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1.
Artigo em Inglês | MEDLINE | ID: mdl-33947582

RESUMO

Raynaud's phenomenon (RP) and digital ulcers (DUs) are important disease manifestations of systemic sclerosis (SSc) that can lead to significant pain and disability. It is essential when studying these disease features to utilize outcome measures that fully evaluate the complexities of RP and DUs . The Outcome Measures in Rheumatology (OMERACT) Vascular Disease in SSc Working Group is applying the OMERACT filter 2.1 to identify a core set of disease domains that encompass the full burden of SSc-related RP and DUs. Progress to date and future research plans were presented during a Special Interest Group held in December 2020.

2.
AIDS ; 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33831905

RESUMO

OBJECTIVE: To evaluate associations between hair antiretroviral (ARV) hair concentrations as an objective, cumulative adherence metric, with self-reported adherence and virologic outcomes. DESIGN: Analysis of cohort A of the ACTG-A5288 study. These patients in resource-limited settings were failing second-line PI-based ART, but were susceptible to ≥1 NRTI and their PI, and continued taking their PI-based regimen. METHODS: ARV hair concentrations participants taking 2 NRTIs with boosted atazanavir (n = 69) or lopinavir (n = 112) were analyzed at weeks 12, 24, 36 and 48 using liquid-chromatography-tandem-mass-spectrometry assays. Participants self-reported percentage of doses taken in the previous month; virologic failure (VF) was confirmed HIV-1 RNA≥1000 copies/mL at week 24 or 48. RESULTS: From 181 participants with hair samples, (61% female median age: 39y; CD4 count: 167 cells/uL; HIV-1 RNA: 18,648 copies/mL), 91 (50%) experienced VF at either visit. At 24 weeks, median hair concentrations were 2.95 (IQR 0.49-4.60) ng/mg for atazanavir, 2.64 (IQR 0.73-7.16) for lopinavir, and 0.44 (IQR 0.11-0.76) for ritonavir. Plasma HIV-1 RNA demonstrated inverse correlations with hair levels (rs -0.46 to -0.74) at weeks 24 and 48. Weaker associations were seen with self-reported adherence (rs -0.03 to -0.24). Decreasing hair concentrations were significantly associated with VF, the hazard ratio (HR) (95%CI) for ATV, LPV and RTV were 0.69 (0.56-0.86), 0.77 (0.68-0.87), and 0.12 (0.06-0.27) respectively. CONCLUSIONS: PI hair concentrations showed stronger associations with subsequent virologic outcomes than self-reported adherence in this cohort. Hair adherence measures could identify individuals at risk of 2nd-line treatment failure in need of interventions.

3.
Semin Arthritis Rheum ; 51(2): 425-429, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33677309

RESUMO

INTRODUCTION/BACKGROUND: Skin ulcers are a complex array of clinical manifestations of systemic sclerosis (SSc) and are often difficult to treat. However, the definition of SSc-skin ulcers has to date not been promising, demonstrating poor reliability and accuracy. There are emerging data that ultrasound has significant potential to evaluate SSc-skin ulcers. OBJECTIVE: To perform a systematic literature review (SLR) to understand the degree to which ultrasound of SSc skin ulcers has been validated according to OMERACT criteria. METHODS: In a SLR, we investigated the Cochrane Library, Web of Science and Pubmed databases for manuscripts from inception to 1st April 2020. Inclusion and exclusion criteria included manuscripts on SSc patients aged over 16 years, performing SSc-related skin ulcer evaluation with ultrasound machines. Papers on animal model, diseases other than SSc, venous ulcers were excluded. Data extraction used a uniform case report form which collected data on patient demographics, disease activity, description of the ultrasound machine and procedures and the degree to which domains of validity were fulfilled. Manuscript evaluation and extraction was performed by two independent assessors, with a third author being consulted in case of disagreement. RESULTS: amongst 308 manuscripts that were identified, 6 published manuscripts/ posters fulfilled the inclusion/exclusion criteria and were extracted. Face validity was found. Three studies developed an US definition of SSc-ulcers across patients (content validity); one study evaluated the concordance between US image and clinical assessment. Criterion validity was shown by one study and ultrasound detected improvement (sensitivity to change) of SSc-skin ulcer in response to therapy. Feasibility was demonstrated by US use for skin ulcers in multiple settings (the 6 manuuscripts/posters). CONCLUSION: This systematic literature review shows that ultrasound for skin ulcers in SSc has been partially validated. It has face, content, criterion validity, responsiveness and reasonable feasibility. Further validation for construct validity, reliability and discrimination is required.

4.
Appl Opt ; 60(4): A1-A7, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33690348

RESUMO

Fiber imaging bundles are widely used as thin, passive image conduits for miniaturized and endoscopic microscopy, particularly for confocal fluorescence imaging. Holographic microscopy through fiber bundles is more challenging; phase conjugation approaches are complex and require extensive calibration. This paper describes how simple inline holographic microscopy can be performed through an imaging bundle using a partially coherent illumination source from a multimode fiber. The sample is imaged in transmission, with the intensity hologram sampled by the bundle and transmitted to a remote camera. The hologram can then be numerically refocused for volumetric imaging, achieving a resolution of approximately 6 µm over a depth range of 1 mm. The scheme does not require any complex prior calibration and hence is insensitive to bending.

5.
BMJ Open ; 11(3): e044765, 2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707273

RESUMO

INTRODUCTION: Limited cutaneous systemic sclerosis (lcSSc) is the most frequent subset of systemic sclerosis. Despite this, lcSSc is not the major focus of clinical studies. The lack of interventional studies in lcSSc is due, in part, to a paucity of relevant outcome measures to effectively evaluate this subset. A combined response index dedicated to lcSSc would facilitate development of well-designed trials and approval of new drugs. The objective of this scoping review is to perform a broad and comprehensive identification of the outcome measures (core set items) within relevant domains, which have been used so far to assess lcSSc. METHODS AND ANALYSIS: The planned scoping review will be based on the approach proposed by Arksey et al and further developed by Levac et al. Development and reporting will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Extension for Scoping Reviews checklist and guidelines. The development of the search strategy was guided by the concepts of domains and outcomes based on the Outcome Measures in Rheumatology approach and by the different names and definitions of SSc, with a specific emphasis on their occurrence in clinical trial studies. Two databases will be searched: MEDLINE and Embase. Studies in English, published from the year 1988 onwards, will be included, since 1988 corresponds to the publication of LeRoy's first consensus definition of lcSSc. Data will be extracted and analysed using a standardised charting tool. ETHICS AND DISSEMINATION: No ethical approval is required for this study. The results will be submitted to an international peer-reviewed journal and scientific conferences, informing the discussion on which items should be included in a combined response index dedicated to lcSSc (the CRISTAL project: Combined Response Index for Scleroderma Trial Assessing lcSSc).

6.
Clin Infect Dis ; 2021 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-33772550

RESUMO

BACKGROUND: Some contacts of patients with tuberculosis remain negative on tests for tuberculosis infection, despite prolonged exposure, suggesting they might be resistant to Mycobacterium tuberculosis infection. The objective of this multinational study was to estimate the proportion of household contacts resistant to Mycobacterium tuberculosis (resisters). METHODS: We conducted a longitudinal study enrolling index patients enrolled in treatment for pulmonary multidrug- or rifampin-resistant tuberculosis and their household contacts. Contacts were tested for tuberculosis infection with a tuberculin skin test (TST) and interferon-gamma release assay (IGRA) at baseline and after 1 year. Exposure was quantified based on index patients' infectiousness, index patient and household contact interaction, and age. We explored multiple definitions of resistance to tuberculosis infection by varying TST negativity cut-offs (0 vs. <5 mm), classification of missing test results, and exposure level. RESULTS: 1016 contacts were evaluated from 284 households; 572 contacts aged ≥5 years had TST and longitudinal IGRA results available. 77 (13%) or 71 (12%) contacts were classified as resisters with a <5 mm or 0 mm TST threshold, respectively. Among 263 highly-exposed contacts, 29 (11%) or 26 (10%) were classified as resisters using TST cut-offs of <5 mm and 0 mm, respectively. The prevalence of resisters did not differ substantially by sex, age, HIV co-infection or co-morbid conditions. CONCLUSION: At least 10% of household contacts can be classified as resistant to tuberculosis infection, depending on the definition used, including those with high exposure. Further studies to understand genetic or immunologic mechanisms underlying the resister phenotype may inform novel strategies for therapeutics and vaccines.

7.
Respir Res ; 22(1): 75, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653328

RESUMO

BACKGROUND: Asthma was identified as the most common comorbidity in hospitalized patients during the 2009 H1N1 influenza pandemic. We determined using a murine model of allergic asthma whether these mice experienced increased morbidity from pandemic H1N1 (pH1N1) viral infection and whether blockade of interleukin-4 receptor α (IL-4Rα), a critical mediator of Th2 signalling, improved their outcomes. METHODS: Male BALB/c mice were intranasally sensitized with house dust mite antigen (Der p 1) for 2 weeks; the mice were then inoculated intranasally with a single dose of pandemic H1N1 (pH1N1). The mice were administered intraperitoneally anti-IL-4Rα through either a prophylactic or a therapeutic treatment strategy. RESULTS: Infection with pH1N1 of mice sensitized to house dust mite (HDM) led to a 24% loss in weight by day 7 of infection (versus 14% in non-sensitized mice; p < .05). This was accompanied by increased viral load in the airways and a dampened anti-viral host responses to the infection. Treatment of HDM sensitized mice with a monoclonal antibody against IL-4Rα prior to or following pH1N1 infection prevented the excess weight loss, reduced the viral load in the lungs and ameliorated airway eosinophilia and systemic inflammation related to the pH1N1 infection. CONCLUSION: Together, these data implicate allergic asthma as a significant risk factor for H1N1-related morbidity and reveal a potential therapeutic role for IL-4Rα signalling blockade in reducing the severity of influenza infection in those with allergic airway disease.

8.
Front Immunol ; 12: 628453, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33659009

RESUMO

The microbiome plays a fundamental role in how the immune system develops and how inflammatory responses are shaped and regulated. The "gut-lung axis" is a relatively new term that highlights a crucial biological crosstalk between the intestinal microbiome and lung. A growing body of literature suggests that dysbiosis, perturbation of the gut microbiome, is a driving force behind the development, and severity of allergic asthma. Animal models have given researchers new insights into how gut microbe-derived components and metabolites, such as short-chain fatty acids (SCFAs), influence the development of asthma. While the full understanding of how SCFAs influence allergic airway disease remains obscure, a recurring theme of epigenetic regulation of gene expression in several immune cell compartments is emerging. This review will address our current understanding of how SCFAs, and specifically butyrate, orchestrates cell behavior, and epigenetic changes and will provide a detailed overview of the effects of these modifications on immune cells in the context of allergic airway disease.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33744916

RESUMO

In patients with systemic sclerosis (SSc), the coexistence of ANCA-associated vasculitis (SSc-AAV) has been reported to be associated with a severe disease course, including significant pulmonary and renal involvement. The presence of ANCA is not uncommon in patients with SSc and therefore clinicians must maintain a high index of clinical suspicion about SSc-AAV. p-ANCA and anti-MPO antibodies are the most common antibodies observed. Patients typically present with clinical features of microscopic polyangiitis or renal-limited vasculitis There are multiple areas of potential interaction in the pathogenesis of SSc and AAV which can exacerbate/compound vascular disease. In addition, similar patterns of major internal organ involvement (e.g., lung and kidneys) are seen in both conditions. We highlight a diagnostic approach to SSc-AAV and the paucity of data to inform management. As such, SSc-AAV is typically treated as per isolated AAV which can potentially be hazardous in patients with SSc (e.g., the association between high-dose steroid and scleroderma renal crisis). We propose that this rare clinical entity warrants rigorous investigation including definition of a therapeutic strategy to ameliorate the potentially devastating combination of pathologies in SSc-AAV.

11.
Autoimmun Rev ; 20(4): 102782, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33609795

RESUMO

OBJECTIVE: To review the extant literature relating to bone health in the idiopathic inflammatory myopathies (IIM) including both adult and juvenile patients. METHODS: A PubMed search® identified relevant studies from 1966 to 2020 in accordance with PRISMA guidelines. Two independent reviewers screened and extracted the abstracts/full manuscripts, and a third author was consulted in the case of disagreement. RESULTS: We identified 37 articles (3 review articles, 2 RCTs, 9 cross-sectional, 16 cohort and 7 case-control studies). The prevalence of osteopenia (n = 7) ranges from 7 to 75% and osteoporosis (n = 7) between 13% to 27%. The prevalence of vertebral fractures ranged from 11 to 75%. Systemic inflammation likely contributes to reduced bone mineral density (BMD) in children with IIM but data is currently lacking in adult patients. Association between with impaired BMD and Vitamin D or calcium intake and physical activity has not been demonstrated in IIM. There is no clear consensus regarding the impact of age, menopause or BMI on bone health. Gender, smoking status, disease activity and inflammatory markers are not obvious independent predictors of low BMD. Several studies have demonstrated that glucocorticoids are associated with an increased risk of low BMD. There are no specific guidelines relating to the management of bone health in adult and juvenile patients with IIM. CONCLUSION: Both adult and juvenile patients with IIM are at high risk of impaired bone health and fracture. The mechanisms behind this are likely multifactorial including systemic inflammation, glucocorticoid treatment, reduced mobility and impaired calcium/vitamin D homeostasis. There are a lack of guidelines and studies relating to the screening, prevention and treatment of impaired bone health in adult and juvenile patients with IIM. Future research is required to understand the complexity of bone health in IIM including to develop much needed disease-specific management recommendations.


Assuntos
Miosite , Osteoporose , Adulto , Densidade Óssea , Criança , Estudos Transversais , Feminino , Humanos , Miosite/complicações , Miosite/epidemiologia , Osteoporose/epidemiologia , Fatores de Risco , Vitamina D
12.
J Nutr Biochem ; 91: 108600, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33577949

RESUMO

Trimethylamine-N-oxide (TMAO) has been reported as a risk factor for atherosclerosis development, as well as for other cardiovascular disease (CVD) pathologies. The objective of this review is to provide a useful summary on the use of phytochemicals as TMAO-reducing agents. This review discusses the main mechanisms by which TMAO promotes CVD, including the modulation of lipid and bile acid metabolism, and the promotion of endothelial dysfunction and oxidative stress. Current knowledge on the available strategies to reduce TMAO formation are discussed, highlighting the effect and potential of phytochemicals. Overall, phytochemicals (i.e., phenolic compounds or glucosinolates) reduce TMAO formation by modulating gut microbiota composition and/or function, inhibiting host's capacity to metabolize TMA to TMAO, or a combination of both. Perspectives for design of future studies involving phytochemicals as TMAO-reducing agents are discussed. Overall, the information provided by this review outlines the current state of the art of the role of phytochemicals as TMAO reducing agents, providing valuable insight to further advance in this field of study.

14.
Presse Med ; 50(1): 104064, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33548375

RESUMO

Digital ulcers (DU) are one of the most common complication of Systemic Sclerosis (SSc)-related vasculopathy and represent an important burden for the patients as well as for the society. Still today there is no agreement on the definition, classification and cathegorization of DU even if they are of pivotal importance in clinical practice, for treatment choice and prognostic outcomes, as well as for clinical trials. DU management requires a dedicated multidisciplinary team, that must remain ever vigilant for the development of infective complications and gangrene throughout their disease course, as well as patient education that is crucial to obtain the best compliance to assure the success of the treatment. Currently several drugs are available for DU treatment but in the future, more investigations will be needed to ameliorate the approach and the systemic and local therapies.

15.
BMC Infect Dis ; 21(1): 205, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627075

RESUMO

BACKGROUND: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs). METHODS: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability. RESULTS: Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens. CONCLUSIONS: RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.


Assuntos
Isoniazida/uso terapêutico , Mycobacterium tuberculosis/isolamento & purificação , Rifampina/uso terapêutico , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adulto , Antituberculosos/uso terapêutico , Estudos Transversais , Estudos de Viabilidade , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
16.
Clin Infect Dis ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33605999

RESUMO

BACKGROUND: The impact of very early infant treatment on HIV reservoir, and markers for treatment success, require study. METHODS: The Early Infant Treatment Study (EIT) enrolled 40 children living with HIV started on antiretroviral treatment (ART) at <7 days of age and 23 who had started treatment between 30-365 days to serve as controls. Quantitative HIV DNA was evaluated every 1-3 months in PBMCs. 84-week repeat qualitative whole blood DNA PCR and dual enzyme EIA were performed. RESULTS: Median quantitative cell-associated DNA after at least 84 weeks was significantly lower among the first 27 EIT children tested than among 10 controls (40.8 vs. 981.4 copies/million cells; p<0.001) and correlated with pre-ART DNA. Median DNA after 84 weeks did not differ significantly by negative or positive serostatus at 84 weeks (p=0.94), and appeared unaffected by periods of unsuppressed plasma RNA from 24-84 weeks (p=0.70). However, negative 84-week serostatus was 67% predictive for sustained RNA suppression and positive serostatus was 100% predictive for viremia. Loss of qualitative DNA positivity at 84 weeks was 73% predictive for sustained suppression and persistent positivity was 77% predictive for viremia. CONCLUSIONS: Lower viral reservoir was associated with starting ART at <1 week. Negative serostatus and qualitative DNA were useful markers of sustained viral suppression from 24-84 weeks.

17.
Clin Rheumatol ; 40(4): 1611-1616, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33486597

RESUMO

INTRODUCTION/OBJECTIVES: To examine how people define Raynaud's phenomenon (RP) based on their lived experiences and explore if differences exist depending on primary or secondary RP diagnosis. METHOD: An international survey was sent to people with RP through health systems, foundations, and social media. Qualitative coding of responses to an open text question regarding one's own definition of RP was performed and themes were identified. The prevalence of themes among the sample and then comparisons between themes among people who self-reported primary versus secondary diagnosis of RP were performed. RESULTS: There were 1345 respondents from 45 countries (mean age 51.5 years, 93% female) who defined RP in their own words; 17% reported primary RP and 83% reported secondary RP (69% of secondary RP was scleroderma-related, n = 927). Over half defined their RP by describing the body parts affected, color changes, pain, and triggers or situations in which an episode occurs. Patients with primary RP more frequently defined RP in terms of its impact on function/quality of life and pain compared to those with secondary RP (34.5% versus 25.3%, respectively, p=0.004; 54.0% versus 46.8%, p=0.05). Patients with secondary RP more frequently included specific body parts, color change, the management of attacks, and other digital vascular complications in their definition of RP. CONCLUSIONS: We have identified differences in how people with primary and secondary RP define RP, in terms of how they feel and function. Our findings have implications for the domains of outcome measures for assessing RP within different patient populations. Key Points • Pain is more often mentioned in primary RP and color change in secondary RP. • Over 25% of patients included reduced the quality of life as part of their RP definition. • The concept of "attack" is used to define RP by only 2% of patients.

18.
Bioinformatics ; 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33515234

RESUMO

MOTIVATION: As experimental efforts are costly and time consuming, computational characterization of enzyme capabilities is an attractive alternative. We present and evaluate several machine-learning models to predict which of 983 distinct enzymes, as defined via the Enzyme Commission (EC) numbers, are likely to interact with a given query molecule. Our data consists of enzyme-substrate interactions from the BRENDA database. Some interactions are attributed to natural selection and involve the enzyme's natural substrates. The majority of the interactions however involve non-natural substrates, thus reflecting promiscuous enzymatic activities. RESULTS: We frame this "enzyme promiscuity prediction" problem as a multi-label classification task. We maximally utilize inhibitor and unlabelled data to train prediction models that can take advantage of known hierarchical relationships between enzyme classes. We report that a hierarchical multi-label neural network, EPP-HMCNF, is the best model for solving this problem, outperforming k-nearest neighbours similarity-based and other machine learning models. We show that inhibitor information during training consistently improves predictive power, particularly for EPP-HMCNF. We also show that all promiscuity prediction models perform worse under a realistic data split when compared to a random data split, and when evaluating performance on non-natural substrates compared to natural substrates. AVAILABILITY AND IMPLEMENTATION: We provide Python code for EPP-HMCNF and other models in a repository termed EPP (Enzyme Promiscuity Prediction) at https://github.com/hassounlab/EPP. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

19.
AIDS Care ; : 1-10, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33487029

RESUMO

We evaluated health-related quality of life (QoL) and self-reported incomplete adherence as predictors of early second-line antiretroviral (ART) virological failure (VF). ACTG A5273 study participants completed the ACTG SF-21 measure which has 8 QoL domains. We used exact logistic regression to assess the association of QoL at baseline and week 4 with early VF adjusted for self-reported adherence. Of 500 individuals (51% women, median age 39 years) in this analysis, 79% and 75% self-reported complete adherence (no missing doses in the past month) at weeks 4 and 24, respectively. Early VF was experienced by 7% and more common among those who self-reported incomplete adherence. Participants with low week 4 QoL scores had higher rates of early VF than participants with high scores. After adjusting for self-reported adherence at week 4, VL and CD4 at baseline, cognitive functioning, pain and mental health domains were significantly associated with subsequent early VF. In this post-hoc analysis, poorer QoL adds to self-reported incomplete adherence after 4 weeks of second-line ART in predicting VF at week 24. Evaluation is needed to assess whether individuals with poorer QoL might be targeted for greater support to reduce risk of VF.Trial registration: ClinicalTrials.gov identifier: NCT01352715.

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