In COVID-19, NLRP3 inflammasome genetic variants are associated with critical disease and these effects are partly mediated by the sickness symptom complex: a nomothetic network approach.

In coronavirus disease (COVID-19), the nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome is activated in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Acute infections are accompanied by a sickness symptom complex (SSC) which is highly conserved and protects against infections and hyperinflammation. The aim of this study is to delineate the associations of COVID-19, SSC and NLPR3 rs10157379 T > C and NLPR3 rs10754558 C > G variants; and the protective role of SSC in SARS-CoV-2 infection. We recruited COVID-19 patients, 308 with critical, 63 with moderate and 157 with mild disease. Increased SSC protects against SARS, critical disease, and death due to COVID-19. Increasing age, male sex and rs10754558 CG significantly reduce SSC protection. The rs10157379 CT and rs10754558 GG genotypes are positively associated with SARS. Partial Least Squares analysis shows that a) 41.8% of the variance in critical COVID-19 symptoms is explained by SSC and oxygen saturation (inversely associated), inflammation, chest computed tomography abnormalities, increased body mass index, SARS and age (positively associated); and b) the effects of the NLRP3 rs10157379 and rs10754558 variants on critical COVID-19 are mediated via SSC (protective) and SARS (detrimental). SSC includes anosmia and dysgeusia, and maybe gastrointestinal symptoms. In conclusion, intersections among the rs10754558 variant, age, and sex increase risk towards critical COVID-19 by attenuating SSC. NLRP3 variants play an important role in SARS, and severe and critical COVID-19 especially in elderly male individuals with reduced SSC and with increased BMI, hypertension, and diabetes type 2.

Immune-inflammatory, oxidative stress and biochemical biomarkers predict short-term acute ischemic stroke death.

The aim of the study was to define new immune-inflammatory, oxidative stress and biochemical biomarkers, which predict mortality within a period of 3 months after acute ischemic stroke (AIS). We recruited 176 healthy volunteers and 145 AIS patients, categorized as AIS survivors and non-survivors, and measured interleukin (IL)-6, high sensitivity C-reactive protein (hsCRP), ferritin, iron, total serum protein (TSP), erythrocyte sedimentation rate (ESR), white blood cells (WBC), 25 hydroxyvitamin D [25(OH)D], lipid hydroperoxides (CL-LOOH), insulin, glucose and high-density lipoprotein (HDL)-cholesterol. In patients, these biomarkers were measured within 24 h after AIS onset. We also computed two composite scores reflecting inflammatory indices, namely INFLAM index1 (sum of z scores of hsCRP+IL-6 + ferritin+ESR + WBC) and INFLAM index2 (z INFLAM index1 - z 25(OH)D - z iron + z TSP). Three months after AIS, non-survivors (n = 54) showed higher baseline levels of IL-6, hsCRP, ferritin and glucose and lower levels of HDL-cholesterol and 25(OH)D than survivors (n = 91). Non-survivors showed higher baseline ESR and lowered TSP than controls, while survivors occupied an intermediate position. Death after AIS was best predicted by increased IL-6, glucose, ferritin and CL-LOOH and lowered 25(OH)D levels. The area under the receiver operating curves computed on the INFLAM index1 and 2 scores were 0.851 and 0.870, respectively. In conclusion, activation of peripheral immune-inflammatory, oxidative and biochemical pathways is critically associated with mortality after AIS. Our results may contribute to identify new biomarker sets, which may predict post-stroke death, as well as suggest that IL-6 trans-signaling coupled with redox imbalances may be possible new targets in the prevention of short-term outcome AIS death.

Elevated plasma homocysteine levels are associated with disability progression in patients with multiple sclerosis.

The aims of this study were to verify whether hyperhomocysteinemia is associated with disability progression in Multiple Sclerosis (MS) patients and whether TNF pathways and cellular adhesion molecules (CAM) are involved in this process. This study included 180 MS patients, who were divided according to their levels of homocysteine (Hyperhomocysteinemia ≥11.35 µmol/L) and 204 healthy individuals (control group). MS patients showed higher levels of homocysteine (p < 0.001), tumor necrosis factor alpha (TNF-α, p < 0.001), TNF receptor 1 (TNFR1, p = 0.038), TNF receptor 2 (TNFR2, p < 0.001), and lower levels of PECAM (p = 0.001), ICAM (p < 0.001) and VCAM (p = 0.005) than controls. The multivariate binary logistic regression analysis showed that plasma levels of homocysteine, TNFR1, TNFR2 and PECAM were associated with the presence of disease. MS patients with hyperhomocysteinemia showed higher disease progression evaluated by the Multiple Sclerosis Severity Score (MSSS, p < 0.001), disability evaluated by Expanded Disability Status Score EDSS (p < 0.001), TNFR1 (p = 0.039) and ICAM (p = 0.034) than MS patients with lower levels of homocysteine. Hyperhomocysteinemia was independently associated with MSSS in MS patients, but were not associated with TNF-α, TNFR, and CAM. Homocysteine levels was higher in progressive forms than relapsing-remitting MS (p < 0.001), independently of sex and age. In conclusion, this is the first study in which homocysteinemia was associated with progression of the disease (MSSS), although this finding was not directly related to TNF-α and TNFR pathways or to CAM.

Development of a Melting-Curve-Based Multiplex Real-Time PCR Assay for the Simultaneous Detection of Viruses Causing Respiratory Infection.

The prompt and accurate identification of the etiological agents of viral respiratory infections is a critical measure in mitigating outbreaks. In this study, we developed and clinically evaluated a novel melting-curve-based multiplex real-time PCR (M-m-qPCR) assay targeting the RNA-dependent RNA polymerase (RdRp) and nucleocapsid phosphoprotein N of SARS-CoV-2, the Matrix protein 2 of the Influenza A virus, the RdRp domain of the L protein from the Human Respiratory Syncytial Virus, and the polyprotein from Rhinovirus B genes. The analytical performance of the M-m-qPCR underwent assessment using in silico analysis and a panel of reference and clinical strains, encompassing viral, bacterial, and fungal pathogens, exhibiting 100% specificity. Moreover, the assay showed a detection limit of 10 copies per reaction for all targeted pathogens using the positive controls. To validate its applicability, the assay was further tested in simulated nasal fluid spiked with the viruses mentioned above, followed by validation on nasopharyngeal swabs collected from 811 individuals. Among them, 13.4% (109/811) tested positive for SARS-CoV-2, and 1.1% (9/811) tested positive for Influenza A. Notably, these results showed 100% concordance with those obtained using a commercial kit. Therefore, the M-m-qPCR exhibits great potential for the routine screening of these respiratory viral pathogens.

Association of Lower Adiponectin Plasma Levels, Increased Age and Smoking with Subclinical Atherosclerosis in Patients with HIV-1 Infection.

BACKGROUND: The association between subclinical atherosclerosis and traditional cardiovascular disease (CVD) risk factors, inflammatory and metabolic biomarkers has been demonstrated around the world and specifically Brazilian human immunodeficiency virus type 1 (HIV-1)- infected individuals. However, the association between subclinical atherosclerosis and these aforementioned factors combined with anti-inflammatory biomarkers has not been examined in these populations. OBJECTIVES: To evaluate the association of the carotid intima-media thickness (cIMT) with CVD risk factors, inflammatory, metabolic and HIV-1 infection markers combined with adiponectin and interleukin (IL)-10 as anti-inflammatory variables. METHODS: In this case-control study, 49 HIV-1-infected patients on combined antiretroviral therapy (cART) and 85 controls were compared for traditional CVD risk factors, inflammatory, metabolic, and anti-inflammatory variables. Further, we compared HIV-1-infected patients according to their cIMT (as continuous and categorized <0.9 or ≥0.9 mm variable) visualized by carotid ultrasonography doppler (USGD). RESULTS: Twenty-four (48.9%) HIV-1-infected patients showed cIMT ≥0.9 mm. The patients had higher levels of C reactive protein on high sensitivity assay (hsCRP), tumor necrosis factor α, IL-6, IL-10, triglycerides, and insulin, and lower levels of adiponectin, total cholesterol and low-density lipoprotein cholesterol than controls (all p<0.05). Low levels of adiponectin were negatively associated with cIMT ≥0.9 mm (p=0.019), and explained 18.7% of the cIMT variance. Age (p=0.033) and current smoking (p=0.028) were positively associated with cIMT values, while adiponectin levels (p=0.008) were negatively associated with cIMT values; together, these three variables explained 27.3% of cIMT variance. CONCLUSION: Low adiponectin was associated with higher cIMT in HIV-1-infected patients on cART. Low adiponectin levels in combination with age and smoking could explain, in part, the increased subclinical atherosclerosis observed in these patients. Adiponectin may be a good candidate for predicting subclinical atherosclerosis in the management of HIV-1-infected patients in public health care, especially where USGD is not available.

TNF-ß +252 A>G (rs909253) polymorphism is independently associated with presence of autoantibodies in rheumatoid arthritis patients.

The TNF-ß +252 A>G (rs909253) polymorphism has been associated with a risk of development of rheumatoid arthritis (RA) and could influence plasma tumor necrosis factor alpha (TNF-α) levels. The aim of the present study was to evaluate the association between the TNF-ß +252 A>G polymorphism with plasma TNF-α levels, the presence of autoantibodies, and the susceptibility for RA. This cross-sectional study included 261 patients with RA and 292 controls. The polymorphism was studied using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Soluble TNF-α and receptors swere measured by multiplex assay. Rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) were measured using immunoassay. No differences were observed in allele frequency and genotype distribution among patients and controls. The presence of RF (p = 0.020) and anti-CCP (p = 0.001) increased 4.23-fold and 8.13-fold, respectively, in patients with B1 allele (B1/B2 + B1/B1 genotypes) independently of demographic, clinical, and inflammatory markers. Among patients with B1/B2 + B1/B1 genotypes, higher TNF-α levels were associated with positive RF (p = 0.040), anti-CCP (p = 0.011), or both (p = 0.038). In patients carrying B1 allele, the increased sTNFR1 together with RF or anti-CCP or both explained about 39.0% the variations in TNF-α level. However, in B2/B2 genotype, the presence of those autoantibodies was not associated with TNF-α level. Our findings indicate that the TNF-ß +252 A>G polymorphism was not associated with RA susceptibility and TNF-α plasma levels. However, B1 allele was associated with the presence of autoantibodies. In addition, interaction between the presence of B1 allele and autoantibodies was associated with the increase of plasma TNF-α level in RA patients.

Safety of monitoring antiretroviral therapy response in HIV-1 infection using CD4+ T cell count at long-term intervals.

The latest Brazilian guideline recommended the reduction of routine CD4+ T cell counts for the monitoring of patients with human immunodeficiency virus type 1 (HIV-1) under combination antiretroviral therapy (cART). The aim of this study was to evaluate the safety of monitoring response to cART in HIV-1 infection using routine viral load at shorter intervals and CD4+ T cell count at longer intervals. CD4+ T cell counts and HIV-1 viral load were evaluated in 1,906 HIV-1-infected patients under cART during a three-year follow-up. Patients were stratified as sustained, non-sustained and non-responders. The proportion of patients who showed a CD4+ T > 350cells/µL at study entry among those with sustained, non-sustained and non-responders to cART and who remained with values above this threshold during follow-up was 94.1%, 81.8% and 71.9%, respectively. HIV-1-infected patients who are sustained virologic responders and have initial CD4+ T cell counts > 350cells/µL showed a higher chance of maintaining the counts of these cells above this threshold during follow-up than those presenting CD4+ T ≤ 350cells/µL (OR = 39.9; 95%CI: 26.5-60.2; p < 0.001). This study showed that HIV-1-infected patients who had sustained virologic response and initial CD4+ T > 350cells/µL were more likely to maintain CD4+ T cell counts above this threshold during the next three-year follow-up. This result underscores that the evaluation of CD4+ T cell counts in longer intervals does not impair the safety of monitoring cART response when routine viral load assessment is performed in HIV-1-infected patients with sustained virologic response.

Cascade of care for people living with HIV infection in Southern Brazil: results from a public health network.

The cascade of care for people living with HIV infection (PLHIV) describes steps in diagnosis, linkage and retention in care, as well as the provision and success of combination antiretroviral therapy (cART). The aim of this study was to evaluate the rates regarding the retention in care, on cART, and suppressed viral load for PLHIV attended at a Brazilian public health network. Data on PLHIV from 116 cities of Paraná, Southern Brazil, attended from 2012 to 2015, were retrospectively collected through the Laboratory Tests Control System (SISCEL). The number of PLHIV related to care increased about 22.5% from 2012 to 2015 (4,106 to 5,030 individuals). The proportion of PLHIV retained in care showed a trend toward stabilization around 81.7-86.9%. Every year, the use of cART increased up to 90.3% for PLHIV retained in care. Viral load suppression was achieved by 72.8% of patients on cART and 57.1% by those linked to care. Retention in care and HIV viral suppression were more likely to occur in older PLHIV than younger ones; similarly, patients living in medium-sized cities were more susceptible to these factors than in large- or small-sized cities. In conclusion, the study showed a high level of retention in care and HIV suppression on cART, as well as emphasized that current efforts for treating already-infected PLHIV remain a challenge for our health public institutions and may contribute to highlight steps for improvement of the HIV cascade of care in our population.

Insulin resistance, atherogenicity, and iron metabolism in multiple sclerosis with and without depression: Associations with inflammatory and oxidative stress biomarkers and uric acid.

Depression is accompanied by metabolic disorders in iron metabolism, lipoproteins, and insulin resistance. We measured plasma levels of ferritin, iron, lipids, insulin, and glucose and computed the homeostasis model assessment (HOMA2IR) and atherogenic index of plasma (AIP) in MS patients with and without depression and healthy controls. Explanatory variables were serum uric acid, interleukin (IL)-6, lipid hydroperoxides (CL-LOOH), albumin, and C-reactive protein (CRP). Depression was assessed using the Hospital Anxiety and Depression Scale (HADS), neurological disability using the Expanded Disability Status Scale (EDSS), and disease progression using ∆EDSS over five years earlier. HOMA2IR and insulin were predicted by diagnosis (increased in MS), age and body mass index (BMI); AIP by diagnosis, sex, BMI, CRP, and uric acid; triglycerides by diagnosis (higher in MS without depression), age, BMI and uric acid; ferritin by diagnosis (higher in MS), sex, CRP, and albumin; and iron by albumin. The HADS score was significantly predicted by ∆EDSS, gastro-intestinal symptoms, iron (inverse), and age. MS is characterized by significantly increased insulin resistance, which is determined by increased insulin levels; and increased ferritin, a biomarker of inflammation. Depression in MS is not associated with increased insulin resistance and atherogenicity but with lowered iron.

Disease progression and oxidative stress are associated with higher serum ferritin levels in patients with multiple sclerosis.

Hyperferritinemia and oxidative stress have been implicated in the pathogenesis of multiple sclerosis (MS). The aim of the present study was to evaluate the serum levels of ferritin and to verify their association with oxidative stress markers and MS progression. This study included 164 MS patients, which were divided in two groups according to their levels of ferritin (cut off 125.6µg/L). Oxidative stress was evaluated by tert-butyl hydroperoxide-initiated chemiluminescence (CL-LOOH), advanced oxidation protein products (AOPP), carbonyl protein, nitric oxide metabolites (NOx), sulfhydryl groups of protein and total radical-trapping antioxidant parameter (TRAP). MS patients with elevated levels of ferritin showed higher disease progression (p=0.030), AOPP (p=0.001), and lower plasma NOx levels (p=0.031) and TRAP (p=0.006) than MS patients with lower ferritin levels. The multivariate binary logistic regression analysis showed that increased AOPP and progression of disease were significantly and positively associated with increase of ferritin. The combination of serum ferritin levels and oxidative stress markers were responsible for 13,9% in the disease progression. In conclusion, our results suggest that ferritin could aggravate oxidative stress in patients with MS and contribute to progression of disease.

Immune-Inflammatory and Oxidative and Nitrosative Stress Biomarkers of Depression Symptoms in Subjects with Multiple Sclerosis: Increased Peripheral Inflammation but Less Acute Neuroinflammation.

There is evidence that activated immune-inflammatory and oxidative and nitrosative stress (IO&NS) pathways play a role in the pathophysiology of multiple sclerosis (MS) and depression. This study examines serum levels of interleukin (IL)-1ß, IL-4, IL-6, and IL-10; peroxides (LOOH); nitric oxide metabolites (NOx); albumin; ferritin; C-reactive protein (CRP); and tumor necrosis factor (TNF)-ß NcoI polymorphism (rs909253) and gadolinium-enhanced magnetic resonance imaging (MRI) scan in MS patients with (n = 42) and without (n = 108) depression and normal controls (n = 249). Depression is scored using the depressive subscale of the Hospital Anxiety and Depression Scale (HADS). The extent of neurological disability is measured using the Expanded Disability Status Scale (EDSS) at the same time of the abovementioned measurements and 5 years earlier. Disease progression is assessed as actual EDSS-EDSS 5 years earlier. Three variables discriminate MS patients with depression from those without depression, i.e., increased IL-6 and lower IL-4 and albumin. Binary logistic regression showed that MS with depression (versus no depression) was characterized by more gastrointestinal symptoms and disease progression, higher serum IL-6, and lower albumin levels. In subjects with MS, the HADS score was significantly predicted by three EDSS symptoms, i.e., pyramidal, gastrointestinal, and visual symptoms. Fifty-eight percent of the variance in the HADS score was predicted by gastrointestinal symptoms, visual symptoms, the TNFB1/B2 genotype, and contrast enhancement (both inversely associated). There were no significant associations between depression in MS and type of MS, duration of illness, age, sex, nicotine dependence, and body mass index. MS with depression is associated with signs of peripheral inflammation, more disability, disease progression, gastrointestinal and visual symptoms, but less contrast enhancement as compared to MS without depression. It is concluded that depression is part of the neurological symptoms of MS and that its expression is primed by peripheral inflammation while acute neuroinflammation and the TNFB1/B2 genotype may be protective.

Fatores sociodemográficos de pacientes HIV em uso de terapia antiretroviral e sua associação ao índice de desenvolvimento humano municipal / Sociodemographic factors of HIV patients on antiretrovirals and their association with the Municipal Human Development Index

O objetivo do trabalho foi avaliar fatores sociodemográficos e laboratoriais dos pacientes infectados pelo HIV em uso de terapia antirretroviral (TARV) associados ao Índice de Desenvolvimento Humano Municipal (IDHM). O estudo envolveu 4.900 pacientes de 116 municípios do Paraná, atendidos no período de 2012 a 2015. Os pacientes foram divididos em três grupos de acordo com o tamanho e o IDHM do município de residência. Cidades de pequeno porte/IDHM médio apresentaram taxas mais elevadas de mulheres, indivíduos mais jovens e baixa escolaridade, quando comparadas com as cidades de grande porte/IDHM alto. As taxas totais de resposta imunológica, virológica e completa à TARV foram de 71,9%, 68,2% e 57,1%, respectivamente, com melhores resultados para o grupo vivendo em municípios de grande porte/IDHM alto. Apesar dessas diferenças, as respostas imunológica e virológica foram semelhantes entre os grupos, sugerindo que o grau de desenvolvimento do município não está associado com a efetividade da terapia para o HIV-1. (AU)

The objective of the study was to evaluate sociodemographic and laboratory factors of HIV patients on use of antiretroviral therapy (cART) associated with the Municipal Human Development Index (IDHM). The study enrolled 4,900 HIV-patients from 116 municipalities in the state of Paraná, in the South of Brazil, attended from 2012 to 2015. Patients were divided into three groups according to the size and the IDHM of the city of origin. Small sized/medium-IDHM cities showed higher rates of women, individuals with low educational level and young age, when compared to large sized/high-IDHM ones. The general rates of immunologic, virologic and complete responses to cART were of 71.9%, 68.2% and 57.1%, respectively, and better results were observed in the group from large size/high-IDHM cities. Despite these differences, immunologic and virologic responses were similar between the groups, demonstrating that the municipality level of development is not associated with the effectiveness of HIV-1 therapy. (AU)

Disability in patients with multiple sclerosis: influence of insulin resistance, adiposity, and oxidative stress.

OBJECTIVE: The aims of the present study were to report the prevalence of insulin resistance (IR) in patients with multiple sclerosis (MS); to verify differences in metabolic and inflammatory biomarkers, and oxidative stress in patients with MS with or without IR; and to assess if IR and adiposity are associated with disability in these patients. METHODS: The study enrolled 110 patients with MS and 175 healthy individuals. Patients with MS were divided in those with IR (n = 44) and those without (n = 66). Metabolic and inflammatory markers, oxidative stress, and disability were evaluated by the Extended Disability Status Scale (EDSS). RESULTS: IR prevalence was verified in 40% of the patients with MS and in 21.1% of the control group (odds ratio, 2.48; 95% confidence interval, 1.469-4.210; P = 0.0006). Patients with the disease and IR showed higher EDSS (P = 0.031), interleukin (IL)-6 (P = 0.028), IL-17 (P = 0.006), oxidative stress evaluated by tert-butyl hydroperoxide-initiated chemiluminescence (P = 0.029), and advanced oxidation protein products (P = 0.025) than those patients without IR. The multivariate analysis showed that disability was associated with IR evaluated by homeostasis model assessment of insulin resistance (P = 0.030) and adiposity evaluated by waist circumference (P = 0.0179) and body mass index (P = 0.0033). CONCLUSION: This is the first study to demonstrate an increase IR prevalence and the association between IR and adiposity with disability assessed by EDSS in patients with MS. IR seems to be associated with chronic inflammatory process and oxidative stress in patients with MS. More studies are warranted to elucidate the mechanisms by which IR and adiposity could contribute to the progression and disability in patients with MS.

Tumor necrosis factor beta NcoI polymorphism is associated with inflammatory and metabolic markers in multiple sclerosis patients.

To evaluate the association between the tumor necrosis factor beta (TNF-ß) NcoI polymorphism and inflammatory and metabolic markers in patients with multiple sclerosis (MS) patients and the association of these markers with disease disability, a 782 base-pair fragment of the TNF-ß gene was amplified from genomic DNA and digested with the NcoI restriction enzyme. The serum levels of numerous cytokines (IL-1ß, IL-12, IL-6, TNF-α, IFN-γ, IL-4, IL-10, and IL-17) serum lipid levels, plasma insulin levels, and the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) levels were evaluated in 123 female and 43 male patients with MS. Females carrying the TNFB2/B2 genotype presented with decreased IL-4 and IL-10 levels and increased TNF-α, glucose, insulin, and HOMA-IR levels; moreover, there were positive correlations between EDSS and glucose and between EDSS and HOMA-IR in these females. Males carrying the TNFB2/B2 genotype exhibited increased levels of TNF-α, IFN-γ, and IL-17 (p=0.0326) and decreased levels of IL-4, IL-10, insulin, and HOMA-IR; there was a positive correlation between EDSS and TNF-α levels. The TNFB2/B2 genotype of TNF-ß NcoI polymorphism was associated with increased inflammatory and metabolic markers and this association was different according to sex of MS patients.

The roles of genetic polymorphisms and human immunodeficiency virus infection in lipid metabolism.

Dyslipidemia has been frequently observed among individuals infected with human immunodeficiency virus type 1 (HIV-1), and factors related to HIV-1, the host, and antiretroviral therapy (ART) are involved in this phenomenon. This study reviews the roles of genetic polymorphisms, HIV-1 infection, and highly active antiretroviral therapy (HAART) in lipid metabolism. Lipid abnormalities can vary according to the HAART regimen, such as those with protease inhibitors (PIs). However, genetic factors may also be involved in dyslipidemia because not all patients receiving the same HAART regimen and with comparable demographic, virological, and immunological characteristics develop variations in the lipid profile. Polymorphisms in a large number of genes are involved in the synthesis of structural proteins, and enzymes related to lipid metabolism account for variations in the lipid profile of each individual. As some genetic polymorphisms may cause dyslipidemia, these allele variants should be investigated in HIV-1-infected patients to identify individuals with an increased risk of developing dyslipidemia during treatment with HAART, particularly during therapy with PIs. This knowledge may guide individualized treatment decisions and lead to the development of new therapeutic targets for the treatment of dyslipidemia in these patients.

Cascade of care for people living with HIV infection in Southern Brazil: results from a public health network / A cascata de cuidados para pessoas vivendo com a infecção pelo HIV no Sul do Brasil: resultados obtidos em uma rede pública de saúde / Serie de cuidados para personas que viven con una infección de VIH en el sur de Brasil: resultados en una red pública de salud

Abstract: The cascade of care for people living with HIV infection (PLHIV) describes steps in diagnosis, linkage and retention in care, as well as the provision and success of combination antiretroviral therapy (cART). The aim of this study was to evaluate the rates regarding the retention in care, on cART, and suppressed viral load for PLHIV attended at a Brazilian public health network. Data on PLHIV from 116 cities of Paraná, Southern Brazil, attended from 2012 to 2015, were retrospectively collected through the Laboratory Tests Control System (SISCEL). The number of PLHIV related to care increased about 22.5% from 2012 to 2015 (4,106 to 5,030 individuals). The proportion of PLHIV retained in care showed a trend toward stabilization around 81.7-86.9%. Every year, the use of cART increased up to 90.3% for PLHIV retained in care. Viral load suppression was achieved by 72.8% of patients on cART and 57.1% by those linked to care. Retention in care and HIV viral suppression were more likely to occur in older PLHIV than younger ones; similarly, patients living in medium-sized cities were more susceptible to these factors than in large- or small-sized cities. In conclusion, the study showed a high level of retention in care and HIV suppression on cART, as well as emphasized that current efforts for treating already-infected PLHIV remain a challenge for our health public institutions and may contribute to highlight steps for improvement of the HIV cascade of care in our population.

Resumo: A cascata de cuidados para pessoas vivendo com a infecção pelo HIV (PVHIV) representa os passos no diagnóstico, vínculo e retenção em tratamento, assim como, no fornecimento e resultado da terapia antirretroviral combinada (TARVc). O estudo teve como objetivo avaliar as taxas relativas à retenção em atendimento, uso de TARVc e supressão da carga viral em PVHIV atendidas em uma rede pública de saúde. Através do Sistema de Controle de Exames Laboratoriais (SISCEL), os dados foram coletados retrospectivamente, referentes às PVHIV de 116 municípios no Estado do Paraná, Sul do Brasil, atendidas entre 2012 e 2015. O número de PVHIV vinculadas ao atendimento aumentou em 22,5% entre 2012 e 2015 (de 4.106 para 5.030 indivíduos). A proporção de PVHIV retidas no atendimento mostrou uma tendência de estabilização, em torno de 81,7-86,9%. O uso de TARVc aumentou a cada ano, chegando a 90,3% das PVHIV retidas em atendimento. A supressão da carga viral foi alcançada por 72,8% dos pacientes em uso de TARVc e em 57,1% daqueles vinculados ao atendimento. A retenção no atendimento e a supressão da carga viral foram mais frequentes em PVHIV mais velhas e em pacientes residentes em municípios de porte médio. Em conclusão, o estudo mostrou um nível elevado de retenção em atendimento e de supressão da carga viral na vigência do uso de TARVc, além de enfatizar que os esforços atuais de tratamento das PVHIV ainda são um desafio para as instituições de saúde pública, podendo ajudar a identificar passos para melhorar a cascata de cuidados em HIV para a população.

Resumen: Este trabajo describe los pasos en la diagnosis, vinculación y retención en el cuidado, así como la provisión y éxito de la terapia antirretroviral combinada (cART por sus siglas en inglés) para personas que viven con una infección de VIH (PLHIV por sus siglas en inglés). El objetivo de este estudio fue evaluar las tasas en relación con la retención en el cuidado, terapia antirretroviral combinada y carga viral eliminada de las personas que viven con una infección de VIH, y reciben atención en la red pública de salud brasileña. Los datos de PLHIV procedieron de 116 ciudades de Paraná, sur de Brasil, desde 2012 a 2015, se recogieron retrospectivamente a través del Sistema de Control de Exámenes de Laboratorio (SISCEL). El número de PLHIV informado con necesidad de cuidados se incrementó un 22,5% de 2012 a 2015 (de 4.106 a 5.030 individuos). La proporción de PLHIV que fue constante en el cuidado mostró una tendencia hacia la estabilización de alrededor de un 81,7 a un 86,9%. Cada año, el uso del cART se incrementó hasta un 90,3% en el caso de PLHIV que fueron constantes en sus cuidados. La eliminación de la carga viral se consiguió en un 72,8% de los pacientes con cART y en un 57,1% por parte de aquellos vinculados a cuidados. La constancia en el cuidado y la eliminación de la carga viral en VIH eran más factibles de producirse en PLHIV más viejas que en las jóvenes; de igual forma, los pacientes que vivían en ciudades de tamaño medio eran más susceptibles hacia estos factores que en ciudades más grandes o pequeñas. Como conclusión, el estudio mostró un alto nivel de constancia en el cuidado y la eliminación de carga viral del HIV con cART, asimismo enfatizó que los actuales esfuerzos para tratar a las PLHIV ya infectadas continuaba siendo un desafío para nuestras instituciones públicas de salud y quizás podría contribuir a resaltar los pasos necesarios hacia la mejora de la serie de cuidados en VIH sobre nuestra población.

Safety of monitoring antiretroviral therapy response in HIV-1 infection using CD4+ T cell count at long-term intervals / Segurança do monitoramento da resposta à terapia antirretroviral em pacientes com infecção pelo HIV-1 através da contagem de linfócitos T CD4+ a intervalos mais longos / Seguridad en la monitorización de la respuesta a la terapia antirretroviral ante el VIH-1, usando el recuento celular CD4+ T en intervalos a largo plazo

Abstract: The latest Brazilian guideline recommended the reduction of routine CD4+ T cell counts for the monitoring of patients with human immunodeficiency virus type 1 (HIV-1) under combination antiretroviral therapy (cART). The aim of this study was to evaluate the safety of monitoring response to cART in HIV-1 infection using routine viral load at shorter intervals and CD4+ T cell count at longer intervals. CD4+ T cell counts and HIV-1 viral load were evaluated in 1,906 HIV-1-infected patients under cART during a three-year follow-up. Patients were stratified as sustained, non-sustained and non-responders. The proportion of patients who showed a CD4+ T > 350cells/µL at study entry among those with sustained, non-sustained and non-responders to cART and who remained with values above this threshold during follow-up was 94.1%, 81.8% and 71.9%, respectively. HIV-1-infected patients who are sustained virologic responders and have initial CD4+ T cell counts > 350cells/µL showed a higher chance of maintaining the counts of these cells above this threshold during follow-up than those presenting CD4+ T ≤ 350cells/µL (OR = 39.9; 95%CI: 26.5-60.2; p < 0.001). This study showed that HIV-1-infected patients who had sustained virologic response and initial CD4+ T > 350cells/µL were more likely to maintain CD4+ T cell counts above this threshold during the next three-year follow-up. This result underscores that the evaluation of CD4+ T cell counts in longer intervals does not impair the safety of monitoring cART response when routine viral load assessment is performed in HIV-1-infected patients with sustained virologic response.

Resumo: O último consenso brasileiro recomenda reduzir a rotina de contagem de linfócitos T CD4+ para monitorar os pacientes com HIV-1 sob terapia antirretroviral combinada (TARV). O estudo teve como objetivo avaliar a segurança do monitoramento à TARV na infecção pelo HIV-1, realizando a carga viral a intervalos mais curtos e a contagem de linfócitos T CD4+ a intervalos mais longos. Foram avaliadas a contagem de linfócitos T CD4+ e a carga viral do HIV-1 em 1.906 pacientes com HIV-1 em uso de TARV durante um seguimento de três anos. Os pacientes foram estratificados em: resposta sustentada, não sustentada e não respondedores. As proporções de pacientes com linfócitos T CD4+ > 350células/µL na linha de base do estudo entre de resposta sustentada, não sustentada e não respondedores à TARV e que permaneceram com valores acima desse limiar ao longo do seguimento foram 94,1%, 81,8% e 71,9%, respectivamente. Os pacientes com resposta virológica sustentada e que tinham contagem de T CD4+ > 350células/µL mostraram maior probabilidade de manter a contagem acima desse limiar durante o seguimento, quando comparados àqueles com T CD4+ ≤ 350células/µL (OR = 39,9; 95%CI: 26,5-60,2; p < 0,001). O estudo mostrou que pacientes HIV-1+ com resposta virológica sustentada e contagem de linfócitos T CD4+ > 350células/µL tinham maior probabilidade de manter a contagem de células T CD4+ acima desse limiar durante o seguimento de três anos subsequentes. O resultado corrobora que a contagem de linfócitos T CD4+ com intervalos mais longos não compromete a segurança do monitoramento da resposta à TARV quando a avaliação da carga viral é feita de rotina em pacientes HIV-1+ com resposta virológica sustentada.

Resumen: Las últimas directrices brasileñas recomendaron la reducción de la rutina en el recuento celular CD4+ T para pacientes con el virus de inmunodeficiencia humano tipo 1 (VIH-1), con terapia de combinación antirretroviral (cART por sus siglas en inglês). El objetivo de este estudio fue evaluar la seguridad de la monitorización de la respuesta a la cART en una infección por VIH-1, usando rutinas de carga viral en intervalos más cortos y recuento celular CD4+ T en intervalos más largos. Se evaluaron el recuento celular CD4+ T y la carga viral VIH-1 en 1.906 pacientes infectados con VIH-1 y con cART durante un seguimiento que duró tres años. Los pacientes fueron estratificados como constantes, inconstantes y sin respuesta. La proporción de pacientes que mostraron CD4+ T > 350células/µL en el estudio entran dentro del grupo de los constantes, inconstantes y sin respuesta al cART, y quienes permanecieron con valores por encima de este umbral durante los seguimientos fueron 94,1%, 81,8% y 71,9%, respectivamente. Los pacientes infectados por VIH-1 que cuentan con la respuesta virológica constante y tienen un recuento inicial CD4+ T > 350células/µL mostraron una oportunidad más alta de mantener el recuento de estas células por encima del umbral durante los seguimientos, respecto a quienes presentaban CD4+ T células ≤ 350células/µL (OR = 39,9; IC95%: 26,5-60,2; p < 0,001). Este estudio expuso que los pacientes infectados por VIH-1, que habían tenido una respuesta virológica constante e inicial CD4+ T > 350células/µL, eran más propensos a mantener el recuento de células CD4+ T por encima de este umbral durante los tres años posteriores de seguimiento. Este resultado destaca que la evaluación del cómputo de células CD4+ T en intervalos más largos no obstaculiza la seguridad al realizar una monitorización en la respuesta a cART, cuando la evaluación de la carga viral rutinaria se realiza en pacientes infectados por VIH-1 con una respuesta virológica constante.

Epstein-Barr virus (EBV) microRNAs: involvement in cancer pathogenesis and immunopathology.

The Epstein-Barr virus (EBV), which infects over 90% of adults, appears to have evolved to exploit the normal biology of B-cell development in order to persist as a life-long asymptomatic infection. However, EBV can contribute to oncogenesis. It has become evident that alterations in the expression of microRNAs (miRNAs) from the host cell and EBV can also contribute to cancer pathogenesis. MicroRNAs function by inhibiting translation of select groups of mRNA transcripts containing imperfect annealing sequences in their 3' untranslated regions (3' UTRs) and less frequently through other regions of the transcript. A number of studies have demonstrated that profiles of miRNA expression could establish phenotypic signatures of different cancer types where viruses have been evolved with highly sophisticated gene silencing machinery to disturb the host-immune response. Based on current review, it is possible that a specific virus miRNA may be involved in cancer pathogenesis.

Avaliação do polimorfismo genético pvuII do receptor de lipoproteína de baixa densidade (RLDL) em pacientes com lúpus eritematoso sistêmico / Evaluation of genetic polymorphism pvuII of low density lipoprotein receptor (LDLR) in patients with systemic lupus erythematosus

Lúpus Eritematoso Sistêmico (LES) é uma doença inflamatória crônica do tecido conjuntivo, relacionada a alterações do perfil lipídico e ao metabolismo de lipoproteínas. Estudos mostram que o polimorfismo genético PvuII do receptor de lipoproteína de baixa densidade (RLDL) está associado às diferentes concentrações de lipoproteína de baixa (LDL) na população em geral. O presente estudo avaliou o polimorfismo genético PvuII do RLDL e o perfil lipídico em pacientes com LES da população sul brasileira. Foram incluídos 72 pacientes com LES e 154 doadores de sangue. Pacientes com LES apresentaram elevados níveis séricos de triglicerídeos (TG) quando comparados com o grupo controle (p<0,0001). Semelhantemente, pacientes com LES ativo apresentaram maiores níveis de TG quando comparados a pacientes com LES sem atividade da doença (p=0,0113). Em relação à frequência do polimorfismo genético PvuII do RLDL, 35 (48,6%) dos pacientes com LES apresentavam o genótipo P1P1, 32 (44,4%) o genótipo P1P2 e 5 (6,9%) o genótipo P2P2. Não foram encontradas diferenças nas frequências do genótipo P1P1 vs P1P2 e P1P1 vs P2P2 quando comparado entre pacientes com LES e controles (p>0,05). Pacientes com LES e genótipo P1P1 apresentaram uma tendência a ter valores mais elevados de TG quando comparados a pacientes com LES e genótipo P1P2+P2P2 (p=0,0687). Conclui-se que polimorfismos genéticos podem contribuir para o aumento de risco cardiovascular; no entanto,deve-se levar em consideração a complexidade dos componentes genéticos e da doença avaliada.Maiores investigações são necessárias para outros genes que possam estar envolvidos na alteração do perfil lipídico nesta população.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of connective tissue related to changes in lipid profile and lipoprotein metabolism. Studies show that the genetic polymorphism of PvuII low density lipoprotein receptor (LDLR) is associated with different concentrations of low-density lipoprotein (LDL) in general population. The present study evaluated the genetic polymorphism of PvuII of LDLR and lipid profile in patients with SLE in southern Brazilian population. We included 72 patients with SLE and 154 blood donors. In assessing the lipid profile, SLE patients had elevated serum triglycerides (TG) levels compared with the control group (p <0.0001). Similarly, patients with active SLE have elevated TG levels when compared to patients without SLE disease activity (p = 0.0113). Regarding the frequency of genetic polymorphism of PvuII of LDLR, 35 (48.6%) patients with SLE had P1P1 genotype, 32 (44.4%) P1P2 genotype and 5 (6.9%) the P2P2 genotype. There were no differences in the genotype frequencies P1P1 vs P1P2 and P1P1vs P2P2 compared between SLE patients and controls (p>0.05). Patients with SLE and P1P1 genotype tended to have higher levels of TG compared with patients with SLE and P1P2 + P2P2 genotype (p = 0.0687). We conclude that genetic polymorphism may contribute to increased cardiovascular risk; however, the complexity of genetic components and disease evaluated should be taken into consideration. Further investigations are needed for other genes that may be involved in altering the lipid profile in this population.

Polimorfismos genéticos associados ao metabolismo lipídico envolvidos na fisiopatologia do acidente vascular encefálico isquêmico / Genetic polymorphisms associated with lipid metabolism involved in the pathophysiology of ischemic stroke

O acidente vascular encefálico (AVE) é uma desordem complexa, multifatorial e poligênica decorrente da interação entre componentes genéticos do indivíduo e fatores ambientais. Estudos prévios têm estabelecido a hipertensão arterial, tabagismo, diabetes mellitus, dislipidemia, elevado índice de massa corpórea, distúrbios da coagulação e aumento da idade como fatores de risco preditores de AVE. A dislipidemia tem sido associada à fisiopatologia do AVE isquêmico e polimorfismos genéticos que ocorrem na via metabólica dos lipídeos têm sido propostos como fatores genéticos associados ao AVE isquêmico. O componente genético na causa da dislipidemia tem sido intensamente investigado nos últimos anos. Entre os vários polimorfismos genéticos,os que ocorrem nos genes Apo E, Apo B, LDLR, Apo A-I, Apo C-III, lipase hepática, proteína transferidorade ésteres de colesterol (CETP), lipase lipoprotéica (LPL) e proteína convertase subtilisina/kexina tipo 9(PCSK9) têm sido objeto de estudos na população em geral. Os dados sobre o perfil lipídico e o estudo dos polimorfismos dos genes que codificam proteínas estruturais e enzimas relacionadas com o metabolismo dos lipídeos podem revelar a prevalência das dislipidemias em uma população, possibilitando uma intervenção direcionada para o controle e prevenção das doenças ateroscleróticas como o AVE isquêmico.

The stroke is a complex, multifactorial, and polygenic disorder that results from the interaction betweenthe individual genetic components and environmental factors. Previous studies have established hypertension, smoking, diabetes mellitus, dyslipidemia, elevated body mass index, disturbances of coagulation and increasing age as predictors of stroke risk factors. Dyslipidemia has been associated with pathophysiology of ischemic stroke and genetic polymorphisms that occur in the metabolic pathway, such as lipids metabolism, has been one of the hereditary factors related to ischemic stroke. The genetic component in the cause of dyslipidemia has been intensively investigated in recent years. Among the several genetic polymorphisms, those that occur in the Apo E, Apo B, low-density lipoprotein receptor (LDLR), Apo A-I, Apo C-III, hepatic lipase, cholesteryl ester transfer protein (CETP), lipoprotein lipase(LPL) and proprotein convertase subtilisin/kexin type 9 (PCSK9). have been the object of many studiesin the population worldwide. Data on lipid profile and study of polymorphisms of genes encoding structural proteins and enzymes related to lipid metabolism may reveal the prevalence of dyslipidemia ina population, enabling a targeted intervention for the control and prevention of atherosclerotic diseasessuch as ischemic stroke.