 100 %) were prepared. By a panel of 101 consumers aged 18-54 years old, using a 5-point facial hedonic scale, said products were sensorially assessed. The results obtained showed that 56.44% of consumers preferred T4 treatment (yogurt) and 51.49% of consumers preferred T3 treatment (cereal bars). The above mentioned leads to conclude that, for yogurt preparations, it is best to sweeten with ripe or even overripe fruit, while for cereal bars it is ideal to use purple passionfruit with a lower stage of ripeness (70%)., La gulupa (Passiflora edulis Sims) es una fruta exótica de sabor dulce y ligeramente ácido, aroma agradable y de gran aceptación principalmente en mercados europeos. En Colombia, una parte de las cosechas producidas está conformada por frutos que no cumplen con los estándares de calidad para la exportación, por lo que se destinan para el consumo nacional, y son comercializados a precios muy bajos; por eso, es necesario proponer alternativas para su aprovechamiento y potencial mercado. El objetivo del presente trabajo fue evaluar la influencia del grado de madurez de gulupa sobre la aceptación sensorial en productos alimenticios. Se elaboraron yogur y barras de cereal endulzados con salsa de gulupa proveniente de frutos con diferentes estados de madurez (T1: 30 %, T2: 50 %, T3: 70 % y T4: 100 %). Estos productos fueron evaluados sensorialmente por un panel de 101 consumidores, de edades entre los 18 y 54 años, por medio de la escala hedónica facial de 5 puntos. Los resultados obtenidos mostraron que el 56.44% de los consumidores mencionaron que les encantó el tratamiento T4 (yogur), y el 51.49% de los consumidores que les gustó el tratamiento T3 (barras de cereal). Lo anterior permite concluir que para el yogur, lo más recomendable es endulzar con frutas maduras, o incluso sobremaduras, mientras que para las barras de cereal lo ideal es usar gulupas con menor estado de maduración (70%).

To determine the influence of periapical lesions on the repeatability of two electronic apex locators (EALs), Root ZX II, and RomiApex A-15, in maxillary anterior teeth, in vivo.After approval by the local ethics committee, 43 maxillary anterior teeth scheduled for root canal therapy were assigned to two groups. The periapical lesion (PAL) group included 21 teeth with necrotic pulps and radiographically visible periapical lesion, and the normal periapex (NPA) group consisted of 22 teeth with vital pulps and no periapical lesion. In each canal, Root ZX II and RomiApex A-15 were used to determine working length defined as the "zero" reading on the display. Two consecutive measurements were performed with each EAL on each tooth and a second operator measured the endodontic file with a digital caliper without knowledge of the EAL being used or the tooth diagnosis. The absolute value of the difference between the first and second measurement (measurement pairs) was calculated. Repeatability was evaluated by the Bland-Altman method, and an aligned ranks transformation ANOVA was conducted to compare the EALs.The median absolute difference between measurement pairs was significantly lower (p0.001) and the limits of agreement were narrower in the NPA group. Among the EALs, median absolute differences were significantly smaller for Root ZX (p0.001).Measurements were more repeatable when no periapical lesion was present. Root ZX showed better repeatability than RomiApex.Periapical lesions seem to influence successive in vivo measurements with EALs.

Pharmaceutic products designed to perturb the function of epigenetic modulators have been approved by regulatory authorities for treatment of advanced cancer. While the predominant effort in epigenetic drug development continues to be in oncology, non-oncology indications are also garnering interest. A survey of pharmaceutical companies was conducted to assess the interest and concerns for developing small molecule direct epigenetic effectors (EEs) as medicines. Survey themes addressed (1) general levels of interest and activity with EEs as therapeutic agents, (2) potential safety concerns, and (3) possible future efforts to develop targeted strategies for nonclinical safety assessment of EEs. Thirteen companies contributed data to the survey. Overall, the survey data indicate the consensus opinion that existing ICH guidelines are effective and appropriate for nonclinical safety assessment activities with EEs. Attention in the framework of study design should, on a case by case basis, be considered for delayed or latent toxicities, carcinogenicity, reproductive toxicity, and the theoretical potential for transgenerational effects. While current guidelines have been appropriate for the nonclinical safety assessments of epigenetic targets, broader experience with a wide range of epigenetic targets will provide information to assess the potential need for new or revised risk assessment strategies for EE drugs.

In a previously reported CD-1 mouse 2-year carcinogenicity study with the sodium glucose cotransporter-2 inhibitor empagliflozin, an increased incidence of renal tubular adenomas and carcinomas was identified only in the male high-dose group. Follow-up investigative studies have shown that the renal tumors in male high-dose mice were preceded by a number of renal degenerative/regenerative findings. Prior cross-species in vitro metabolism studies using microsomes identified an oxidative metabolite (M466/2) predominantly formed in the male mouse kidney and which spontaneously degrades to a metabolite (M380/1) and reactive 4-OH crotonaldehyde (CTA). In order to further evaluate potential modes of action for empagliflozin-associated male mouse renal tumors, we report here a series of in vitro investigative toxicology studies conducted to evaluate the cytotoxic and genotoxic potential of empagliflozin and M466/2. To assess the cytotoxic potential of empagliflozin and M466/2, a primary mouse renal tubular epithelial (mRTE) cell model was used. In mRTE cells, M466/2-derived in vitro 4-OH CTA exposure was cytotoxic, while empagliflozin was not cytotoxic or mitogenic. Empagliflozin and M466/2 were not genotoxic, supporting an indirect mode of action for empagliflozin-associated male mouse renal tumorigenesis. In conclusion, these in vitro data show that M466/2-derived 4-OH CTA exposure is associated with cytotoxicity in renal tubule cells and may be involved in promoting compound-related in vivo renal metabolic stress and chronic low-level renal injury, in turn supporting a nongenotoxic mode of tumor pathogenesis specific to the male mouse.

In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP. A key difference between these proposed genetic toxicology AOPs versus traditional AOPs is that the AO is a genetic toxicology endpoint of potential significance in risk characterization, in contrast to an adverse state of an organism or a population. The first two detailed case studies describe provisional AOPs for aurora kinase inhibition and tubulin binding, leading to the common AO of aneuploidy. The remaining three case studies highlight provisional AOPs that lead to chromosome breakage or mutation via indirect DNA interaction (inhibition of topoisomerase II, production of cellular reactive oxygen species, and inhibition of DNA synthesis). These case studies serve as starting points for genotoxicity AOPs that could ultimately be published and utilized by the broader toxicology community and illustrate the practical considerations and evidence required to formalize such AOPs so that they may be applied to genetic toxicity evaluation schemes. Environ. Mol. Mutagen. 61:114-134, 2020. © 2019 Wiley Periodicals, Inc.

The International Workshop on Genotoxicity Testing (IWGT) meets every four years to obtain consensus on unresolved issues associated with genotoxicity testing. At the 2017 IWGT meeting in Tokyo, four sub-groups addressed issues associated with the Organization for Economic Cooperation and Development (OECD) Test Guideline TG471, which describes the use of bacterial reverse-mutation tests. The strains sub-group analyzed test data from >10,000 chemicals, tested additional chemicals, and concluded that some strains listed in TG471 are unnecessary because they detected fewer mutagens than other strains that the guideline describes as equivalent. Thus, they concluded that a smaller panel of strains would suffice to detect most mutagens. The laboratory proficiency sub-group recommended (a) establishing strain cell banks, (b) developing bacterial growth protocols that optimize assay sensitivity, and (c) testing "proficiency compounds" to gain assay experience and establish historical positive and control databases. The sub-group on criteria for assay evaluation recommended that laboratories (a) track positive and negative control data; (b) develop acceptability criteria for positive and negative controls; (c) optimize dose-spacing and the number of analyzable doses when there is evidence of toxicity; (d) use a combination of three criteria to evaluate results: a dose-related increase in revertants, a clear increase in revertants in at least one dose relative to the concurrent negative control, and at least one dose that produced an increase in revertants above control limits established by the laboratory from historical negative controls; and (e) establish experimental designs to resolve unclear results. The in silico sub-group summarized in silico utility as a tool in genotoxicity assessment but made no specific recommendations for TG471. Thus, the workgroup identified issues that could be addressed if TG471 is revised. The companion papers (a) provide evidence-based approaches, (b) recommend priorities, and (c) give examples of clearly defined terms to support revision of TG471.

espanolIntroduccion: Las sustancias relacionadas con los microorganismos involucrados en la enfermedad periodontal puedan llegar a la interfaz materno-fetal por via hematogena y estimular la contractilidad uterina. Objetivo: Determinar la asociacion entre enfermedad periodontal con nacimiento pretermino. Metodo: Estudio de casos y controles de 343 embarazadas pretermino y 686 de termino. Se calculo la edad gestacional por fecha de ultimo periodo menstrual y se confirmo con los metodos de Capurro y Ballard. La enfermedad periodontal se diagnostico por la profundidad del espacio entre la raiz dental y la encia. La asociacion fue medida con regresion logistica. Resultados: La edad de las madres en los casos fue de 23.8 ± 6.7 anos y en los controles de 23.2 ± 6.7 anos. La enfermedad periodontal estuvo presente en 66.8 % de los casos y 40.5 % de los controles. Los factores asociados con nacimiento pretermino fueron enfermedad periodontal (RM = 2.26), antecedente de nacimiento pretermino (RM = 4.96), embarazo no planeado (RM = 2.15), control prenatal deficiente (RM = 2.53), infeccion de vias urinarias (RM = 2.22), preeclampsia (RM = 4.49), ruptura prematura de membranas amnioticas (RM = 2.59) y nacer por cesarea (RM = 9.15). Conclusion: La enfermedad periodontal en el embarazo constituyo un factor de riesgo independiente para nacimiento pretermino. EnglishIntroduction: Substances related to microorganisms involved in periodontal disease can reach the maternal-fetal interface via the hematogenous route and stimulate uterine contractility. Objective: To determine the association between periodontal disease and preterm birth. Method: Case-control study in 343 preterm and 686 full-term pregnant women. Gestational age was calculated based on the date of the last menstrual period and confirmed with Capurro and Ballard methods. Periodontal disease was diagnosed according to the depth of the space between the tooth root and the gum. The association was measured with logistic regression. Results: Maternal age of the cases was 23.8 ± 6.7 years, and 23.2 ± 6.7 in the controls. Periodontal disease was present in 66.8% of cases and 40.5% of controls. The factors associated with preterm birth were periodontal disease (Odds ratio [OR] = 2.26), history of preterm birth (OR = 4.96), unplanned pregnancy (OR = 2.15) poor prenatal control (OR = 2.53), urinary tract infection (OR = 2.22), preeclampsia (OR = 4.49), premature rupture of membranes (OR = 2.59) and caesarean section delivery (OR = 9.15). Conclusion: Periodontal disease in pregnancy was an independent risk factor for preterm birth.

Arylboronic acids and esters (referred to collectively as arylboronic compounds) are commonly used intermediates in the synthesis of pharmaceuticals but pose a challenge for chemical syntheses because they are often positive for bacterial mutagenicity in vitro. As such, arylboronic compounds are then typically controlled to levels that are acceptable for mutagenic impurities, that is, the threshold of toxicological concern (TTC). This study used ICH M7 guidance to design and conduct a testing strategy to investigate the in vivo relevance of the in vitro positive findings of arylboronic compounds. Eight arylboronic compounds representing a variety of chemical scaffolds were tested in Sprague Dawley and/or Wistar rats in the in vivo Pig-a (peripheral blood reticulocytes and mature red blood cells) and/or comet assays (duodenum and/or liver). Five of the eight compounds were also tested in the micronucleus (peripheral blood) assay. The arylboronic compounds tested orally demonstrated high systemic exposure; thus the blood and bone marrow were adequately exposed to test article. One compound was administered intravenously due to formulation stability issues. This investigation showed that arylboronic compounds that were mutagenic in vitro were not found to be mutagenic in the corresponding in vivo assays. Therefore, arylboronic compounds similar to the scaffolds tested in this article may be considered non-mutagenic and managed in accordance with the ICH Q3A/Q3B guidelines. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.

The bacterial reverse mutation test is a mainstay for evaluation of mutagenicity predicting the carcinogenic potential of a test substance and is recommended by regulatory agencies across the globe. The popularity of the test is due, in part, to the relatively low cost, rapid results and small amount of test material required compared to most other toxicological tests as well as the near universal acceptance of the toxicological significance of a clear positive or negative result. Most laboratories follow the Organization for Economic Cooperation and Development Test Guideline 471 (TG471) or national guidelines based on TG471. Regulatory agencies in most countries are obligated to consider results from tests which meet the recommendations laid out in TG471. Nonetheless, laboratories unfamiliar with the test sometimes have trouble generating reliable, reproducible results. TG471 is a test guideline, not a detailed test protocol. A group of experts from regulatory agencies and laboratories which use the assay has assembled here a set of recommendations which if followed, will allow an inexperienced laboratory to acquire proficiency in assay conduct. These include recommendations for how to create a cell bank for the 5 Salmonella typhimurium/Escherichia coli strains and develop a laboratory protocol to reliably culture each strain to ensure each culture has the characteristics which allow adequate sensitivity for detection of mutagens using the test as described in TG471. By testing compounds on the provided lists of positive and negative test substances, the laboratory will have surmounted many of the problems commonly encountered during routine testing of unknown chemicals and will have gained the experience necessary to prepare the detailed protocol needed for performing the test under Good Laboratory Procedures and the laboratory will have generated the historical positive and negative control databases which are needed for test reports which adhere to TG471.

A database of 91 chemicals with published data from both transgenic rodent mutation (TGR) and rodent comet assays has been compiled. The objective was to compare the sensitivity of the two assays for detecting genotoxicity. Critical aspects of study design and results were tabulated for each dataset. There were fewer datasets from rats than mice, particularly for the TGR assay, and therefore, results from both species were combined for further analysis. TGR and comet responses were compared in liver and bone marrow (the most commonly studied tissues), and in stomach and colon evaluated either separately or in combination with other GI tract segments. Overall positive, negative, or equivocal test results were assessed for each chemical across the tissues examined in the TGR and comet assays using two approaches: 1) overall calls based on weight of evidence (WoE) and expert judgement, and 2) curation of the data based on a priori acceptability criteria prior to deriving final tissue specific calls. Since the database contains a high prevalence of positive results, overall agreement between the assays was determined using statistics adjusted for prevalence (using AC1 and PABAK). These coefficients showed fair or moderate to good agreement for liver and the GI tract (predominantly stomach and colon data) using WoE, reduced agreement for stomach and colon evaluated separately using data curation, and poor or no agreement for bone marrow using both the WoE and data curation approaches. Confidence in these results is higher for liver than for the other tissues, for which there were less data. Our analysis finds that comet and TGR generally identify the same compounds (mainly potent mutagens) as genotoxic in liver, stomach and colon, but not in bone marrow. However, the current database content precluded drawing assay concordance conclusions for weak mutagens and non-DNA reactive chemicals.

This case report describes a technique in which endodontic treatment and permanent indirect restoration were completed in the same clinical appointment with the aid of a computer-aided design/computer-aided manufacturing (CAD/CAM) system. Two patients were diagnosed with irreversible pulpitis of the mandibular first molar. After access preparation, root canals were located, irrigation was performed until bleeding ceased, and the coronal tooth structure was prepared for indirect restoration. Then, utilizing an interim 3-mm build-up of the endodontic access cavity, a hemi-arch digital scan was performed with an intraoral scanner. Subsequent to digital scanning, restoration design was performed simultaneously with the endodontic procedure. The root canals were shaped using the Race system under irrigation with 2.5% sodium hypochlorite followed by root canal filling. The pulp chamber was subsequently filled with a 3-mm-thick composite resin restoration mimicking the interim build-up previously utilized to facilitate block milling in the CAD/CAM system. Clinical try-in of the permanent onlay restoration was followed by acid etching, application of a 5th generation adhesive, and cementation of the indirect restoration. Once the restoration was cemented, rubber dam isolation was removed, followed by occlusal adjustment and polishing. After 2 years of follow-up, the restorations were esthetically and functionally satisfactory, without complications.

BACKGROUND Health information technology (IT) tools are increasingly used to improve patient care. However, implementation of English-only health IT tools could potentially worsen health disparities for non-English speakers. OBJECTIVE We aim to describe the “trans-creation” process of developing linguistically and culturally appropriate health IT tools through a detailed case analysis of a waiting room health mobile app designed to help Spanish-speaking Latino people prepare for primary care visits. METHODS We adapted the English-language Visit Planner mobile app for Spanish-speaking Latino patients. We applied culturally defined themes derived from prior published research and input by both skilled linguists and potential end users. Initial changes were iteratively reviewed and edited by a team of writers, health care educators, subject matter experts, patients, and providers. RESULTS The trans-creation process resulted in the following key culturally mediated changes to the tool: replacing the “provider” actors with “patient” actors; changing the choice of “Stress at Home or Work” (represented by an icon of a house) to “Mi Familia” (translation: my family; icon is an outline of family members holding hands); replacing the English terms “anxiety” and “depression” with “Me siento desanimado”(translation: I am feeling down) to avoid mental health stigma; and using more concise text translation to ensure the wording fit the available on-screen space. CONCLUSIONS The trans-creation process of cultural and linguistic adaptation led to several design changes that would not have been implemented if we had simply translated the words from English to Spanish.

As a part of the 6th IWGT, an expert working group on the comet assay evaluated critical topics related to the use of the in vivo comet assay in regulatory genotoxicity testing. The areas covered were: identification of the domain of applicability and regulatory acceptance, identification of critical parameters of the protocol and attempts to standardize the assay, experience with combination and integration with other in vivo studies, demonstration of laboratory proficiency, sensitivity and power of the protocol used, use of different tissues, freezing of samples, and choice of appropriate measures of cytotoxicity. The standard protocol detects various types of DNA lesions but it does not detect all types of DNA damage. Modifications of the standard protocol may be used to detect additional types of specific DNA damage (e.g., cross-links, bulky adducts, oxidized bases). In addition, the working group identified critical parameters that should be carefully controlled and described in detail in every published study protocol. In vivo comet assay results are more reliable if they were obtained in laboratories that have demonstrated proficiency. This includes demonstration of adequate response to vehicle controls and an adequate response to a positive control for each tissue being examined. There was a general agreement that freezing of samples is an option but more data are needed in order to establish generally accepted protocols. With regard to tissue toxicity, the working group concluded that cytotoxicity could be a confounder of comet results. It is recommended to look at multiple parameters such as histopathological observations, organ-specific clinical chemistry as well as indicators of tissue inflammation to decide whether compound-specific toxicity might influence the result. The expert working group concluded that the alkaline in vivo comet assay is a mature test for the evaluation of genotoxicity and can be recommended to regulatory agencies for use.

Lesser toe deformities are one of the most common conditions faced by orthopedic surgeons. Knowledge of the anatomy of the lesser toes is important for ensuring correct diagnosis and treatment of deformities, which are caused by factors such as muscle imbalance between the extensor apparatus and flexor tendons. However, this apparatus has not received sufficient attention in the literature. In addition, the large number of inaccurate and erroneous descriptions means that gaining an understanding of these structures is problematic. The objective of the present article is to clarify the anatomy of the extensor apparatus by means of a pictorial essay, in which the structures involved will be grouped and discussed in detail. The most relevant clinical implications will be addressed. Level of Evidence: Level V, expert opinion.

A committee was constituted within the International Workshop on Genetic Toxicology Testing (IWGT) to evaluate the current criteria for a valid Ames test and to provide recommendations for interpretation of test results. Currently, determination of a positive vs. a negative result is made by applying various data evaluation procedures for comparing dosed plates with the concurrent solvent control plates. These evaluation procedures include a requirement for a specific fold increase (2- or 3-fold, specific to the bacterial strain), formal statistical procedures, or subjective (expert judgment) evaluation. After extensive discussion, the workgroup was not able to reach consensus recommendations in favor of any of these procedures. There was a consensus that combining additional evaluation criteria to the comparison between dosed plates and the concurrent solvent control plates improves test interpretation. The workgroup recommended using these additional criteria because the induction of mutations is a continuum of responses and there is no biological relevance to a strict dividing line between a positive (mutagenic) and not-positive (nonmutagenic) response. The most useful additional criteria identified were a concentration-response relationship and consideration of a possible increase above the concurrent control in the context of the laboratory’s historical solvent control values for the particular tester strain. The workgroup also emphasized the need for additional testing to resolve weak or inconclusive responses, usually with altered experimental conditions chosen based on the initial results. Use of these multiple criteria allowed the workgroup to reach consensus on definitions of “clear positive” and “clear negative” responses which would not require a repeat test for clarification. The workgroup also reached consensus on recommendations to compare the responses of concurrent positive and negative controls to historical control distributions for assay acceptability, and the use of control charts to determine the validity of the individual test.

Este trabajo tiene por objetivo mostrar cómo se han tejido algunos entramados sociales, culturales y académicos alrededor de la conformación de una nueva sociedad, la sociedad de la información, mediada por lo informacional y generada principalmente por la aparición de la internet. Destaca el artículo los apuntes de referencia al uso de la web con fines académicos a partir del manejo de los rastreos bibliográficos. Se pretende, además, que los maestros pongan la mirada en algunos principios propios del quehacer docente como son la enseñanza, la puesta en práctica del currículo oculto y el manejo de la didáctica para el uso de la información virtual en el aula.Palabras clave: rastreo bibliográfico, ciberespacio, autopista electrónica, investigación, realidad virtual.

The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Project Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity (IVGT) Testing established an Emerging Technologies and New Strategies Workgroup to review the current State of the Art in genetic toxicology testing. The aim of the workgroup was to identify promising technologies that will improve genotoxicity testing and assessment of in vivo hazard and risk, and that have the potential to help meet the objectives of the IVGT. As part of this initiative, HESI convened a workshop in Washington, DC in May 2008 to discuss mature, maturing, and emerging technologies in genetic toxicology. This article collates the abstracts of the New and Emerging Technologies Workshop together with some additional technologies subsequently considered by the workgroup. Each abstract (available in the online version of the article) includes a section addressed specifically to the strengths, weaknesses, opportunities, and threats associated with the respective technology. Importantly, an overview of the technologies and an indication of how their use might be aligned with the objectives of IVGT are presented. In particular, consideration was given with regard to follow-up testing of positive results in the standard IVGT tests (i.e., Salmonella Ames test, chromosome aberration assay, and mouse lymphoma assay) to add weight of evidence and/or provide mechanism of action for improved genetic toxicity risk assessments in humans.