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Obesity is a well-recognized risk factor for critical illness and death among adult patients with SARS-CoV-2 infection.This study aimed to characterize the clinical outcomes and risk factors of death related to obesity in a cohort of hospitalized paediatric patients with COVID-19.We performed an analysis of all paediatric patients with obesity and COVID-19 registered in SIVEP-Gripe, a Brazilian nationwide surveillance database, between February 2020 and May 2021. The primary outcome was time to death, which was evaluated by using cumulative incidence function.Among 21 591 hospitalized paediatric patients with COVID-19, 477 cases (2.2%) had obesity. Of them, 71 (14.9%) had a fatal outcome as compared with 7.5% for patients without obesity (hazard ratio [HR] = 2.0, 95% confidence interval [CI] 1.59-2.53, p 0.001). After adjustment, the factors associated with death among patients with obesity were female gender (HR = 2.8, 95% CI 1.70-4.61), oxygen saturation 95% (HR = 2.58, 95% CI 1.38-4.79), presence of one (HR = 1.91, 95% CI 1.11-3.26), and two or more comorbidities (HR = 4.0, 95% CI 2.21-7.56).Children and adolescents with obesity had higher risk of death compared with those without obesity. The higher risk of death was associated with female gender, low oxygen saturation at admission, and presence of other comorbidities.

The aim of this study was to describe the oral health services offered by the Unified Health System in the northern macro-region of Minas Gerais, Brazil, during the COVID-19 pandemic. This was an observational, cross-sectional and descriptive study. Data collection took place between August and September 2020 through the completion of online questionnaires by oral health managers in the northern municipalities of Minas Gerais and by consultation of information available in the Special Epidemiological Bulletin Coronavirus North Macro-region n° 14. After collection, data were transferred to SPSS® (Statistical Package for the Social Sciences for Windows, version 24.0). Analyses were performed using frequency, mean, standard deviation and percentages. It was found that all included municipalities suspended elective treatments and maintained emergency dental care at all levels of care. In 62.5% of municipalities there were oral health professionals contaminated by COVID-19. Oral health teams implemented specific interventions to address the pandemic,with the most frequent being tele-orientation (74.7%), use of sanitary barriers (72%), and telemonitoring (68%). At the beginning of the pandemic, 62.5% of municipalities lacked personal protective equipment. Comsidering these results, it was found that the COVID-19 pandemic impacted the supply of dental services in northern Minas Gerais due to the suspension of elective care, contamination of professionals, lack of personal protective equipment, and development of new interventions. Thus, oral health teams had to adapt to new contexts of health interventionsto face COVID-19 and maintain dental care services.

Based on an extensive analysis of public databases, we provide an overview of the global scientific output and describe the dynamics of the profound changes in the scientific enterprise during the last decades. The analysis included the scientific production of 53 countries over the 1996-2018 period. During this period, the production of articles per year has tripled. There was a strong correlation between the growth of the global gross domestic product and the increase in the number of articles (R2 = 0.973, P

This review outlines the historical perspective, status, and future challenges of oral medicine (stomatology) in Brazil based on the records of the Brazilian Society of Stomatology and Oral Pathology (SOBEP) and the Brazilian Federal Dental Council as well as expert evidence input from academic leaders from 3 different generations of Brazilian oral medicine specialists. The beginning of oral medicine in Brazil dates to 1969, followed by the organization of SOBEP in 1974; however, official recognition as an independent specialty was achieved more recently within the Brazilian Federal Dental Council in 1992. After a 50-year maturation period of oral medicine in Brazil in terms of specialty crystallization across dentistry, medicine, and research, it is now time to follow the historical trends of the specialty internationally and establish a standard curriculum at a post-graduate level that will lead to uniformity of training for oral medicine in Brazil.

We analyzed the distribution characteristics of the scientific production of Brazilian dentistry researchers of the Brazilian National Council for Scientific and Technological Development. The Lattes curriculum data of 211 researchers from Oral Pathology, Oral Surgery, and Oral Medicine fields were included (2018-2020). Over their academic career, 39 researchers published 7,555 papers (average, 175 articles/researcher); 3,876/7,555 papers were indexed in the Web of Science. During 2018-2020, 1,440/7,555 (19%) papers were published. Brazilian dental researchers contribute significantly to international research by participating in scientific journals' editorial boards, evaluating research promotion agencies, training researchers, and contributing to scientific and technological development.

BACKGROUND: The COVID-19 pandemic has raised challenges in adapting to teaching and learning methods in dental education. OBJECTIVE: This study aimed to evaluate the impact of the COVID-19 pandemic on the academic activities of undergraduate (UDG) and graduate (GD) dental students in Brazil. Additionally, students’ perceptions and attitudes toward teaching activities during this period were analyzed. METHODS: A nationwide cross-sectional survey was conducted with a sample of Brazilian UDG and GD dentistry students. Data were collected in 2020 through an online, self-administered, and anonymous questionnaire, which comprised 26 questions related to demographic data, activities of the college, family and individual student income, and attitudes and perceptions about e-learning during the pandemic. The data were tabulated and analyzed using descriptive statistics. RESULTS: The sample included 1,166 students (779 UDG and 387 GD). Among these, 425 (54.6%) UDG and 270 (69.8%) GD students remotely participated in teaching activities, of which 42.6% of the UDG considered their performance in e-learning to be bad or very bad and 49.8% of the GD regarded it as good or excellent. The survey also showed that 354 (45.4%) UDG and 102 (26.4%) GD expressed a desire to discontinue the course following the outbreak of the pandemic. Among the GD, 225 (58.4%) said that their experiments were completely interrupted. CONCLUSIONS: This study reveals the poor perception and performance of dental students regarding e-learning. Additionally, the findings suggest a negative impact of the pandemic on dental education in Brazil. Effective measures should be taken to mitigate these significant consequences.

OBJECTIVE To investigate the association of single-nucleotide polymorphisms (SNP) in grainyhead-like 3 (GRHL3) and to verify its possible interactions with others genes responsible for craniofacial development in the risk of non-syndromic oral cleft (NSOC). METHODS Applying TaqMan allelic discrimination assays, we evaluated GRHL3 SNPs (rs10903078, rs41268753, and rs4648975) in an ancestry-structured case-control sample composed of 1,127 Brazilian participants [272 non-syndromic cleft palate only (NSCPO), 242 non-syndromic cleft lip only (NSCLO), 319 non-syndromic cleft lip and palate (NSCLP), and 294 healthy controls]. Additionally, SNP-SNP interactions of GRHL3 and previously reported variants in FAM49A, FOXE1, NTN1, and VAX1 were verified in non-syndromic cleft lip with or without cleft palate (NSCL ± P). To eliminate false-positive associations, Bonferroni correction or 1,000 permutation method was applied. RESULTS The multiple logistic regression analysis showed that the CC genotype of rs10903078 (p = .03) and the haplotype C-C formed by the SNPs rs10903078 and rs41268753 (p = .04) were associated with NSCLO, but the p-values did not withstand Bonferroni correction. However, SNP-SNP test revealed significant interactions between GRHL3 SNPs and FAM49A (rs7552), FOXE1 (rs3758249), VAX1 (rs7078160 and rs751231), and NTN1 (rs9891446). CONCLUSIONS Our results confirm the importance of GRHL3 and its interactions with previously NSOC-associated genes, including FAM49A, FOXE1, NTN1, and VAX1, in the pathogenesis of NSOC in the Brazilian population.

How the COVID-19 pandemic is affecting the incidence of syphilis remains unclear.1–4 We extracted data from the Brazilian Unified Health System public disease notification database to compare the mean number of syphilis cases reported from March to December 2017–2019 with those reported the same period of 2020. In all Brazilian macroregions, the incidence rates of syphilis per million population increased significantly during the COVID-19 pandemic, reaching …

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has limited the access of patients with Hansen's disease (HD) to care due to changes in routine health services. METHODS: To ascertain this, we compared the number of HD cases diagnosed before and after the COVID-19 pandemic. RESULTS: The decrease in HD cases in Brazil reached 18,223 (-48.4%), corresponding to an average reduction of 1,518 cases per month during the COVID-19 pandemic. CONCLUSION: Therefore, effective measures should be implemented to minimize the damage and the consequent negative health impact of COVID-19 on the care of HD patients.

Summary Background COVID-19 is usually less severe and has lower case fatality in children than in adults. We aimed to characterise the clinical features of children and adolescents hospitalised with laboratory-confirmed SARS-CoV-2 infection and to evaluate the risk factors for COVID-19-related death in this population. Methods We did an analysis of all patients younger than 20 years who had quantitative RT-PCR-confirmed COVID-19 and were registered in the Influenza Epidemiological Surveillance Information System (SIVEP-Gripe, a nationwide surveillance database of patients admitted to hospital with severe acute respiratory disease in Brazil), between Feb 16, 2020, and Jan 9, 2021. The primary outcome was time to recovery (discharge) or in-hospital death, evaluated by competing risks analysis using the cumulative incidence function. Findings Of the 82 055 patients younger than 20 years reported to SIVEP-Gripe during the study period, 11 613 (14·2%) had available data showing laboratory-confirmed SARS-CoV-2 infection and were included in the sample. Among these patients, 886 (7·6%) died in hospital (at a median 6 days [IQR 3–15] after hospital admission), 10 041 (86·5%) patients were discharged from the hospital, 369 (3·2%) were in hospital at the time of analysis, and 317 (2·7%) were missing information on outcome. The estimated probability of death was 4·8% during the first 10 days after hospital admission, 6·7% during the first 20 days, and 8·1% at the end of follow-up. Probability of discharge was 54·1% during the first 10 days, 78·4% during the first 20 days, and 92·0% at the end of follow-up. Our competing risks multivariate survival analysis showed that risk of death was increased in infants younger than 2 years (hazard ratio 2·36 [95% CI 1·94–2·88]) or adolescents aged 12–19 years (2·23 [1·84–2·71]) relative to children aged 2–11 years; those of Indigenous ethnicity (3·36 [2·15–5·24]) relative to those of White ethnicity; those living in the Northeast region (2·06 [1·68–2·52]) or North region (1·55 [1·22–1·98]) relative to those in the Southeast region; and those with one (2·96 [2·52–3·47]), two (4·96 [3·80–6·48]), or three or more (7·28 [4·56–11·6]) pre-existing medical conditions relative to those with none. Interpretation Death from COVID-19 was associated with age, Indigenous ethnicity, poor geopolitical region, and pre-existing medical conditions. Disparities in health care, poverty, and comorbidities can contribute to magnifying the burden of COVID-19 in more vulnerable and socioeconomically disadvantaged children and adolescents in Brazil. Funding National Council for Scientific and Technological Development, Research Support Foundation of Minas Gerais.

The comprehensive care and treatment for cancer patients in Brazil, regulated by the National Cancer Prevention and Control Policy, is provided by Brazilian Unified Healthcare System (SUS) in certified health institution. Due the COVID-19 pandemic, several restrictive measures have been implemented by the State federation's governments, and cancer diagnosis reference centers were also impacted by these measures. Thus, this study aimed to compare SUS-oriented cancer diagnosis in Brazil before and during the pandemic so far. The average number of cancer diagnoses has dropped considerably in all Brazilian Regions since the pandemic period started. The number of new cancer cases has plunged in all regions, ranged from -24.3% in the North to -42.7% in Northeast region. The overall Brazilian average deficit reached 35.5%, corresponding to about 15,000 undiagnosed cases of cancer monthly. The pandemic period has dramatically reduced the diagnosis of new cases of cancer in Brazil, since consultations in public health services were compromised by restrictive measures. Therefore, effective measures must be urgently put in action in order to minimize the damage, and consequently, the negative health impacts caused by the COVID-19 pandemic in the care of cancer patients.

International audience; Coronavirus 2019 (COVID-19), caused by the pathogen SARS-CoV-2, was declared a pandemic in March 2020. Recently, studies have discussed reports of patients infected with COVID-19 associated with vesicular manifestations of Herpes Zoster. The objective of this study was to compare the data from the Unified Health System (SUS) on the number of diagnoses of Herpes Zoster from March to August from 2017 to 2019, with the same period in 2020, in the five Brazilian regions (North, Northeast, Southeast, South, and Midwest). The data were extracted from the public database (DATASUS) of Brazil's Ministry of Health. The data showed an increase in the number of Herpes Zoster diagnoses over the years and the negative impact from the COVID-19 disease, revealing an average increase corresponding to an extra 10.7 cases per million inhabitants during the pandemic in all Brazilian Regions. Therefore, although the association between HZ and COVID-19 is not well established, we observed in this study an increase in HZ cases during the COVID-19 pandemic, which suggests a correlation between these diseases.

The newly emerged Coronavirus disease 2019 (COVID‐19) is an infectious disease that has spread rapidly throughout the world. The most common signs and symptoms are fever, dry cough and shortness of breath which can progress to severe viral pneumonia and multi‐organ failure in susceptive patients (Chen et al. 2020, Wang et al. 2020). Droplet transmission and person‐person transmission appear to be the main route of transmission of COVID‐19, however asymptomatic patients are also carriers of the virus (Rothe et al. 2020).

Coronavirus disease 19 (Covid‐19) was declared a pandemic by the World Health Organization on March 11th, 2020 (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen). As of May 19th, 2020, approximately 4,731,458 cases of contamination and 316,169 deaths from Covid‐19 were recorded (https://who.sprinklr.com).

The Brazilian scientific community and health care workers are working hard to provide support for the political health measures to deal with this unprecedented crisis of the COVID-19 pandemic. Paradoxically, while the society is looking forward for an immediate response of the scientific community, Brazilian scientists are facing a dramatic reduction in financial support for research and graduate programs.

Introduction: Bifid uvula is a frequently observed anomaly in the general population and can be regarded as a marker for submucous cleft palate. Objective: In this study aimed to determine the frequency of bifid uvula and submucous cleft palate and their relationship with oral clefts in a Brazilian population. Methods: We conducted a transversal, descriptive and quantitative study of 1206 children between August 2014 and December 2015. A clinical examination of the children was conducted by means of inspection of the oral cavity with the aid of a tongue depressor and directed light. After the clinical examination in children, parents answered a questionnaire with questions about basic demographic information and their family history of oral clefts in their first-degree relatives. After application of the questionnaires, the information collected was archived in a database and analyzed by the statistical program SPSS® version 19.0, by applying Chi-Square tests. Values with p

The population of Brazil is highly admixed, with each individual showing variable levels of Amerindian, European and African ancestry, which may interfere in the genetic susceptibility of known risk loci to nonsyndromic cleft lip with or without cleft palate (NSCL±P). Here, we investigated 5 reported genome-wide loci for NSCL±P in an ancestry-structured case-control study containing 1697 Brazilian participants (831 NSCL±P and 866 healthy controls). SNPs rs7552 in 2q24.2, rs8049367 in 16p13.3, rs1880646, rs7406226, rs9891446 in 17p13, rs1588366 in 17q23.2 and rs73039426 in 19q13.11 were genotyped using TaqMan allelic discrimination assays and genomic ancestry was estimated using a panel of 40 biallelic short insertion/deletion polymorphic markers informative of the Brazilian population. Logistic regression analysis of the single-markers revealed rs7552 in 2p24.2 as a susceptibility risk marker for NSCL±P, yielding an odds ratio (OR) of 1.71 (95% confidence interval (CI): 1.31-2.24, P = 9 × 10-6 ) in the homozygous state. Several SNP-SNP interactions containing rs7552 reached significance after adjustment for multiple tests (both Bonferroni assumption and 1000 permutation test), with the most significant interaction involving the 3-loci among rs7552, rs9891446 and rs73039426 (P = 6.1 × 10-9 and p1000 permutation = 0.001). Our study is the first to support the association of rs7552 in 2p24.2 with NSCL±P in the highly admixed Brazilian population.

Background Although various genes and genomic regions were described as of susceptibility for nonsyndromic oral clefts (NOC), recent reports have demonstrated significant interethnic variations in the genetic predisposition, a situation that affects the Brazilian population, one of the most admixed populations in the world. Therefore, the purpose of this review was to describe the available information on genetic risk markers for NOC in the Brazilian population. Methods A systematic search of the literature was performed using LILACS, LIVIVO, PubMed, Scopus, and Web of Science databases, and studies that investigated genetic susceptibility markers for NOC in the Brazilian population were retrieved. Markers with enough statistical data were subjected to meta-analysis using random- or fixed-effects model with odds ratio (OR) and 95% confidence intervals (95% CI) as effect measures. Results Forty-nine studies conducted since 1999 were found, and in these 114 markers were evaluated throughout case-control or family-based approaches. Most of the studies were conducted with patients affected by nonsyndromic cleft lip with or without cleft palate (NSCL ± P), and 79 markers (69.3%) were evaluated by a single study only. Meta-analysis was performed with nine markers, and the most promising results were obtained for IRF6 (rs642961), 8q24 (rs987525 and rs1530300) and MTHFR (rs1801133), which were associated with increased risk for NSCL ± P, and for BMP4 (rs17563) that showed a protective effect for NSCL ± P. Conclusion A large number of genetic markers distributed in several genes/loci was associated with NOC in the Brazilian population, but in general the original studies included limited number of samples and unsatisfactory protocols. The classical risk markers located in IRF6 and 8q24 showed promising results as well as rs1801133 in MTHFR and rs17563 in BMP4, and they should be validated in larger and multicenter studies taking in consideration the variations in the miscegenation of Brazilian population.

Nonsyndromic oral clefts are common congenital birth defects that exhibit variable prevalence around the world, often influenced by population-dependent genetic predisposition. Few studies have been performed with nonsyndromic cleft palate only (NSCPO), limiting the knowledge of the genetic risk factors related to this type of oral cleft. Genetic variants in golgin subfamily B member 1 (GOLGB1), a gene that is essential for normal murine palatogenesis, were analyzed in this study to establish its potential association with NSCPO risk in the Brazilian population. Five tag-single nucleotide polymorphisms (SNPs) of GOLGB1 (rs1169, rs7153, rs9968051, rs9819530, and rs6794341), which capture the majority of alleles spanning within gene, were genotyped in a case-control study with 270 patients with NSCPO and 284 unrelated healthy controls. The samples were also genotyped for 40 biallelic polymorphic markers to characterize the genetic ancestry. After adjustment for co-variants, the GOLGB1 tag-SNPs and the haplotypes formed by those SNPs were not significantly associated with NSCPO in this Brazilian case-control cohort. Our results suggest that common polymorphisms of GOLGB1 are not associated NSCPO susceptibility in the Brazilian population.

SUMMARY BACKGROUND. This study aimed to evaluate the scientific production of researchers in the field of Medicine who receive a productivity grant from the CNPq. METHODS: The curriculum Lattes of 542 researchers with active grants from 2012 to 2014 were included in the analysis. Grants categories/levels were stratified into three groups according to the CNPq database (1A-B, 1C-D, and 2). RESULTS. There was a predominance of grants in category 2. During their academic career, Medicine researchers published 76512 articles, with a median of 119 articles per researcher (IQ, interquartile range, 77 to 174). Among the 76512 articles, 36584 (47.8%) were indexed in the Web of Science (WoS database). Researchers in Medicine were cited 643159 times in the WoS database, with a median of 754 citations (IQ, 356 to 1447). There were significant differences among the categories of grants concerning the number of citations in WoS (P

ObjectiveTo determine the association of single-nucleotide polymorphisms (SNPs) in genes related to craniofacial development, which were previously identified as susceptibility signals for nonsyndromic oral clefts, in Brazilians with nonsyndromic cleft lip and/or palate (NSCL/P).DesignThe SNPs rs748044 (TNP1), rs1106514 (MSX1), rs28372960, rs15251 and rs2569062 (TCOF1), rs7829058 (FGFR1), rs1793949 (COL2A1), rs11653738 (WNT3), and rs242082 (TIMP3) were assessed in a family-based transmission disequilibrium test (TDT) and a structured case-control analysis based on the individual ancestry proportions.SettingThe SNPs were initially analyzed by TDT, and polymorphisms showing a trend toward excess transmission were subsequently studied in an independent case-control sample.ParticipantsThe study sample consisted of 189 case-parent trios of nonsyndromic cleft lip with or without cleft palate (NSCL±P), 107 case-parent trios of nonsyndromic cleft palate (NSCP), 318 isolated samples of NSCL±P, 189 isolated samples of NSCP, and 599 healthy controls.Main Outcome MeasureAssociation of alleles with NSCL/P pathogenesis.ResultsPreferential transmission of SNPs rs28372960 and rs7829058 in NSCL±P trios and rs11653738 in NSCP trios ( P = .04) were observed, although the structured case-control analysis did not confirm these associations. The haplotype T-C-C formed by TCOF1 SNPs rs28372960, rs15251, and rs2569062 was more frequently transmitted from healthy parents to NSCL±P offspring, but the P value ( P = .01) did not withstand Bonferroni correction for multiple tests.ConclusionsWith the modest associations, our results do not support the hypothesis that TNP1, MSX1, TCOF1, FGFR1, COL2A1, WNT3, and TIMP3 variants are risk factors for nonsyndromic oral clefts in the Brazilian population.

Objective: To evaluate the scientific production, generation of patents and researchers training among Brazilian Collective Health professors who were awarded a Pq/CNPq productivity scholarship from 2000 to 2012 and to verify the existence of an association between these production modalities and the characteristics of the professors, such as gender, training and origin. Method: An analytical cross-sectional study was carried out from 2000 to 2012, and the Prevalence Ratio was calculated using Poisson regression. For the statistical analyzes, the SPSS® program was used. Results: Of particular note are regional and institutional concentration, consistent scientific output, important researchers training, and a primordial but still timid generation of patents. We found an association between the "scientific production", "researchers training" outcomes, and the gender characteristics, such as the formation and origin of the Pq professor. Conclusion: These findings can guide the decision-making aimed at the deconcentration of scientific production and researchers training in the Brazilian Collective Health. RESUMEN El objetivo del trabajo fue evaluar la producción científica, la generación de patentes y la formación de investigadores entre docentes de la Salud Colectiva brasileña que fueron contemplados con becas de productividad Pq/CNPq en el período de verano y verificar la existencia de la asociación entre estas modalidades de producción; y las características de los docentes, como el género, la formación y el origen. Método: Se realizó un estudio transversal analítico en el período de referencia y se calculó la razón de prevalencia por medio de la regresión de Poisson. Para los análisis estadísticos se utilizó el programa SPSS®. Resultados: Se destacan la concentración regional e institucional, la consistente producción científica, la importante formación de investigadores; y la significativa, pero aún tímida, generación de patentes. Se encontró una asociación entre los resultados de la producción científica, la formación de investigadores y las características género, formación y origen del docente Pq. Conclusión: Esos hallazgos pueden orientar la toma de decisiones dirigidas a la desconcentración de la producción científica y la formación de investigadores en Salud Colectiva en Brasil. RESUMO Objetivo: Avaliar a produção científica, geração de patentes e formação de pesquisadores entre docentes da Saúde Coletiva brasileira que foram contemplados com bolsas de produtividade Pq/CNPq no período 2000-2012 e verificar a existência de associação entre estas modalidades de produção e características dos docentes, como gênero, formação e origem. Método: Foi realizado um estudo transversal analítico no período 2000-2012 e foi calculada a razão de prevalência por meio da regressão de Poisson. Para as análises estatísticas, utilizou-se o programa SPSS®. Resultados: Destacam-se a concentração regional e institucional, consistente produção científica, importante formação de pesquisadores e primordial, mas ainda tímida geração de patentes. Foi encontrada associação entre os desfechos "produção científica", "formação de pesquisadores", e as características de gênero, como formação e origem do docente Pq. Conclusão: Estes achados podem orientar a tomada de decisões voltadas para a desconcentração da produção científica e formação de pesquisadores em Saúde Coletiva no Brasil.

Objective To evaluate the association of single nucleotide polymorphisms (SNPs) in genes/loci consistently altered in nonsyndromic oral clefts in patients with oral and breast cancer in a Brazilian population. Design This case-control study evaluated the association of SNPs in IRF6 (rs642961), WNT3A (rs708111), GSK3β (rs9879992), 8q24 (rs987525) and WNT11 (rs1533767), representing regions consistently identified as of susceptibility for oral clefts, with oral cancer (oral squamous cell carcinoma) and breast cancer. Logistic regression analyses were used for confounding adjustments, and p values ≤0.01 were considered statistically significant (Bonferroni correction = 0.05/5 polymorphic markers). Results The minor G allele of rs9879992 in GSK3β was associated with oral cancer risk (p = 0.02), whereas rs1533767 in WNT11 showed a protective effect against it (p = 0.04). Several SNP-SNP interactions containing GSK3β rs9879992 were significantly associated with oral cancer after 1000 permutation test. To breast cancer, the A allele of rs987525 was associated with increase risk in early stage (p = 0.02) and SNP-SNP interactions involving the 5 SNPs were significantly observed, with the most significant interaction among rs708111, rs1533767, rs9879992 and rs642961 (p1000permutation Conclusion Our results reveal associations of SNPs consistently altered in oral cleft with oral and breast cancer risk, raising interesting possibilities to identify risk markers for those tumors.

BACKGROUND GREM1, which encodes Gremlin 1, an antagonist of bone morphogenic proteins with effects on proliferation and apoptosis, has been considered a candidate gene for nonsyndromic cleft lip with or without cleft palate (NSCL±P). In this study, we investigated potential associations of single nucleotide polymorphisms (SNP) in GREM1 and NSCL±P risk in the Brazilian population. Additionally, SNP-SNP interactions of GREM1 with previously reported rs1880646 variant in NTN1 (netrin 1), a gene also responsible for apoptotic phenotypes were verified. METHODS Applying Taqman allelic discrimination assays, we evaluated the variants rs16969681, rs16969816, rs16969862, and rs1258763 in 325 case-parent trios and in 1,588 isolated samples in a case-control study. Allelic and genotypic analyses, as well as interaction tests assessing gene-environmental factor (GxE) and SNP-SNP interaction with rs1880646 variant in NTN1, were performed based on logistic regression analysis adjusted for the effects of gender and genomic ancestry proportions. RESULTS The risk alleles of all SNP were undertransmitted in NSCL±P trios, though the case-control analysis confirmed only the association with rs16969862 alleles (OR: 0.78, 95% CI: 0.63-0.96, p = .02). The GxE interaction analysis revealed a significant interaction between maternal environmental contact with agrotoxics and rs16969816 (OR: 0.25, 95% CI: 0.08-0.74, p = .01), and pairwise interaction test with NTN1 rs1880646 yielded significant p values in the 1,000 permutation test for rs16969681, rs16969816, and rs16969862. CONCLUSION The GREM1 is involved in the etiology of NSCL±P in the Brazilian population and reveal that the interaction between GREM1 and NTN1 may be related with the pathogenesis of this common craniofacial malformation.

During development, oxidative stress is hypothesized to mediate embryotoxicity, which may be intensified by exposition to environmental factors and by genetic variations in the enzymes involved in protecting cells from these damaging effects, including superoxide dismutase (SOD) and paraoxonase (PON). The aim of this study was to evaluate the influence of single-nucleotide polymorphisms (SNP) in genes associated with the neutralization of oxidative stress (SOD and PON family members) in the risk of nonsyndromic oral cleft in the Brazilian population. Initially, we tested for association between 28 SNP in SOD1, SOD2, SOD3, PON1, PON2, and PON3 among 325 nonsyndromic cleft lip with or without cleft palate (NSCL±P) case-parent trios. Multiple logistic regression analyses were used to explore gene, GxG and GxE, involving factors that induce oxidative stress accumulation during pregnancy. Signals still significant after both Bonferroni correction and in permutation test were subsequently confirmed in an ancestry-structured case-control analysis with 722 NSCL±P and 866 controls from the same population. In the trio sample, transmission disequilibrium test (TDT) (allele and haplotype) and GxE analysis showed no significant associations, but multiple pairwise GxG interactions involving 10 SNP in PON1, PON2, and PON3 were detected and further examined in the case-control sample. The PON1 rs2237583 and PON2 rs17166879 yielded significant evidence of SNP-SNP interactions after adjustment for multiple tests (both Bonferroni correction and 10,000 permutation test). The C allele and the CT genotype of PON1 rs2237583 were associated with significant protective effects against NSCL±P, while rs3917490 showed a significant association only in the sample composed of patients displaying high African ancestry. Our results reveal associations between rs2237583 and rs3917490 in PON1 and GxG interactions containing rs2237583 and rs17166879 with the susceptibility of NSCL±P in the Brazilian population. Furthermore, this study underlines the recent tendency of taking into account potential GxG interactions to clarify the underlying mechanisms associated with the etiology of this common malformation. Environ. Mol. Mutagen. 60: 185-196, 2019. © 2018 Wiley Periodicals, Inc.

INTRODUCTION: Cleft lip and/or palate (CL/P) represent the most common congenital anomalies of the face.OBJECTIVE: To evaluate the prevalence of depressive symptoms in children and adolescents with nonsyndromic cleft lip and/or palate (nsCL/P).METHODS: We conducted an observational, case-control study, with a case study group composed of 61 patients with nsCL/P, aged 7-17 years, and a control group of 61clinically normal patients. Both groups were selected at the same institution.RESULTS: Depressive symptoms were observed in the case group (nsCL/P), but there were no statistically significant differences compared to the control group. No association was found between the two groups (case and control) in relation to sociodemographic variables: gender, age and education.CONCLUSIONS: This study identified the prevalence of depressive symptoms in children and adolescents with nsCL/P from a localized geographic population, although the results were not statistically significant when compared to the control group, not justifying the use of CDI (Child Depression Inventory) as a screening instrument for depressive symptoms in the examined population. INTRODUÇÃO: Fissuras labiais e/ou palatinas (FL/Ps) representam as anomalias craniofaciais mais comuns.OBJETIVOS: Avaliar a prevalência de sintomas depressivos em crianças e adolescentes não sindrômicos com FL/P (FL/PNS).MÉTODO: Foi realizado um estudo observacional de caso-controle com uma amostra populacional de conveniência, com um grupo caso (61 pacientes com FL/PNS, tendo idades entre 7 a 17 anos) e um grupo controle (61 pacientes clinicamente normais). Ambos os grupos foram selecionados na mesma Instituição.RESULTADOS: Sintomas depressivos foram observados no grupo caso (FL/PNS), mas não houve diferenças estatisticamente significantes quando comparado com o grupo controle. Não foi encontrada associação entre os dois grupos (caso e controle) em relação às variáveis sociodemográficas: gênero, idade e educação.CONCLUSÕES: Este estudo observou a prevalência de sintomas depressivos em crianças e adolescentes com FL/PNS de uma população geográfica localizada, embora os resultados não tenham sido estatisticamente significantes quando comparado com o grupo controle, não justificando assim a utilização de instrumentos rastreadores de sintomas depressivos na população analisada.

Background Epidemiological studies have indicated a higher incidence of breast and gastric cancer in patients with nonsyndromic cleft lip with or without cleft palate (NSCL ± P) and their relatives, which can be based on similar genetic triggers segregated within family with NSCL ± P. Methods This multicenter study evaluated the association of 9 single nucleotide polymorphisms (SNP) in AXIN2 and CDH1, representing genes consistently altered in breast and gastric tumors, with NSCL ± P in 223 trios (father, mother and patient with NSCL ± P) by transmission disequilibrium test (TDT). Results Our results showed that the minor A allele of rs7210356 (p = 0.01) and the T-G-G-A-G haplotype formed by rs7591, rs7210356, rs4791171, rs11079571 and rs3923087 SNPs (p = 0.03) in AXIN2 were significantly under-transmitted to patients with NSCL ± P. In CDH1 gene, the C-G-A-A and A-G-A-G haplotypes composed by rs16260, rs9929218, rs7186053 and rs4783573 polymorphisms were respectively over-transmitted (p = 0.01) and under-transmitted (p = 0.008) from parents to the children with NSCL ± P. Conclusions The results suggest that polymorphic variants in AXIN2 and CDH1 may be associated with NSCL ± P susceptibility, and reinforce the putative link between cancer and oral clefts. Electronic supplementary material The online version of this article (doi:10.1186/s12881-017-0390-y) contains supplementary material, which is available to authorized users.

CONTEXT AND OBJECTIVE: Retinopathy of prematurity (ROP) is a known cause of blindness in which diagnosis and timely treatment can prevent serious harm to the child. This study aimed to evaluate the incidence of ROP and its association with known risk factors. DESIGN AND SETTING: Longitudinal incidence study in the neonatal intensive care unit (NICU) of Universidade Estadual de Montes Claros. METHODS: Newborns admitted to the NICU with gestational age less than 32 weeks and/or birth weight less than 1,500 grams, were followed up over a two-year period. The assessment and diagnosis of ROP were defined in accordance with a national protocol. The chi-square test or Fisher's exact test were used to determine associations between independent variables and ROP. Analysis on the independent effect of the variables on the results was performed using multiple logistic regression. RESULTS: The incidence of ROP was 44.5% (95% confidence interval, CI = 35.6-46.1) in the study population. The risk factors associated with the risk of developing the disease were: birth weight less than 1,000 grams (odds ratio, OR = 4.14; 95% CI = 1.34-12.77); gestational age less than 30 weeks (OR = 6.69; 95% CI = 2.10-21.31); use of blood derivatives (OR = 4.14; 95% CI = 2.99-8.99); and presence of sepsis (OR = 1.99; 95% CI = 1.45-2.40). CONCLUSIONS: The incidence of ROP was higher than that found in the literature. The main risk factors were related to extreme prematurity. CONTEXTO E OBJETIVO: A retinopatia da prematuridade (ROP) é causa conhecida de cegueira e diagnóstico e tratamento oportunos podem evitar graves danos à criança. Este estudo objetivou avaliar a incidência da ROP e sua associação com fatores de risco conhecidos.

Congenital malformations and cancer may share common etiological factors and the association between nonsyndromic cleft lip and/or palate (NSCL/P) and cancers has been observed in different studies. The objective of this study was to evaluate the frequency of cancer in relatives of patients with NSCL/P. This investigation was a cross-sectional, case-controlled study, evaluating 358 patients with NSCL/P treated at a Referral Center for craniofacial deformities (case group) and 358 patients without craniofacial alterations (control group). Information concerning the gender, age and family history of cancer in first-degree relatives for both groups was obtained. The frequency of cancer was 6.4% (n=46) in the studied population, with 18 subjects in the case group (5%) and 28 (7.8%) in control. In both groups, the most frequently reported cases were those of breast, colorectal, stomach, prostate and uterus cancers, but there was no association between the two groups. There was no association with a family history of cancer among the first-degree relatives (odds ratio=0.62; 95% IC: 0.34 to 1.15), neither when the analysis was made by type of cancer. In conclusion, both epidemiological and genetic studies have suggested common etiological factors for NSCL/P and cancer. However, in this population-based study, no association between cancer and NSCL/P could be confirmed.

The objective of this study was to compare the quality of life of women who survived breast cancer and women who have not had the disease, and to identify associated factors. It is cross-sectional study in which the comparison group includes survivors of breast cancer aged between 40 and 69 years. One hundred and fifty-four women were included, 70 with breast cancer and 84 without the disease. The SF-36 was used to evaluate quality of life. The chi-square test and multivariate linear models were used to compare the groups. The estimated mean physical and mental components were significantly better for the group who survived the disease (51.10 and 52.25, respectively) compared to the group without cancer (47.26 and 47.93, respectively). The study indicates that survivors of breast cancer had a better quality of life compared to women without the disease.

Objective The aim of this study was to radiographically investigate the prevalence of dental anomalies outside the cleft area in a group of Brazilian patients with nonsyndromic cleft lip and/or palate (NSCL/P). Design, Participants, and Setting A retrospective analysis of 207 panoramic radiographs of patients with NSCL/P aged 12 to 45 years without history of tooth extraction and orthodontic treatment was performed. Results Dental anomalies were found in 75.4% of the patients, and tooth agenesis (29.2%) and supernumerary tooth (2.6%) were the most common anomalies. The risk of agenesis was higher among the individuals with cleft palate (CP) compared with individuals with cleft lip (CL) and cleft lip and palate (CLP) (agenesis: CP versus CL: odds ratio 6.27, 95% confidence interval 2.21-17.8, P = .0003; CP versus CLP: odds ratio 2.94; 95% confidence interval 1.27-6.81, P = .01). The frequency of dental agenesis was higher in patients with unilateral complete CLP (agenesis: P < .0001), incomplete bilateral CLP (agenesis: P = .0013), complete CP (agenesis: P < .0001), and incomplete CP (agenesis: P < .0001). The frequency of supernumerary teeth was higher in patients with bilateral complete CLP ( P < .0001). The frequency of dental agenesis ( P < .0001) and ectopic tooth ( P = .009) was higher than the frequency estimated for general population. Conclusions The prevalence of dental anomalies in patients with NSCL/P was higher than that reported in overall population. This study found preferential associations between dental anomalies and specific extensions of NSCL/P, suggesting that dental agenesis and ectopic tooth may be part of oral cleft subphenotypes.

BACKGROUND Polymorphisms in genes that are involved in folic acid metabolism may be important maternal risk factors for the birth of a child with nonsyndromic cleft lip and/or palate (NSCL/P). The aim of this study was to determine the involvement of polymorphic variants in four genes (MTHFR,MTHFD1,MTR, and SLC19A1) that encode proteins related to folic acid metabolism in the women with susceptibility for having a child with NSCL/P. METHODS DNA samples from 106 mothers of children with NSCL/P (case group) and from 184 mothers of healthy children (control group) were genotyped by polymerase chain reaction associated with restriction fragment length polymorphism (PCR-RFLP). RESULTS One of 29 polymorphisms was associated with significantly increased maternal risk for NSCL/P. Mothers exhibiting the A variant allele (GA genotype) of the MTHFR rs2274976 polymorphism demonstrated a ∼6 times increased risk for having a child with NSCL/P compared to G allele carriers (OR, 5.76; 95% CI, 3.32–9.99, p = 0.000001). Among mothers who did not use vitamins, the OR of NSCL/P was increased to 8.34 (95% CI, 3.75–18.55, p = 0.000001) in the presence of the GA genotype of the MTHFR rs2274976 polymorphism compared to those with the GG genotype. Gene-gene interaction analysis showed that the combination of MTHFR rs2274976, MTHFD1 rs2236225, and SLC19A1 rs1051266 was the best model for prediction of maternal risk for NSCL/P. CONCLUSION The findings of the present study suggested that genetic variants of folic acid metabolic genes may modulate maternal susceptibility for having an offspring with NSCL/P. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Summary Cleft lip and palate (CL/P) are the most common congenital anomalies of the craniofacial region. Aim to evaluate the surgical techniques used in CL/P treatment in a craniofacial deformities ward, in Minas Gerais. Materials and Methods In this retrospective study, carried out between 2002 and 2007, we studied 109 individuals with non-syndromic CL/P submitted to treatment. The aspects analyzed (personal identification, classification of CL/P and surgical treatment performed) were obtained from patient charts, and then we built a database and ran statistical analyses through the SPSS 13.0 software. Followed by descriptive analysis of the surgical procedures depending on the type of CL/P found. Results Among the 109 patients, 65.1% were males and 34.8% females. We found that 45% of patients had cleft lip and palate, 37.6% cleft lip only and 17.4% cleft palate only. The surgical techniques employed were predominantly those from Millard and Spina for cheiloplasty, McComb for rhinoplasty and, Veau and Van Langenbeeck for palatoplasty. Conclusions This study is the first to address treatment procedures for individuals with CL/P in the state of Minas Gerais. For unilateral CL/P we predominantly used the association of McComb, Veau and Millard techniques, respectively, for rhinoplasty, palatoplasty and cheiloplasty, in 76.9% of the patients.

Sickle cell anemia (SCA) is the most prevalent genetic disease worldwide. Recurrent vaso-occlusive infarcts predispose SCA patients to infections, which are the primary causes of morbidly and mortality. This study aimed to evaluate the relationship between SCA and endodontic diseases. Personal information, medical data (hematological indices, virologic testing, blood transfusions, medications received, splenectomy) and information on the need for endodontic treatment were obtained from SCA patients who were registered and followed up by the Fundação Hemominas, Minas Gerais, Brazil.These data were compared with the need for root canal treatment in SCA patients. One hundred eight patients comprised the studied population, and the rate of the need for endodontic therapy was 10.2%. Among the medical data, a significant difference was observed for eosinophil (p = 0.045) counts and atypical lymphocyte counts (p = 0.036) when the groups (with and without the need for endodontic treatment) were compared. Statistical relevance was observed when comparing the patients with and without the need for root canal therapy concerned eosinophil counts and atypical lymphocyte counts. The differences in statistical medical data, observed between the groups suggest that both parameters are naturally connected to the stimulation of the immune system that can occur in the presence of root canal infections and that can be harmful to SCA individuals.

INTRODUCTION: Cleft lip and/or palate (CL/P) represent the most common congenital anomalies of the face. OBJECTIVE: To assess the relationship between maternal smoking, gender and CL/P. METHODS: This is an epidemiological cross-sectional study. We interviewed 1519 mothers divided into two groups: Cases: mothers of children with CL/P (n = 843) and Controls: mothers of children without CL/P (n = 676). All mothers were classified as smoker or non-smoker subjects during the first trimester of pregnancy. To determine an association among maternal smoking, gender, and CL/P, odds ratios were calculated and the adjustment was made by a logistic regression model. RESULTS: An association between maternal smoking and the presence of cleft was observed. There was also a strong association between male gender and the presence of cleft (OR = 3.51; 95% CI 2.83-4.37). By binary logistic regression analysis, it was demonstrated that both variables were independently associated with clefts. In a multivariate analysis, male gender and maternal smoking had a 2.5- and a 1.5-time greater chance of having a cleft, respectively. CONCLUSION: Our findings are consistent with a positive association between maternal smoking during pregnancy and CL/P in male gender. The results support the importance of smoking prevention and introduction of cessation programs among women with childbearing potential. RESUMO Introdução: Fendas labiais e/ou palatinas (FL/P) representam as anomalias congênitas mais comuns da face. Objetivo: Avaliar a relação entre tabagismo materno, gênero e FL/P. Método: Realizou-se um estudo epidemiológico, de corte transversal. Foram entrevistadas 1.519 mães, divididas em dois grupos: Casos: mães de crianças com FL/P (n = 843); e Controles: mães de crianças sem FL/P (n = 676). Todas as mães foram classificadas como fumantes ou não fumantes durante o primeiro trimestre de gravidez. Para determinar a associação entre tabagismo materno, gênero e FL/P, odds ratios foram calculadas e o ajuste realizado pelo modelo de regressão logística. Resultados: Observou-se associação entre tabagismo materno, e fendas. Houve também forte associação entre sexo masculino e presença de fendas (OR = 3,51; 95% IC 2,83-4,37). Regressão logística binária demonstrou que ambas as variáveis foram independentemente associadas coma ocorrência de fendas. Na análise multivariada, o sexo masculino teve 2,5 vezes mais chance de apresentar fendas e tabagismo materno teve 1,5 vez mais chance dessa ocorrência. Conclusão: Os resultados são consistentes com a associação positiva entre tabagismo materno durante a gravidez e a ocorrência de FL/P no gênero masculino. Os resultados suportam a importância da prevenção do tabagismo e a aplicação de programas entre mulheres com potencial de gravidez.

Background Fanconi syndrome (FS) is a generalized dysfunction of renal proximal tubules resulting in impaired reabsorption of amino acids, phosphate, urate, bicarbonate, glucose, and electrolytes. FS can be a primary renal impairment due to genetic origin or secondary to inborn errors of metabolism or systemic diseases. Main clinical findings are polyuria, failure to thrive, rickets/osteomalacia, metabolic acidosis, bone deformities, and, occasionally, nephrocalcinosis. Although dental abnormalities have been reported in patients with tubulopathies, oral manifestations in FS were very rarely described. Case report Two patients with FS exhibiting important dental alterations were reported. Oral examination of the first patient revealed teeth with rough surfaces and white opaque areas. Early loss of primary teeth and delayed eruption of permanent teeth were also observed. Oral examination of the second patient detected delayed eruption of permanent teeth and X-ray images revealed loss of contrast between enamel and dentin. In both patients with FS, loss of bone density in maxilla and mandible was observed in X-ray images. Conclusions This study is the first report of dental abnormalities in Brazilian patients with FS. Furthermore, our findings support the general idea that renal tubular disorders might impact on mineralized tissues of the oral cavity.

The purpose of this study was to evaluate the prevalence of taurodontism in patients with nonsyndromic cleft lip and palate (NSCLP) within a Brazilian population.The study was designed as an epidemiologic case-control single-center study. Three hundred eighty-eight patients were included: 88 had NSCLP, and 300 comprised the control group. The first and second permanent mandibular molars were included in this study. By using panoramic radiographs, taurodontism was categorized as mesotaurodontism, hypotaurodontism, and hypertaurodontism.Seventy patients (23.3%) from the control group and 36 patients (40.9%) from the case group presented taurodontism (P.001). In the control group, 108 (9%) teeth showed taurodontism, whereas in the case group with cleft lip and palate (CLP), 64 (18.2%) teeth showed dental anomalies (P.001). In both groups, most taurodontic teeth presented hypotaurodontism, followed by mesotaurodontism, while hypertaurodontism was found in only two teeth. The probability of taurodontism in patients with cleft lip (CL) was 2.36 (P = .010) times higher compared with those with CLP, whereas the occurrence of taurodontism in patients with cleft palate (CP) was 3.15 (P = .002) times greater than in patients with CLP.The results from this study indicate a close relationship between taurodontism and NSCLP and the possibility of different cleft subphenotypes.

Pfeiffer syndrome (PS) is mainly characterized by craniosysnostosis, midface hypoplasia, great toes with partial syndactyly of the digits and broad and medially deviated thumbs. It is caused by allelic mutations in the fibroblast growth factor receptor 1 and 2 (FGFR1 and 2) genes. This study describes the clinical and genetic features of five Brazilian families affected by PS. All patients exhibited the classical phenotypes related to PS. The genetic analysis was able to detect the mutations Cys278Phe, Cys342Arg, and Val359Leu in three of these families. Two mutations were de novo, with one familial. We identified pathogenic mutations in four PS cases in five Brazilian families by PCR sequencing of FGFR1 exon 5 and FGFR2 exons 5, 8, 10, 11, 15, and 16. The clinical and genetic aspects of these families confirm that this syndrome can be clinically variable, with different mutations in the FGFR2 responsible for PS.

Objective: several studies have examined the academic production of the researchers at the CNPq, in several areas of knowledge. The aim of this study was to evaluate the scientific production of researchers in Hematology/Oncology who hold scientific productivity grants from the Brazilian Council for Scientific and Technological Development. Methods: the Academic CVs of 28 researchers in Hematology/Oncology with active grants in the three-year period from 2006 to 2008 were included in the analysis. The variables of interest were: institution, researchers’ time after doctorate, tutoring of undergraduate students, masters and PhD degree, scientific production and its impact. Results: from a total of 411 researchers in Medicine, 28 (7%) were identified as being in the area of Hematology/Oncology. There was a slight predominance of males (53.6%) and grant holders in category 1. Three Brazilian states are responsible for approximately 90% of the researchers: São Paulo (21,75%), Rio de Janeiro (3,11%), and Minas Gerais (2, 7%). During their academic careers, the researchers published 2,655 articles, with a median of 87 articles per researcher (IQR = 52 to 122). 65 and 78% of this total were indexed on the Web of Science and Scopus databases, respectively. The researchers received 14,247 citations on the WoS database with a median of 385 citations per researcher. The average number of citations per article was 8.2. Conclusion: in this investigation, it was noted that researchers in the field of Hematology/Oncology have a relevant scientific output from the point of view of quantity and quality compared to other medical specialties. Objectivo: vários estudos têm analisado a produção acadêmica dos pesquisadores do Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), em diversas áreas do conhecimento. O objetivo deste estudo foi avaliar a produção científica de pesquisadores de Hematologia- Oncologia, cadastrados como bolsistas de produtividade científica do CNPq. Métodos: os currículos Lattes de 28 pesquisadores em Hematologia-Oncologia, com bolsas ativas no triênio 2006 a 2008, foram incluídos na análise. As variáveis de interesse foram: instituição, tempo de doutoramento, orientação de alunos de graduação, mestres e doutores, artigos publicados e seu impacto. Resultados: de um total de 411 pesquisadores em Medicina, 28 (7%) foram identificados como da área da Hematologia- Oncologia. Houve uma discreta predominância do gênero masculino (53,6%) e de bolsistas na categoria 1 (53,6%). Três Estados da Federação são responsáveis por 90% dos pesquisadores: São Paulo (21; 75%), Rio de Janeiro (3; 11%) e Minas Gerais (2; 7%). No total da carreira acadêmica, os pesquisadores publicaram 2.655 artigos em periódicos, sendo a mediana de 87 artigos por pesquisador (intervalo interquartil [IQ] = 52-122). Desse total, 65% e 78% foram artigos indexados nas bases de dados Web of Science (WoS) e Scopus, respectivamente. Os pesquisadores receberam 14.247 citações na base de dados WoS, sendo a mediana por pesquisador de 385 citações. A média de citações por artigo foi de 8,2. Conclusão: na presente investigação, observou-se que os pesquisadores na área de Hematologia-Oncologia apresentam uma produção científica relevante do ponto de vista qualitativo quando comparada a das demais especialidades médicas.