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Br J Ophthalmol ; 103(2): 157-160, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30196272


Patients with AIDS-related cytomegalovirus (CMV) retinitis receiving combined antiretroviral therapy (cART), but not specific anti-CMV therapy, consistently showed active retinitis for several months. Delayed diagnosis and treatment of CMV retinitis may have severe consequences. Patients first entering care with advanced HIV infection and vulnerability to reactivation of latent CMV infection should be screened immediately for CMV retinitis by dilated indirect ophthalmoscopy and treated with specific anti-CMV therapy without delay, in addition to cART.

Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Antivirais/uso terapêutico , Retinite por Citomegalovirus/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/imunologia , Adulto , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Estudos Transversais , Retinite por Citomegalovirus/tratamento farmacológico , Retinite por Citomegalovirus/imunologia , Feminino , Humanos , Masculino , Oftalmoscopia , Estudos Retrospectivos , Acuidade Visual/fisiologia
Lancet Glob Health ; 7(1): e119-e131, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30554748


BACKGROUND: In southeast Asia, antibiotic prescription in febrile patients attending primary care is common, and a probable contributor to the high burden of antimicrobial resistance. The objective of this trial was to explore whether C-reactive protein (CRP) testing at point of care could rationalise antibiotic prescription in primary care, comparing two proposed thresholds to classify CRP concentrations as low or high to guide antibiotic treatment. METHODS: We did a multicentre, open-label, randomised, controlled trial in participants aged at least 1 year with a documented fever or a chief complaint of fever (regardless of previous antibiotic intake and comorbidities other than malignancies) recruited from six public primary care units in Thailand and three primary care clinics and one outpatient department in Myanmar. Individuals were randomly assigned using a computer-based randomisation system at a ratio of 1:1:1 to either the control group or one of two CRP testing groups, which used thresholds of 20 mg/L (group A) or 40 mg/L CRP (group B) to guide antibiotic prescription. Health-care providers were masked to allocation between the two intervention groups but not to the control group. The primary outcome was the prescription of any antibiotic from day 0 to day 5 and the proportion of patients who were prescribed an antibiotic when CRP concentrations were above and below the 20 mg/L or 40 mg/L thresholds. The primary outcome was analysed in the intention-to-treat and per-protocol populations. The trial is registered with, number NCT02758821, and is now completed. FINDINGS: Between June 8, 2016, and Aug 25, 2017, we recruited 2410 patients, of whom 803 patients were randomly assigned to CRP group A, 800 to CRP group B, and 807 to the control group. 598 patients in CRP group A, 593 in CRP group B, and 767 in the control group had follow-up data for both day 5 and day 14 and had been prescribed antibiotics (or not) in accordance with test results (per-protocol population). During the trial, 318 (39%) of 807 patients in the control group were prescribed an antibiotic by day 5, compared with 290 (36%) of 803 patients in CRP group A and 275 (34%) of 800 in CRP group B. The adjusted odds ratio (aOR) of 0·80 (95% CI 0·65-0·98) and risk difference of -5·0 percentage points (95% CI -9·7 to -0·3) between group B and the control group were significant, although lower than anticipated, whereas the reduction in prescribing in group A compared with the control group was not significant (aOR 0·86 [0·70-1·06]; risk difference -3·3 percentage points [-8·0 to 1·4]). Patients with high CRP concentrations in both intervention groups were more likely to be prescribed an antibiotic than in the control group (CRP ≥20 mg/L: group A vs control group, p<0·0001; CRP ≥40 mg/L: group B vs control group, p<0·0001), and those with low CRP concentrations were more likely to have an antibiotic withheld (CRP <20 mg/L: group A vs control group, p<0·0001; CRP <40 mg/L: group B vs control group, p<0·0001). 24 serious adverse events were recorded, consisting of 23 hospital admissions and one death, which occurred in CRP group A. Only one serious adverse event was thought to be possibly related to the study (a hospital admission in CRP group A). INTERPRETATION: In febrile patients attending primary care, testing for CRP at point of care with a threshold of 40 mg/L resulted in a modest but significant reduction in antibiotic prescribing, with patients with high CRP being more likely to be prescribed an antibiotic, and no evidence of a difference in clinical outcomes. This study extends the evidence base from lower-income settings supporting the use of CRP tests to rationalise antibiotic use in primary care patients with an acute febrile illness. A key limitation of this study is the individual rather than cluster randomised study design which might have resulted in contamination between the study groups, reducing the effect size of the intervention. FUNDING: Wellcome Trust Institutional Strategic Support Fund grant (105605/Z/14/Z) and Foundation for Innovative New Diagnostics (FIND) funding from the Australian Government.

Antibacterianos/uso terapêutico , Proteína C-Reativa/análise , Febre/tratamento farmacológico , Testes Imediatos , Prescrições/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mianmar , Tailândia , Adulto Jovem
BMJ Open ; 8(4): e020841, 2018 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-29705765


INTRODUCTION: Current evidence on epidemiology and outcomes of invasively mechanically ventilated intensive care unit (ICU) patients is predominantly gathered in resource-rich settings. Patient casemix and patterns of critical illnesses, and probably also ventilation practices are likely to be different in resource-limited settings. We aim to investigate the epidemiological characteristics, ventilation practices and clinical outcomes of patients receiving mechanical ventilation in ICUs in Asia. METHODS AND ANALYSIS: PRoVENT-iMIC (study of PRactice of VENTilation in Middle-Income Countries) is an international multicentre observational study to be undertaken in approximately 60 ICUs in 11 Asian countries. Consecutive patients aged 18 years or older who are receiving invasive ventilation in participating ICUs during a predefined 28-day period are to be enrolled, with a daily follow-up of 7 days. The primary outcome is ventilatory management (including tidal volume expressed as mL/kg predicted body weight and positive end-expiratory pressure expressed as cm H2O) during the first 3 days of mechanical ventilation-compared between patients at no risk for acute respiratory distress syndrome (ARDS), patients at risk for ARDS and in patients with ARDS (in case the diagnosis of ARDS can be made on admission). Secondary outcomes include occurrence of pulmonary complications and all-cause ICU mortality. ETHICS AND DISSEMINATION: PRoVENT-iMIC will be the first international study that prospectively assesses ventilation practices, outcomes and epidemiology of invasively ventilated patients in ICUs in Asia. The results of this large study, to be disseminated through conference presentations and publications in international peer-reviewed journals, are of ultimate importance when designing trials of invasive ventilation in resource-limited ICUs. Access to source data will be made available through national or international anonymised datasets on request and after agreement of the PRoVENT-iMIC steering committee. TRIAL REGISTRATION NUMBER: NCT03188770; Pre-results.

Unidades de Terapia Intensiva , Adolescente , Adulto , Ásia , Países em Desenvolvimento , Humanos , Estudos Multicêntricos como Assunto , Estudos Observacionais como Assunto , Estudos Prospectivos , Síndrome do Desconforto Respiratório do Adulto , Resultado do Tratamento
Bull World Health Organ ; 92(12): 903-8, 2014 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-25552774


PROBLEM: Acquired immunodeficiency syndrome (AIDS)-related cytomegalovirus (CMV) retinitis continues to be a neglected source of blindness in resource-poor settings. The main issue is lack of capacity to diagnose CMV retinitis in the clinical setting where patients receive care and all other opportunistic infections are diagnosed. APPROACH: We developed and implemented a four-day workshop to train clinicians working in human immunodeficiency virus (HIV) clinics how to perform binocular indirect ophthalmoscopy and diagnose CMV retinitis. Workshops comprised both classroom didactic instruction and direct clinical eye examinations in patients with advanced AIDS. Between 2007 and 2013, 14 workshops were conducted in China, Myanmar and the Russian Federation. LOCAL SETTING: Workshops were held with local clinicians at HIV clinics supported by nongovernmental organizations, public-sector municipal hospitals and provincial infectious disease referral hospitals. Each setting had limited or no access to locally- trained ophthalmologists, and an HIV-infected population with advanced disease. RELEVANT CHANGES: Clinicians learnt how to do binocular indirect ophthalmoscopy and to diagnose CMV retinitis. One year after the workshop, 32/38 trainees in Myanmar did systematic eye examination for early diagnosis of CMV retinitis as standard care for at-risk patients. In China and the Russian Federation, the success rates were lower, with 10/15 and 3/5 trainees, respectively, providing follow-up data. LESSONS LEARNT: Skills necessary for screening and diagnosis of CMV retinitis can be taught in a four-day task-oriented training workshop. Successful implementation depends on institutional support, ongoing training and technical support. The next challenge is to scale up this approach in other countries.

Retinite por Citomegalovirus/diagnóstico , Oftalmologia/educação , Oftalmologia/métodos , Oftalmoscopia/métodos , Infecções Oportunistas Relacionadas com a AIDS/complicações , China , Competência Clínica , Retinite por Citomegalovirus/complicações , Educação Médica Continuada/métodos , Infecções por HIV/complicações , Humanos , Mianmar , Avaliação de Programas e Projetos de Saúde , Federação Russa , Testes Visuais/métodos
New Phytol ; 178(3): 515-31, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18298431


* Here, cytokinin-induced nitric oxide (NO) biosynthesis and cytokinin responses were investigated in Arabidopsis thaliana wild type and mutants defective in NO biosynthesis or cytokinin signaling components. * NO release from seedlings was quantified by a fluorometric method and, by microscopy, observed NO biosynthesis as fluorescence increase of DAR-4M AM (diaminorhodamine 4M acetoxymethyl ester) in different tissues. * Atnoa1 seedlings were indistinguishable in NO tissue distribution pattern and morphological responses, induced by zeatin, from wild-type seedlings. Wild-type and nia1,2 seedlings, lacking nitrate reductase (NR), responded to zeatin with an increase within 3 min in NO biosynthesis so that NR does not seem relevant for rapid NO induction, which was mediated by an unknown 2-(2-aminoethyl)2-thiopseudourea (AET)-sensitive enzyme and was quenched by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-1-oxy-3-oxide (PTIO). Long-term morphological responses to zeatin were severely altered and NO biosynthesis was increased in nia1,2 seedlings. As cytokinin signaling mutants we used the single-receptor knockout cre1/ahk4, three double-receptor knockouts (ahk2,3, ahk2,4, ahk3,4) and triple-knockout ahp1,2,3 plants. All cytokinin-signaling mutants showed aberrant tissue patterns of NO accumulation in response to zeatin and altered morphological responses to zeatin. * Because aberrant NO biosynthesis correlated with aberrant morphological responses to zeatin the hypothesis was put forward that NO is an intermediate in cytokinin signaling.

Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Óxido Nítrico/biossíntese , Transdução de Sinais/genética , Zeatina/farmacologia , Arabidopsis/citologia , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Óxidos N-Cíclicos/farmacologia , Relação Dose-Resposta a Droga , Imidazóis/farmacologia , Mutação , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Folhas de Planta/metabolismo , Raízes de Plantas/metabolismo , Plântula
Plant Cell Physiol ; 47(3): 346-54, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16415068


In this study, we examined the regulation by putrescine, spermidine and spermine of nitric oxide (NO) biosynthesis in Arabidopsis thaliana seedlings. Using a fluorimetric method employing the cell-impermeable NO-binding dye diaminorhodamine-4M (DAR-4M), we observed that the polyamines (PAs) spermidine and spermine greatly increased NO release in the seedlings, whereas arginine and putrescine had little or no effect. Spermine, the most active PA, stimulated NO release with no apparent lag phase. The response was quenched by addition of 2-aminoethyl-2-thiopseudourea (AET), an inhibitor of the animal nitric oxide synthase (NOS) and plant NO biosynthesis, and by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-1-oxy-3-oxide (PTIO), an NO scavenger. By fluorescence microscopy, using the cell-permeable NO-binding dye diaminorhodamine-4M acetoxymethyl ester (DAR-4M AM), we observed that PAs induced NO biosynthesis in specific tissues in Arabidopsis seedlings. Spermine and spermidine increased NO biosynthesis in the elongation zone of the Arabidopsis root tip and in primary leaves, especially in the veins and trichomes, while in cotyledons little or no effect of PAs beyond the endogenous levels of NO-induced fluorescence was observed. We conclude that PAs induce NO biosynthesis in plants.

Arabidopsis/efeitos dos fármacos , Arabidopsis/metabolismo , Óxido Nítrico/biossíntese , Poliaminas/farmacologia , Plântula/efeitos dos fármacos , Plântula/metabolismo , Arginina/farmacologia , Óxidos N-Cíclicos/farmacologia , Fluorescência , Imidazóis/farmacologia , Microscopia de Fluorescência , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Folhas de Planta/citologia , Folhas de Planta/efeitos dos fármacos , Putrescina/farmacologia , Rodaminas/farmacologia , Espermina/farmacologia , beta-Aminoetil Isotioureia/farmacologia