Endotoxin tolerance and low activation of TLR-4/NF-κB axis in monocytes of COVID-19 patients.

Higher endotoxin in the circulation may indicate a compromised state of host immune response against coinfections in severe COVID-19 patients. We evaluated the inflammatory response of monocytes from COVID-19 patients after lipopolysaccharide (LPS) challenge. Whole blood samples of healthy controls, patients with mild COVID-19, and patients with severe COVID-19 were incubated with LPS for 2 h. Severe COVID-19 patients presented higher LPS and sCD14 levels in the plasma than healthy controls and mild COVID-19 patients. In non-stimulated in vitro condition, severe COVID-19 patients presented higher inflammatory cytokines and PGE-2 levels and CD14 + HLA-DRlow monocytes frequency than controls. Moreover, severe COVID-19 patients presented higher NF-κB p65 phosphorylation in CD14 + HLA-DRlow, as well as higher expression of TLR-4 and NF-κB p65 phosphorylation in CD14 + HLA-DRhigh compared to controls. The stimulation of LPS in whole blood of severe COVID-19 patients leads to lower cytokine production but higher PGE-2 levels compared to controls. Endotoxin challenge with both concentrations reduced the frequency of CD14 + HLA-DRlow in severe COVID-19 patients, but the increases in TLR-4 expression and NF-κB p65 phosphorylation were more pronounced in both CD14 + monocytes of healthy controls and mild COVID-19 patients compared to severe COVID-19 group. We conclude that acute SARS-CoV-2 infection is associated with diminished endotoxin response in monocytes. KEY MESSAGES: Severe COVID-19 patients had higher levels of LPS and systemic IL-6 and TNF-α. Severe COVID-19 patients presented higher CD14+HLA-DRlow monocytes. Increased TLR-4/NF-κB axis was identified in monocytes of severe COVID-19. Blunted production of cytokines after whole blood LPS stimulation in severe COVID-19. Lower TLR-4/NF-κB activation in monocytes after LPS stimulation in severe COVID-19.

Alterations in CD39/CD73 axis of T cells associated with COVID-19 severity.

Purinergic signaling modulates immune function and is involved in the immunopathogenesis of several viral infections. This study aimed to investigate alterations in purinergic pathways in coronavirus disease 2019 (COVID-19) patients. Mild and severe COVID-19 patients had lower extracellular adenosine triphosphate and adenosine levels, and higher cytokines than healthy controls. Mild COVID-19 patients presented lower frequencies of CD4+ CD25+ CD39+ (activated/memory regulatory T cell [mTreg]) and increased frequencies of high-differentiated (CD27- CD28- ) CD8+ T cells compared with healthy controls. Severe COVID-19 patients also showed higher frequencies of CD4+ CD39+ , CD4+ CD25- CD39+ (memory T effector cell), and high-differentiated CD8+ T cells (CD27- CD28- ), and diminished frequencies of CD4+ CD73+ , CD4+ CD25+ CD39+ mTreg cell, CD8+ CD73+ , and low-differentiated CD8+ T cells (CD27+ CD28+ ) in the blood in relation to mild COVID-19 patients and controls. Moreover, severe COVID-19 patients presented higher expression of PD-1 on low-differentiated CD8+ T cells. Both severe and mild COVID-19 patients presented higher frequencies of CD4+ Annexin-V+ and CD8+ Annexin-V+ T cells, indicating increased T-cell apoptosis. Plasma samples collected from severe COVID-19 patients were able to decrease the expression of CD73 on CD4+ and CD8+ T cells of a healthy donor. Interestingly, the in vitro incubation of peripheral blood mononuclear cell from severe COVID-19 patients with adenosine reduced the nuclear factor-κB activation in T cells and monocytes. Together, these data add new knowledge to the COVID-19 immunopathology through purinergic regulation.

Anger and substance abuse: a systematic review and meta-analysis

Objective: Conduct a systematic review and meta-analysis to evaluate levels of anger among substance users compared to non-user controls and to analyze the possible association between anger and psychoactive substance use (PSU). Methods: The procedures of this review followed the Meta-Analyzes of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Four electronic databases (MEDLINE, EMBASE, BIREME, PsycINFO) were searched. Results: Twelve studies were included in the meta-analysis; 10 used the State-Trait Anger Expression Inventory (STAXI) anger trait subscale and two used the Buss-Perry-Aggression Questionnaire (BPAQ) anger subscale. The sample included 2,294 users of psychoactive substances and 2,143 non-users, all male. The mean difference in anger scale scores between users and non-users was 2.151 (95%CI 1.166-3.134, p ≤ 0.00, inconsistency index [I2] = 98.83) standard deviations. Age and abstinence duration did not moderate the difference in anger between substance users and non-users. Conclusion: Users of psychoactive substances had elevated anger scores compared to non-users, which represents a high risk of relapse. It is suggested that PSU treatment programs include intensive anger management modules, focusing on factors such as dealing with daily stressors, family conflicts, frustrations, and problems.

Effectiveness of a universal vaccination program with an HPV quadrivalent vaccine in young Brazilian women.

We examined human papillomavirus (HPV) vaccine effectiveness in a nationwide sample of women aged 16 to 25 years who utilized the public health system in Brazil. This was a cross-sectional, multicentric survey conducted between September 2016 and November 2017 (POP-Brazil Study). A total of 5,945 young adult women were recruited from 119 public primary care units from all 27 federative units of Brazil by trained health professionals. The participants participated in a face-to-face interview and provided biological samples for genital HPV analysis. HPV genotyping was performed using a Linear Array HPV genotyping test in a central laboratory. Sampling weights were applied to the data. Overall, 11.92% (95% CI 10.65, 13.20) of the participants reported having been vaccinated. The frequency of vaccination was highest in 16- to 17-year-old women, with a decreasing vaccination rate with increasing age, and vaccinated women were more likely to belong to the high socioeconomic status group. The use of a quadrivalent vaccine decreased the HPV types 6, 11, 16, and 18 by 56.78%, from 15.64% in unvaccinated women to 6.76% in vaccinated women (P < 0.01), even after adjustment for age. Those who received the vaccine had lower HPV 16 (2.34% in vaccinated vs 8.91% in unvaccinated, P < 0.01) and 6 rates (2.06% vs 5.77%, P < 0.01). Additionally, a higher rate of high-risk HPV types other than HPV 16 and 18 (40.47% in vaccinated vs 32.63% in unvaccinated, P < 0.01) was observed. In conclusion, the results of this study support the effectiveness of HPV vaccination in Brazil. Continuous surveillance must be assured to monitor the HPV infection rate in the vaccination era.

The impact of socioeconomic status on HPV infection among young Brazilians in a nationwide multicenter study.

The aim of this study is to evaluate genital human papillomavirus (HPV) infection according to socioeconomic categories in Brazil. This cross-sectional, nationwide study included 7,694 sexually active women and men aged 16-25 years. Individuals of all socioeconomic groups in all 26 Brazilian capitals and the Federal District were enrolled through public primary care units between September 2016 and November 2017. All participants answered a standardized interview administered by trained primary care health professionals. Socioeconomic class was analyzed using a pricing classification system for the Brazilian public that divides the market exclusively in terms of economic class based on the ownership of assets and the education level. Cervical samples were obtained using a Digene® HC2 DNA Collection, and penile/scrotum samples were obtained using a wet Dacron swab. HPV typing (overall and high-risk) was performed in a central lab. Of the 7,694 participants (47.85% women), 17.92% belonged to class A-B, 56.08% to class C, and 26.00% to class D-E. The prevalence of overall HPV was similar among the social classes: 51.16% for classes A-B, 53.39% for class C, and 55.47% for classes D-E (P = 0.479). Similar results were found for high-risk HPV. After adjustments, the presence of HPV in individuals with a brown skin color belonging to classes A-B was 57.00% higher [prevalence ratio 1.57 (95%: 1.23, 2.01)] than that in whites and had no impact on the other social classes. In conclusion, HPV infection affects all socioeconomic classes in Brazil, evidencing the importance of offering the HPV vaccine to the entire population.

Human papillomavirus knowledge, beliefs, and behaviors: A questionnaire adaptation.

OBJECTIVE: This study aims to adapt a questionnaire about the knowledge, beliefs and behaviors regarding HPV and related subjects into Brazilian Portuguese. STUDY DESIGN: National Survey. METHODS: The instrument was translated into Portuguese and retranslated into English separately. Experts assessed the validity of the content and cross-cultural adaptation of the instrument. The instrument was administered to 8580 male and female Brazilian adolescents and young adults (aged between 16 and 25 years) who participated in the National Survey of Human Papillomavirus Prevalence (POP-Brazil). This large-scale survey enrolled participants from 26 Brazilian capitals and the Federal District. RESULTS: The full questionnaire is composed of 30 questions, with a good absolute agreement between its two halves (61.16 ± 9.97). The preventive behavior section showed the lowest agreement. Men and women showed a difference concerning their knowledge about HPV (score for men 0.48 (± 8.93) vs. women 0.55 (± 4.51), p < 0.001). CONCLUSION: The proposed questionnaire is the first instrument able to describe the knowledge, beliefs and behaviors regarding HPV and related subjects in Brazilian women and men. This questionnaire appears to be adequate for use in future studies that may produce evidence and knowledge on these specific topics.

Prevalence of papillomavirus in Brazil: a systematic review protocol.

INTRODUCTION: Human papillomavirus (HPV) infection is a cause of premalignant and malignant cancer in the lower genital and digestive tracts. In Brazil, there have been no prevalence studies that included a nationwide sample, and the prevalence of HPV has not been determined in many regions. METHODS: We will search the EMBASE, LILACS, MEDLINE, Web of Science and SciELO databases and previously published review articles to identify original research articles assessing HPV prevalence of the perineal (cervical, penile and anal) and oral areas. No exclusion criteria related to language or publication date will apply. 2 reviewers will independently screen for eligibility and perform data extraction. Discrepancies will be resolved through consensus; the opinion of a third reviewer will be sought as necessary. Relevant measures and data about study and population characteristics will be extracted from the included studies. Where possible, study prevalence will be pooled using a random-effects meta-analysis. The methodological quality of the studies will be assessed using an adapted version of the NIH 'Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies'. The overall quality of evidence will be assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). ETHICS AND DISSEMINATION: We expect to estimate the prevalence of perineal and oral HPV infection in the general population as well as the prevalence of HPV infection in individuals with premalignant and malignant lesions in Brazil and its 5 geographic regions. This systematic review does not require ethical approval. TRIAL REGISTRATION NUMBER: CRD42016032751.

Is full-field digital mammography more accurate than screen-film mammography in overall population screening? A systematic review and meta-analysis.

OBJECTIVE: To compare the accuracy of screen-film mammography (SFM) and full-field digital mammography (FFDM) for population-based breast cancer screening. STUDY DESIGN AND SETTING: A quantitative systematic review was performed including randomized controlled trials and cohort studies. RESULTS: Ten studies (comprising 667,649 women, 82,573 of whom underwent SFM and FFDM) were included. The area under the summary receiver operating characteristic (SROC) curve was 0.92 (SE ± 0.06) for SFM and 0.91 (SE ± 0.11) for FFDM. The results in the random-effects model were 0.95 (95% CI, 0.72-1.24) and 0.52 (95% CI, 0.28-0.95) for SFM versus FFDM in all age and younger groups, respectively. CONCLUSION: FFDM is more accurate than SFM only in women less than 50 years old.

Cigarette smoking and risk of gestational diabetes: a systematic review of observational studies.

BACKGROUND: Gestational diabetes is a prevalent disease associated with adverse outcomes of pregnancy. Smoking as been associated with glucose intolerance during pregnancy in some but not all studies. Therefore, we aimed to systematically review all epidemiological evidence to examine the association between cigarette smoking during pregnancy and risk of developing gestational diabetes mellitus. METHODS: We conducted a systematic review of articles published up to 2007, using PubMed, Embase, LILACS e CINAHL to identify the articles. Because this review focuses on studies of smoking during pregnancy, we excluded studies evaluating smoking outside pregnancy. Two investigators independently abstracted information on participant's characteristics, assessment of exposure and outcome, and estimates for the association under study. We evaluated the studies for publication bias and performed heterogeneity analyses. We also assessed the effect of each study individually through sensitivity analysis. RESULTS: We found and critically reviewed 32 studies, of which 12 met the criteria for inclusion in the review. Most of the studies provided only unadjusted measurements. Combining the results of the individual studies, we obtained a crude odds ratio of 1.03 (99% CI 0.85-1.25). Only 4 studies presented adjusted measurements of association, and no association was found when these alone were analyzed (OR 0.95; 99% CI 0.85-1.07). Subgroup analysis could not be done due to small sample size. CONCLUSION: The number of studies is small, with major heterogeneity in research design and findings. Taken together, current data do not support an association between cigarette smoking during pregnancy and the risk of gestational diabetes.

Gestational diabetes and pre-eclampsia: common antecedents?

OBJECTIVE: To evaluate commonality of risk factor profiles of women who develop gestational diabetes and pre-eclampsia. METHODS: Prospective cohort study in prenatal clinics of the Brazilian Unified Health System in six state capitals. 4.766 pregnant women between 20 to 48 years old were consecutively enrolled between 20th and 28th gestational weeks. Smoking habits and traditional risk factors for pre-eclampsia and gestational diabetes were obtained by the interview at enrollment. Gestational diabetes was diagnosed using a 75-g oral glucose tolerance test and pre-eclampsia through chart review. RESULTS: Both gestational diabetes and pre-eclampsia were associated with age (OR 2.07; 95% CI 1.65-2.23 and OR 1.55; 95% CI 1.08-2.23, respectively), pre-pregnancy body mass index (OR 1.62; 95% CI 1.40-3.53 and OR 1.83; 95% CI 1.52-4.80, respectively) and weight gain in early pregnancy (OR 1.28; 95% CI 1.12-1.47 and OR 1.27; 95% CI 1.06-1.52, respectively). Lower odds of gestational diabetes (OR 0.31; 95% CI 0.22-0.44) and pre-eclampsia (OR 0.36; 95% CI 0.20-0.51) were observed in nulliparous women who have smoked during pregnancy. CONCLUSIONS: Gestational diabetes and pre-eclampsia share a pattern of risk factors, suggesting the possibility of common aetiology.

Gestational diabetes and pre-eclampsia: common antecedents? / Diabetes gestacional e pré-eclâmpsia: antecedentes comuns?

OBJECTIVE: To evaluate commonality of risk factor profiles of women who develop gestational diabetes and pre-eclampsia. METHODS: Prospective cohort study in prenatal clinics of the Brazilian Unified Health System in six state capitals. 4.766 pregnant women between 20 to 48 years old were consecutively enrolled between 20th and 28th gestational weeks. Smoking habits and traditional risk factors for pre-eclampsia and gestational diabetes were obtained by the interview at enrollment. Gestational diabetes was diagnosed using a 75-g oral glucose tolerance test and pre-eclampsia through chart review. RESULTS: Both gestational diabetes and pre-eclampsia were associated with age (OR 2.07; 95 percent CI 1.65-2.23 and OR 1.55; 95 percent CI 1.08-2.23, respectively), pre-pregnancy body mass index (OR 1.62; 95 percent CI 1.40-3.53 and OR 1.83; 95 percent CI 1.52-4.80, respectively) and weight gain in early pregnancy (OR 1.28; 95 percent CI 1.12-1.47 and OR 1.27; 95 percent CI 1.06-1.52, respectively). Lower odds of gestational diabetes (OR 0.31; 95 percent CI 0.22-0.44) and pre-eclampsia (OR 0.36; 95 percent CI 0.20-0.51) were observed in nulliparous women who have smoked during pregnancy. CONCLUSIONS: Gestational diabetes and pre-eclampsia share a pattern of risk factors, suggesting the possibility of common aetiology.

OBJETIVO: Avaliar a concordância do padrão de fatores de risco de mulheres que desenvolvem diabetes gestacional e pré-eclâmpsia. MÉTODOS: Estudo de coorte prospectivo em clínicas de atendimento pré-natal do Sistema Único de Saúde de seis capitais do Brasil, 4.766 mulheres grávidas de 20 a 48 anos de idade foram arroladas de maneira consecutiva entre a 20º e 28º semanas de gestação. O hábito de fumar e os fatores de risco tradicionais para pré-eclâmpsia e diabetes gestacional foram obtidos por entrevista no arrolamento. Diabetes gestacional foi diagnosticada usando um teste oral de tolerância a glicose com 75 g e pré-eclâmpsia por meio de revisão de prontuário. RESULTADOS: Diabetes gestacional e pré-eclâmpsia são associadas com idade (RC 2,07; 95 por cento IC 1,65-2,23 e RC 1,55; 95 por cento IC 1,08-2,23, respectivamente), índice de massa corporal pré-gestacional (RC 1,62; 95 por cento IC 1,40-3,53 e RC 1,83; 95 por cento IC 1,52-4,80, respectivamente) e ganho de peso precocemente durante a gestação (RC 1,28; 95 por cento IC 1,12-1,47 e RC 1,27; 95 por cento IC 1,06-1,52, respectivamente). Menor chance de diabetes gestacional (RC 0,31; 95 por cento IC 0,22-0,44) e pré-eclâmpsia (RC 0,36; 95 por cento IC 0,20-0,51) foram observados em mulheres nulíparas que fumaram durante a gestação. CONCLUSÃO: Diabetes gestacional e pré-eclâmpsia compartilham um padrão de fatores de risco, sugerindo a possibilidade de uma etiologia comum.

Waist circumference in the prediction of obesity-related adverse pregnancy outcomes / Circunferência da cintura na predição de desfechos adversos da gestação relacionados à obesidade

The aim of this study is to evaluate the diagnostic properties of waist circumference in the prediction of obesity-related gestational outcomes. Pregnant women 20 years or older were consecutively enrolled in six Brazilian State capitals from 1991 to 1995. Weight, height, and waist circumference were measured and an oral glucose tolerance test was performed. Patients were followed through childbirth by chart review. Diagnostic performance for the different outcomes, as measured by area under the receiver operating characteristic (ROC) curve, was estimated through logistic regression. Areas under the ROC curve (95 percentCI) for waist circumference were 0.621(0.589-0.652) for gestational diabetes, 0.640 (0.588-0.692) for preeclampsia, and 0.645(0.617-0.673) for macrosomia. These areas were similar to those for BMI (p > 0.05). A waist circumference of 82cm jointly maximized sensitivity (63 percent) and specificity (57 percent). Cutoff points of 23kg/m² for pre-pregnancy BMI and 26kg/m² for BMI at enrollment produced similar diagnostic properties. In conclusion, waist circumference predicts obesity-related adverse pregnancy outcomes at least as well as BMI.

O objetivo deste estudo é avaliar as propriedades diagnósticas da circunferência da cintura na predição de desfechos adversos da gestação relacionados à obesidade. Gestantes com 20 ou mais anos de idade, foram arroladas consecutivamente, entre 20 e 28 semanas de gestação, em seis capitais do Brasil, entre 1991 e 1995. Peso, altura e circunferência da cintura foram aferidos e um teste de tolerância à glicose foi realizado. As pacientes foram acompanhadas até o parto através de revisão de prontuários. Propriedades diagnósticas para os diferentes desfechos, mensurados através da área sob a curva Receiver Operator Charactheristic (ROC), foram estimadas por regressão logística. Areas (IC95 por cento) sob as curvas ROC para a cintura foram 0,621 (0,589-0,652) para diabetes gestacional, 0,640 (0,588-0,692) para pré-eclâmpsia e 0,645 (0,617-0,673) para macrossomia. Estas áreas foram similares às encontradas para o IMC (p > 0,05). A cintura de 82cm apresentou máximas sensibilidade (63 por cento) e especificidade (57 por cento). Um ponto de corte de 23kg/m² para o IMC pré-gestacional e de 26kg/m² para o IMC no arrolamento produziu propriedades diagnósticas semelhantes. A medida da circunferência da cintura prediz complicações como diabete gestacional, pré-eclâmpsia e macrossomia fetal tão bem quanto o IMC.