Prediabetes Induces More Severe Acute COVID-19 Associated With IL-6 Production Without Worsening Long-Term Symptoms.

Aims: Pre-existing conditions, such as age, hypertension, obesity, and diabetes, constitute known risk factors for severe COVID-19. However, the impact of prediabetes mellitus (PDM) on COVID-19 severity is less clear. This study aimed to evaluate the influence of PDM in the acute and long-term phases of COVID-19. Materials and methods: We compared inflammatory mediators, laboratory and clinical parameters and symptoms in COVID-19 patients with prediabetes (PDM) and without diabetes (NDM) during the acute phase of infection and at three months post-hospitalization. Results: Patients with PDM had longer hospital stays and required intensive care unit admission more frequently than NDM. Upon hospitalization, PDM patients exhibited higher serum levels of interleukin 6 (IL-6), which is related to reduced partial pressure of oxygen (PaO2) in arterial blood, oxygen saturation (SpO2) and increased COVID-19 severity. However, at three months after discharge, those with PDM did not exhibit significant alterations in laboratory parameters or residual symptoms; however, PDM was observed to influence the profile of reported symptoms. Conclusions: PDM seems to be associated with increased risk of severe COVID-19, as well as higher serum levels of IL-6, which may constitute a potential biomarker of severe COVID-19 risk in affected patients. Furthermore, while PDM correlated with more severe acute-phase COVID-19, no long-term worsening of sequelae was observed.

The health facility as a risk factor for multidrug-resistant gram-negative bacteria in critically ill patients with COVID-19

Abstract Background The relationship between Multidrug Resistant-Gram Negative Bacteria (MDR-GNB) infection and colonization in critically ill COVID-19 patients has been observed, however, it is still poorly understood. This study evaluated the risk factors for acquiring MDR-GNB in patients with severe COVID-19 in Intensive Care Units (ICU). Methods This is a nested case-control study in a cohort of 400 adult patients (≥ 18 years old) with COVID-19, hospitalized in the ICU of 4 hospitals in the city of Curitiba, Brazil. Cases were critical COVID-19 patients with one or more MDR GNB from any surveillance and/or clinical cultures were taken during their ICU stay. Controls were patients from the same units with negative cultures for MDR-GNB. Bivariate and multivariate analyses were done. Results Sixty-seven cases and 143 controls were included. Independent risk factors for MDR bacteria were: male gender (OR = 2.6; 95% CI 1.28‒5.33; p = 0.008); the hospital of admission (OR = 3.24; 95% CI 1.39‒7.57; p = 0.006); mechanical ventilation (OR = 25.7; 95% CI 7.26‒91; p < 0.0001); and desaturation on admission (OR = 2.6; 95% CI 1.27‒5.74; p = 0.009). Conclusions Male gender, desaturation, mechanical ventilation, and the hospital of admission were the independent factors associated with MDR-GNB in patients in the ICU with COVID-19. The only modifiable factor was the hospital of admission, where a newly opened hospital posed a higher risk. Therefore, coordinated actions toward a better quality of care for critically ill COVID-19 patients are essential.

Métodos para avaliação da efetividade de vacinas para COVID-19 com ênfase em abordagens quase-experimentais / Methods to evaluate COVID-19 vaccine effectiveness, with an emphasis on quasi-experimental approaches

Resumo A avalição da efetividade de vacinas é feita com dados do mundo real e é essencial para monitorar o desempenho dos programas de vacinação ao longo do tempo bem como frente a novas variantes. Até o momento, a avaliação da efetividade das vacinas para COVID-19 tem sido baseada em métodos clássicos como estudos de coorte e caso controle teste-negativo, que muitas vezes podem não permitir o adequado controle dos vieses intrínsecos da alocação das campanhas de vacinação. O objetivo dessa revisão foi discutir os desenhos de estudo disponíveis para avaliação de efetividade das vacinas, enfatizando os estudos quase-experimentais, que buscam mimetizar os estudos aleatorizados ao introduzir um componente exógeno para atribuição ao tratamento, bem como suas vantagens, limitações e aplicabilidade no contexto dos dados brasileiros. O emprego de métodos quase-experimentais, incluindo as séries temporais interrompidas, o método de diferença em diferenças, escore de propensão, variáveis instrumentais e regressão descontínua, são relevantes pela possibilidade de gerar estimativas mais acuradas da efetividade de vacinas para COVID-19 em cenários como o brasileiro, que se caracteriza pelo uso de várias vacinas, com respectivos número e intervalos entre doses, aplicadas em diferentes faixas etárias e em diferentes momentos da pandemia.

Abstract The evaluation of vaccine effectiveness is conducted with real-world data. They are essential to monitor the performance of vaccination programmes over time, and in the context of the emergence of new variants. Until now, the effectiveness of COVID-19 vaccines has been assessed based on classic methods, such as cohort and test-negative case-control studies, which may often not allow for adequate control of inherent biases in the assignment of vaccination campaigns. The aim of this review was to discuss the study designs available to evaluate vaccine effectiveness, highlighting quasi-experimental studies, which seek to mimic randomized trials, by introducing an exogenous component to allocate to treatment, in addition to the advantages, limitations, and applicability in the context of Brazilian data. The use of quasi-experimental approaches, such as interrupted time series, difference-in-differences, propensity scores, instrumental variables, and regression discontinuity design, are relevant due to the possibility of providing more accurate estimates of COVID-19 vaccine effectiveness. This is especially important in scenarios such as the Brazilian, which characterized by the use of various vaccines, with the respective numbers and intervals between doses, applied to different age groups, and introduced at different times during the pandemic.

Cellular infiltrate in cutaneous leishmaniasis lesions and therapeutic outcome

Abstract Background: The treatment of cutaneous leishmaniasis is a challenge. A better understanding of the in situ mechanisms involved in the evolution and cure of the disease is essential for the development of new therapies. Objective: Correlate histopathological and immunological characteristics of cutaneous leishmaniasis lesions with clinical outcome after different treatment regimens. Methods: The authors analyzed cellular infiltration and immunohistochemistry staining for CD4, CD8 and IL-17 in biopsy samples from 33 patients with cutaneous leishmaniasis before treatment. All patients were recruited in a randomized clinical trial at Corte de Pedra (Bahia-Brazil) and assigned to receive Glucantime®, Glucantime® + Oral Tamoxifen or Glucantime® + Topical Tamoxifen. Patients were followed for 2 to 6 months to define disease outcome. Results: A similar expression of CD4, CD8 and IL-17 was observed in lesion samples regardless of clinical outcome. In general, a higher amount of CD8 cells were observed compared with CD4 cells. An important observation was that all patients whose cellular infiltrate did not contain plasma cells were cured after treatment. Study limitations: Isolated quantification of TCD8 and IL-17 using immunohistochemistry is insufficient to analyze the role of these molecules in the immunopathogenesis of cutaneous leishmaniasis. In addition, the expansion of the immunohistochemistry panel would allow a more complete analysis of the immune response in situ. Conclusions: The absence of plasma cells in cutaneous leishmaniasis lesions was related to a favorable therapeutic outcome.

Evaluation of ELISA-Based Multiplex Peptides for the Detection of Human Serum Antibodies Induced by Zika Virus Infection across Various Countries.

Zika virus (ZIKV) is a mosquito-borne Flavivirus with a positive-sense RNA genome, which are generally transmitted through the bite of an infected Aedes mosquito. ZIKV infections could be associated with neurological sequelae that, and otherwise produces similar clinical symptoms as other co-circulating pathogens. Past infection with one member of the Flavivirus genus often induces cross-reactive antibodies against other flaviruses. These attributes complicate the ability to differentially diagnose ZIKV infection from other endemic mosquito-borne viruses, making it both a public health issue as well as a diagnostic challenge. We report the results from serological analyses using arbovirus-specific peptides on 339 samples that were previously collected from 6 countries. Overall, we found that our multiplexed peptide-based ELISA was highly efficient for identifying ZIKV antibodies as early as 2 weeks post infection, and that it correlates with microneutralization, plaque reduction neutralization tests (PRNTs) and commercial tests for ZIKV in previously characterized samples. We observed that seropositivity varied by patient cohort, reflecting the sampling period in relation to the 2015-2016 ZIKV outbreak. This work evaluates the accuracy, specificity, and sensitivity of our peptide-based ELISA method for detecting ZIKV antibodies from geographically diverse regions. These findings can contribute to ongoing serological methods development and can be adapted for use in future studies.

Cellular infiltrate in cutaneous leishmaniasis lesions and therapeutic outcome.

BACKGROUND: The treatment of cutaneous leishmaniasis is a challenge. A better understanding of the in situ mechanisms involved in the evolution and cure of the disease is essential for the development of new therapies. OBJECTIVE: Correlate histopathological and immunological characteristics of cutaneous leishmaniasis lesions with clinical outcome after different treatment regimens. METHODS: The authors analyzed cellular infiltration and immunohistochemistry staining for CD4, CD8 and IL-17 in biopsy samples from 33 patients with cutaneous leishmaniasis before treatment. All patients were recruited in a randomized clinical trial at Corte de Pedra (Bahia-Brazil) and assigned to receive Glucantime®, Glucantime® + Oral Tamoxifen or Glucantime® + Topical Tamoxifen. Patients were followed for 2 to 6 months to define disease outcome. RESULTS: A similar expression of CD4, CD8 and IL-17 was observed in lesion samples regardless of clinical outcome. In general, a higher amount of CD8 cells were observed compared with CD4 cells. An important observation was that all patients whose cellular infiltrate did not contain plasma cells were cured after treatment. STUDY LIMITATIONS: Isolated quantification of TCD8 and IL-17 using immunohistochemistry is insufficient to analyze the role of these molecules in the immunopathogenesis of cutaneous leishmaniasis. In addition, the expansion of the immunohistochemistry panel would allow a more complete analysis of the immune response in situ. CONCLUSIONS: The absence of plasma cells in cutaneous leishmaniasis lesions was related to a favorable therapeutic outcome.

A Double-blind, Randomized Trial to Evaluate Miltefosine and Topical Granulocyte Macrophage Colony-stimulating Factor in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania braziliensis in Brazil.

BACKGROUND: The treatment of cutaneous leishmaniasis (CL) in Brazil using pentavalent antimony (Sbv) is associated with a high rate of failure. Miltefosine has proven efficacy for CL caused by L. braziliensis, with a cure rate (CR) of 75%. A combined treatment with granulocyte macrophage colony-stimulating factor (GM-CSF) and miltefosine could increase CR and decrease healing time. METHODS: A randomized, double-blind clinical trial to evaluate the efficacy of miltefosine combined with topical GM-CSF (M + GM) vs miltefosine and placebo (M + P) vs Sbv in 133 patients with CL caused by L. braziliensis in Bahia, Brazil. RESULTS: The final CR at 180 days after the initiation of treatment was 44.4% in the Sbv group, 76.6% in the M + P group (P = .003 vs Sbv), and 75.6% in the M + GM group (P = .004 vs Sbv). The median healing time for cure was 102 days for the Sbv group and 60 days for both miltefosine groups (P = .0009). During the 6-month follow-up period, 4 relapses were documented: 1 in the Sbv group, 1 in the M + P group, and 2 in the M + GM group. Mild adverse events occurred in 65% of patients from the Sbv group, 76% and 79% from the M + P and M + GM groups respectively. CONCLUSIONS: Miltefosine is more effective than Sbv for the treatment of CL caused by L. braziliensis in Brazil and accelerates the healing time. Association with GM-CSF does not improve therapeutic outcome. CLINICAL TRIALS REGISTRATION: NCT03023111.

Integrated Analysis Reveals That miR-193b, miR-671, and TREM-1 Correlate With a Good Response to Treatment of Human Localized Cutaneous Leishmaniasis Caused by Leishmania braziliensis.

Localized cutaneous leishmaniasis (LCL) is a chronic disease characterized by ulcerated skin lesion(s) and uncontrolled inflammation. The mechanisms underlying the pathogenesis of LCL are not completely understood, and little is known about posttranscriptional regulation during LCL. MicroRNAs (miRNAs) are non-coding small RNAs that regulate gene expression and can be implicated in the pathogenesis of LCL. We investigated the involvement of miRNAs and their targets genes in human LCL using publicly available transcriptome data sets followed by ex vivo validation. Initial analysis highlighted that miRNA expression is altered during LCL, as patients clustered separately from controls. Joint analysis identified eight high confidence miRNAs that had altered expression (-1.5 ≤ fold change ≥ 1.5; p < 0.05) between cutaneous ulcers and uninfected skin. We found that the expression of miR-193b and miR-671 are greatly associated with their target genes, CD40 and TNFR, indicating the important role of these miRNAs in the expression of genes related to the inflammatory response observed in LCL. In addition, network analysis revealed that miR-193b, miR-671, and TREM1 correlate only in patients who show faster wound healing (up to 59 days) and not in patients who require longer cure times (more than 60 days). Given that these miRNAs are associated with control of inflammation and healing time, our findings reveal that they might influence the pathogenesis and prognosis of LCL.

Differential Expression of the Eicosanoid Pathway in Patients With Localized or Mucosal Cutaneous Leishmaniasis.

Unfettered inflammation is thought to play critical role in the development of different clinical forms of tegumentary leishmaniasis. Eicosanoids are potent mediators of inflammation and tightly associated with modulation of immune responses. In this cross-sectional exploratory study, we addressed whether targets from the eicosanoid biosynthetic pathway, assessed by multiplexed expression assays in lesion biopsy and plasma specimens, could highlight a distinct biosignature in patients with mucocutaneous leishmaniasis (MCL) or localized cutaneous leishmaniasis (LCL). Differences in immunopathogenesis between MCL and LCL may result from an imbalance between prostaglandins and leukotrienes, which may serve as targets for future host-directed therapies.

Arginase I, polyamine, and prostaglandin E2 pathways suppress the inflammatory response and contribute to diffuse cutaneous leishmaniasis.

Diffuse cutaneous leishmaniasis (DCL) is a rare clinical manifestation of tegumentary leishmaniasis. The molecular mechanisms underlying DCL pathogenesis remain unclear, and there is no efficient treatment available. This study investigated the systemic and in situ expression of the inflammatory response that might contribute to suppression in DCL. The plasma levels of arginase I, ornithine decarboxylase (ODC), transforming growth factor ß (TGF-ß), and prostaglandin E2 (PGE2) were higher in patients with DCL, compared with patients with localized cutaneous leishmaniasis (LCL) or with controls from an area of endemicity. In situ transcriptomic analyses reinforced the association between arginase I expression and enzymes involved in prostaglandin and polyamine synthesis. Immunohistochemistry confirmed that arginase I, ODC, and cyclooxygenase2 expression was higher in lesion biopsy specimens from patients with DCL than in those from patients with LCL. Inhibition of arginase I or ODC abrogates L. amazonensis replication in infected human macrophages. Our data implicate arginase I, ODC, PGE2, and TGF-ß in the failure to mount an efficient immune response and suggest perspectives in the development of new strategies for therapeutic intervention for patients with DCL.

Análise do conhecimento teórico e prática científica entre otorrinolaringologistas brasileiros / Analysis of theoretical knowledge and the practice of science among Brazilian otorhinolaryngologists

A compreensão dos princípios científicos e a interpretação de artigos é necessária em qualquer especialidade médica. Entretanto, inexistem publicações sobre o conhecimento teórico e prático dos otorrinolaringologistas brasileiros. OBJETIVO: Avaliar a formação e o conhecimento científico de médicos da área de Otorrinolaringologia. MÉTODO: Durante dois congressos nacionais da especialidade, os participantes foram convidados a preencher questionário sobre prática e conhecimento científico para residentes e especialistas dessa área. RESULTADOS E CONCLUSÃO: Participaram do estudo 73 médicos (52% otorrinolaringologistas e 38% residentes), com idade entre 18 e 65 anos. Cerca de dois terços envolveram-se em alguma atividade científica durante a graduação e/ou referiram já ter escrito um artigo científico. Os médicos que já participaram de projetos de pesquisa sentem-se mais preparados para interpretar um artigo científico e conduzir um projeto de pesquisa (p = 0,0103 e p = 0,0240, respectivamente). Aqueles que participaram de projetos de pesquisa ou já escreveram um artigo tiveram melhor desempenho nos conceitos científicos teóricos (p = 0,0101 e p = 0,0103, respectivamente). Entretanto, o índice geral de acertos nas questões referentes ao conhecimento científico foi de 46,1%. Dessa forma, identificamos que há deficiências na formação científica dos otorrinolaringologistas brasileiros que podem ser atenuadas pela participação em projetos de pesquisa.

Physicians from all medical specialties are required to understand the principles of science and to interpret medical literature. Yet, the levels of theoretical and practical knowledge held by Brazilian otorhinolaryngologists has not been evaluated to date. OBJECTIVE: To assess the background and level of scientific knowledge of Brazilian otorhinolaryngologists. METHOD: Participants of two national ENT meetings were invited to answer a questionnaire to assess scientific practice and knowledge. RESULTS AND CONCLUSION: This study included 73 medical doctors (52% otorhinolaryngologists and 38% residents) aged between 18 and 65 years. About two-thirds have been involved in some form of scientific activity during undergraduate education and/or reported to have written at least one scientific paper. Physicians who took part in research projects felt better prepared to interpret scientific papers and carry out research projects (p = 0.0103 and p = 0.0240, respectively). Respondents who claimed to have participated in research or to have written papers had higher scores on theoretical scientific concepts (p = 0.0101 and p = 0.0103, respectively). However, the overall rate of right answers on questions regarding scientific knowledge was 46.1%. Therefore, a deficiency was observed in the scientific education of Brazilian otorhinolaryngologists. Such deficiency may be mitigated through participation in research.

Human mucosal leishmaniasis: neutrophils infiltrate areas of tissue damage that express high levels of Th17-related cytokines.

Mucosal leishmaniasis (ML) is characterised by severe tissue destruction. Herein, we evaluated the involvement of the IL-17-type response in the inflammatory infiltrate of biopsy specimens from 17 ML patients. IL-17 and IL-17-inducing cytokines (IL-1ß, IL-23, IL-6 and TGF-ß) were detected by immunohistochemistry in ML patients. IL-17(+) cells exhibited CD4(+), CD8(+) or CD14(+) phenotypes, and numerous IL-17(+) cells co-expressed the CC chemokine receptor 6 (CCR6). Neutrophils, a hallmark of Th17-mediated inflammation, were regularly detected in necrotic and perinecrotic areas and stained positive for neutrophil elastase, myeloperoxidase and MMP-9. Taken together, these observations demonstrate the existence of Th17 cells in ML lesions associated with neutrophils in areas of tissue injury and suggest that IL-17 is involved in ML pathogenesis.

Surgical treatment of non-embolized patients with nasoangiofibroma.

UNLABELLED: Juvenile nasopharyngeal angiofibroma (JNA) is an uncommon tumor of the sphenopalatine foramen. Surgery combined with preoperative embolization has been the treatment of choice for JNA patients without intracranial invasion. This study aims to assess the viability of surgically treating non-embolized patients with JNA (types I-III according to Fisch). MATERIAL AND METHOD: This is a retrospective, descriptive study based on the medical records of 15 patients with histologically confirmed JNA (Fisch's types I- III), who underwent surgical treatment without pre-op embolization in our institution between 2000 and 2005. RESULTS: Seven of the fifteen patients were approached endoscopically, four through the transantral approach, three were treated with the combined transmaxillary and endoscopic approach, and one with the combined transmaxillary and transpalatal approach. Six patients required intraoperatory blood transfusion, averaging volumes of 1.3 unit/patient. There were no cases of death or significant morbidity. Eleven of the fifteen patients were followed for an average of twelve months and 27% of them relapsed. Four patients did not comply with the follow-up scheme. CONCLUSION: Resection of JNF types I-III was safely completed in non-embolized patients. The observed levels of intraoperative bleeding, occurrence of complications, and rates of recurrence were close to those seen in embolized patients as found in the literature.

Tratamento cirúrgico de nasoangiofibroma sem embolização / Surgical Treatment of Non-embolized Patients with Nasoangiofibroma

Nasoangiofibroma juvenil (NAFJ) é um tumor incomum que se localiza na região do forame esfenopalatino. A cirurgia combinada à embolização pré-operatória tem sido a opção terapêutica mais empregada nos pacientes com NAFJ sem invasão intracraniana. O objetivo desse estudo é avaliar a viabilidade do tratamento cirúrgico do nasoangiofibroma em pacientes estágios I- III de Fisch, sem uso de embolização pré- operatória. MATERIAL E MÉTODO: Estudo descritivo, retrospectivo, utilizando-se dados de revisão de prontuário de quinze pacientes com NAFJ estágio I a III de Fisch submetidos à cirurgia sem embolização pré-operatória, entre os anos de 2000 e 2005. RESULTADOS: Dos quinze pacientes, sete pacientes foram submetidos à cirurgia endoscópica, quatro via transmaxilar, três via endoscópica e transmaxilar e um via transmaxilar e transpalatina. Seis pacientes necessitaram de hemotransfusão no intra-operatório, com média geral de 1.3 bolsa/paciente. Nenhum caso de mortalidade ou morbidade significativa foi registrado. Onze dos quinze pacientes foram acompanhados por tempo médio de doze meses com taxa de recidiva de 27 por cento. Quatro pacientes perderam seguimento. CONLUSÃO: A ressecção de NAFJ classes I- III foi realizada com segurança em pacientes não-embolizados, com taxa de sangramento intraoperatório, ocorrência de complicações e taxa de recorrência próximas dos valores pesquisados na literatura para pacientes embolizados.

Juvenile nasopharyngeal angiofibroma (JNA) is an uncommon tumor of the sphenopalatine foramen. Surgery combined with preoperative embolization has been the treatment of choice for JNA patients without intracranial invasion. This study aims to assess the viability of surgically treating non-embolized patients with JNA (types I-III according to Fisch). MATERIAL AND METHOD: This is a retrospective, descriptive study based on the medical records of 15 patients with histologically confirmed JNA (Fisch’s types I- III), who underwent surgical treatment without pre-op embolization in our institution between 2000 and 2005. RESULTS: Seven of the fifteen patients were approached endoscopically, four through the transantral approach, three were treated with the combined transmaxillary and endoscopic approach, and one with the combined transmaxillary and transpalatal approach. Six patients required intraoperatory blood transfusion, averaging volumes of 1.3 unit/patient. There were no cases of death or significant morbidity. Eleven of the fifteen patients were followed for an average of twelve months and 27 percent of them relapsed. Four patients did not comply with the follow-up scheme. CONCLUSION: Resection of JNF types I-III was safely completed in non-embolized patients. The observed levels of intraoperative bleeding, occurrence of complications, and rates of recurrence were close to those seen in embolized patients as found in the literature.

Características clínicas dos pacientes alérgicos que vivem em cidade de clima tropical / Clinical characteristics of allergic pacients living in a tropical climate city

A rinossinusite alérgica é uma das principais patologias respiratórias crônicas, pela sua alta prevalência, pela associação com asma e sinusite e pelo impacto na qualidade de vida do portador. Os pacientes portadores de rinossisusite alérgica apresentam reação de hipersensibilidade tipo 1, com inflamação persistente da mucosa nasal...

The alergic rhinosinusitis is one of the main chronic respiratory pathologies, for its high prevalence, the asssociation with asthma and sinusitis and for the impact in the quality of life of the carrier. The carrying patients of allergic rhinosinusitis presents hyper sensibility reaction type 1, with persistent inflammation of the nasal mucous...

Polymerase chain reaction (PCR) is highly sensitive for diagnosis of mucosal leishmaniasis.

We evaluated the use of polymerase chain reaction (PCR) for diagnosis of mucosal leishmaniasis (ML) in an endemic area in Acre, Brazil, where Leishmania braziliensis is present. Leishmania DNA was detected 34 of 35 cases, yielding a positivity rate of 97.1%, which was higher than the positivity rates for all of the other diagnostic methods studied, namely Montenegro skin test (MST), anti-Leishmania serological testing and microscopic examination of lesion biopsy specimens. These findings have led us to propose guidelines for the diagnosis of ML that use PCR as the principal method of parasitological confirmation of cases.