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1.
PLoS One ; 17(1): e0260733, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35061702

RESUMO

BACKGROUND: COVID-19 is rapidly spreading causing extensive burdens across the world. Effective vaccines to prevent COVID-19 are urgently needed. METHODS AND FINDINGS: Our objective was to assess the effectiveness and safety of COVID-19 vaccines through analyses of all currently available randomized clinical trials. We searched the databases CENTRAL, MEDLINE, Embase, and other sources from inception to June 17, 2021 for randomized clinical trials assessing vaccines for COVID-19. At least two independent reviewers screened studies, extracted data, and assessed risks of bias. We conducted meta-analyses, network meta-analyses, and Trial Sequential Analyses (TSA). Our primary outcomes included all-cause mortality, vaccine efficacy, and serious adverse events. We assessed the certainty of evidence with GRADE. We identified 46 trials; 35 trials randomizing 219 864 participants could be included in our analyses. Our meta-analyses showed that mRNA vaccines (efficacy, 95% [95% confidence interval (CI), 92% to 97%]; 71 514 participants; 3 trials; moderate certainty); inactivated vaccines (efficacy, 61% [95% CI, 52% to 68%]; 48 029 participants; 3 trials; moderate certainty); protein subunit vaccines (efficacy, 77% [95% CI, -5% to 95%]; 17 737 participants; 2 trials; low certainty); and viral vector vaccines (efficacy 68% [95% CI, 61% to 74%]; 71 401 participants; 5 trials; low certainty) prevented COVID-19. Viral vector vaccines decreased mortality (risk ratio, 0.25 [95% CI 0.09 to 0.67]; 67 563 participants; 3 trials, low certainty), but comparable data on inactivated, mRNA, and protein subunit vaccines were imprecise. None of the vaccines showed evidence of a difference on serious adverse events, but observational evidence suggested rare serious adverse events. All the vaccines increased the risk of non-serious adverse events. CONCLUSIONS: The evidence suggests that all the included vaccines are effective in preventing COVID-19. The mRNA vaccines seem most effective in preventing COVID-19, but viral vector vaccines seem most effective in reducing mortality. Further trials and longer follow-up are necessary to provide better insight into the safety profile of these vaccines.

2.
Front Psychol ; 12: 762772, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790154

RESUMO

The current study empirically tests a financial well-being (FWB) model built on financial socialization (FS) and early childhood consumer experience (ECCE). The current study was conducted based on primary data obtained through structured questionnaires. By using a convenient sampling technique, data were collected from 1,500 respondents from Pakistan. Results advocated that childhood experiences directly affect the FWB in adults. In addition, FS agents, such as parents, have direct and indirect effects on the FWB in adults. Findings revealed that financial coping behaviors mediate the relationship among FS agents, such as parents, students, and the FWB. Surprisingly, FS agent peers do not impact adult FWBs. The study concluded that FWB could be improved by socializing with parents and teachers and using childhood experiences. Considering the importance of the role of parents and teachers, they should discuss financial issues with children. Policymakers should work to provide some opportunities for children so that they can practice and gain experience.

3.
Syst Rev ; 10(1): 227, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389045

RESUMO

BACKGROUND: Major depressive disorder is a common psychiatric disorder causing great burden on patients and societies. Tricyclic antidepressants are frequently used worldwide to treat patients with major depressive disorder. It has repeatedly been shown that tricyclic antidepressants reduce depressive symptoms with a statistically significant effect, but the effect is small and of questionable clinical importance. Moreover, the beneficial and harmful effects of all types of tricyclic antidepressants have not previously been systematically assessed. Therefore, we aim to investigate the beneficial and harmful effects of tricyclic antidepressants versus 'active placebo', placebo or no intervention for adults with major depressive disorder. METHODS: This is a protocol for a systematic review with meta-analysis that will be reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols, bias will be assessed with the Cochrane Risk of Bias tool-version 2, our eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, Trial Sequential Analysis will be conducted to control random errors and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. To identify relevant trials, we will search both for published and unpublished trials in major medical databases and trial registers, such as CENTRAL, MEDLINE, EMBASE and ClinicalTrials.gov from their inception to 12 May 2021. Clinical study reports will be applied for from regulatory authorities and pharmaceutical companies. Two review authors will independently screen the results from the literature searches, extract data and perform risk of bias assessment. We will include any published or unpublished randomised clinical trial comparing tricyclic antidepressants with 'active placebo', placebo or no intervention for adults with major depressive disorder. The following interventions will be assessed: amineptine, amitriptyline, amoxapine, butriptyline, cianopramine, clomipramine, desipramine, demexiptiline, dibenzepin, dosulepin, dothiepin, doxepin, imipramine, iprindole, lofepramine, maprotiline, melitracen, metapramine, nortriptyline, noxiptiline, opipramol, protriptyline, tianeptine, trimipramine and quinupramine. Primary outcomes will be depressive symptoms, serious adverse events and quality of life. Secondary outcomes will be suicide or suicide-attempts and non-serious adverse events. If feasible, we will assess the intervention effects using random-effects and fixed-effect meta-analyses. DISCUSSION: Tricyclic antidepressants are recommended by clinical guidelines and frequently used worldwide in the treatment of major depressive disorder. There is a need for a thorough systematic review to provide the necessary background for weighing the benefits against the harms. This review will ultimately inform best practice in the treatment of major depressive disorder. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021226161 .


Assuntos
Transtorno Depressivo Maior , Adulto , Antidepressivos Tricíclicos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Metanálise como Assunto , Qualidade de Vida , Literatura de Revisão como Assunto
4.
Syst Rev ; 10(1): 171, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108032

RESUMO

BACKGROUND: Major depression significantly impairs quality of life, increases the risk of suicide, and poses tremendous economic burden on individuals and societies. Duloxetine, a serotonin norepinephrine reuptake inhibitor, is a widely prescribed antidepressant. The effects of duloxetine have, however, not been sufficiently assessed in earlier systematic reviews and meta-analyses. METHODS/DESIGN: A systematic review will be performed including randomised clinical trials comparing duloxetine with 'active' placebo, placebo or no intervention for adults with major depressive disorder. Bias domains will be assessed, an eight-step procedure will be used to assess if the thresholds for clinical significance are crossed. We will conduct meta-analyses. Trial sequential analysis will be conducted to control random errors, and the certainty of the evidence will be assessed using GRADE. To identify relevant trials, we will search Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, PsycINFO, Science Citation Index Expanded, Social Sciences Citation Index, Conference Proceedings Citation Index-Science and Conference Proceedings Citation Index-Social Science & Humanities. We will also search Chinese databases and Google Scholar. We will search all databases from their inception to the present. Two review authors will independently extract data and perform risk of bias assessment. Primary outcomes will be the difference in mean depression scores on Hamilton Depression Rating Scale between the intervention and control groups and serious adverse events. Secondary outcomes will be suicide, suicide-attempts, suicidal ideation, quality of life and non-serious adverse events. DISCUSSION: No former systematic review has systematically assessed the beneficial and harmful effects of duloxetine taking into account both the risks of random errors and the risks of systematic errors. Our review will help clinicians weigh the benefits of prescribing duloxetine against its adverse effects and make informed decisions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2016 CRD42016053931.


Assuntos
Transtorno Depressivo Maior , Adulto , Antidepressivos/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Cloridrato de Duloxetina/uso terapêutico , Humanos , Metanálise como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Ideação Suicida , Revisões Sistemáticas como Assunto
5.
Int J Parasitol Drugs Drug Resist ; 16: 102-118, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34090067

RESUMO

Emergence and spread of resistance in Plasmodium falciparum to the frontline treatment artemisinin-based combination therapies (ACTs) in the epicenter of multidrug resistance of Southeast Asia threaten global malaria control and elimination. Artemisinin (ART) resistance (or tolerance) is defined clinically as delayed parasite clearance after treatment with an ART drug. The resistance phenotype is restricted to the early ring stage and can be measured in vitro using a ring-stage survival assay. ART resistance is associated with mutations in the propeller domain of the Kelch family protein K13. As a pro-drug, ART is activated primarily by heme, which is mainly derived from hemoglobin digestion in the food vacuole. Activated ARTs can react promiscuously with a wide range of cellular targets, disrupting cellular protein homeostasis. Consistent with this mode of action for ARTs, the molecular mechanisms of K13-mediated ART resistance involve reduced hemoglobin uptake/digestion and increased cellular stress response. Mutations in other genes such as AP-2µ (adaptor protein-2 µ subunit), UBP-1 (ubiquitin-binding protein-1), and Falcipain 2a that interfere with hemoglobin uptake and digestion also increase resistance to ARTs. ART resistance has facilitated the development of resistance to the partner drugs, resulting in rapidly declining ACT efficacies. The molecular markers for resistance to the partner drugs are mostly associated with point mutations in the two food vacuole membrane transporters PfCRT and PfMDR1, and amplification of pfmdr1 and the two aspartic protease genes plasmepsin 2 and 3. It has been observed that mutations in these genes can have opposing effects on sensitivities to different partner drugs, which serve as the principle for designing triple ACTs and drug rotation. Although clinical ACT resistance is restricted to Southeast Asia, surveillance for drug resistance using in vivo clinical efficacy, in vitro assays, and molecular approaches is required to prevent or slow down the spread of resistant parasites.


Assuntos
Antimaláricos , Malária Falciparum , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Resistência a Medicamentos/genética , Humanos , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/genética , Proteínas de Protozoários/genética
6.
Syst Rev ; 10(1): 154, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34034811

RESUMO

BACKGROUND: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide. Antidepressants are frequently used to treat major depressive disorder. It has been shown repeatedly that antidepressants seem to reduce depressive symptoms with a statistically significant effect, but the clinical importance of the effect sizes seems questionable. Both beneficial and harmful effects of antidepressants have not previously been sufficiently assessed. The main objective of this review will be to evaluate the beneficial and harmful effects of antidepressants versus placebo, 'active placebo', or no intervention for adults with major depressive disorder. METHODS/DESIGN: A systematic review with meta-analysis will be reported as recommended by Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), bias will be assessed with the Cochrane Risk of Bias tool-version 2 (ROB2), our eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, Trial Sequential Analysis will be conducted to control for random errors, and the certainty of the evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. To identify relevant trials, we will search both for published and unpublished trials in major medical databases from their inception to the present. Clinical study reports will be obtained from regulatory authorities and pharmaceutical companies. Two review authors will independently screen the results of the literature searches, extract data, and perform risk of bias assessment. We will include any published or unpublished randomised clinical trial comparing one or more antidepressants with placebo, 'active placebo', or no intervention for adults with major depressive disorder. The following active agents will be included: agomelatine, amineptine, amitriptyline, bupropion, butriptyline, cianopramine, citalopram, clomipramine, dapoxetine, demexiptiline, desipramine, desvenlafaxine, dibenzepin, dosulepin, dothiepin, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, iprindole, levomilnacipran, lofepramine, maprotiline, melitracen, metapramine, milnacipran, mirtazapine, nefazodone, nortriptyline, noxiptiline, opipramol, paroxetine, protriptyline, quinupramine, reboxetine, sertraline, trazodone, tianeptine, trimipramine, venlafaxine, vilazodone, and vortioxetine. Primary outcomes will be depressive symptoms, serious adverse events, and quality of life. Secondary outcomes will be suicide or suicide attempt, suicidal ideation, and non-serious adverse events. DISCUSSION: As antidepressants are commonly used to treat major depressive disorder in adults, a systematic review evaluating their beneficial and harmful effects is urgently needed. This review will inform best practice in treatment and clinical research of this highly prevalent and burdensome disorder. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020220279.


Assuntos
Transtorno Depressivo Maior , Adulto , Antidepressivos/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Metanálise como Assunto , Qualidade de Vida , Revisões Sistemáticas como Assunto , Vortioxetina/uso terapêutico
7.
PLoS One ; 16(3): e0248132, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33705495

RESUMO

BACKGROUND: COVID-19 is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. This is the second edition of a living systematic review of randomized clinical trials assessing the effects of all treatment interventions for participants in all age groups with COVID-19. METHODS AND FINDINGS: We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review was based on PRISMA and Cochrane guidelines, and our eight-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. According to the number of outcome comparisons, we adjusted our threshold for significance to p = 0.033. We used GRADE to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until November 2, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 82 randomized clinical trials enrolling a total of 40,249 participants. 81 out of 82 trials were at overall high risk of bias. Meta-analyses showed no evidence of a difference between corticosteroids versus control on all-cause mortality (risk ratio [RR] 0.89; 95% confidence interval [CI] 0.79 to 1.00; p = 0.05; I2 = 23.1%; eight trials; very low certainty), on serious adverse events (RR 0.89; 95% CI 0.80 to 0.99; p = 0.04; I2 = 39.1%; eight trials; very low certainty), and on mechanical ventilation (RR 0.86; 95% CI 0.55 to 1.33; p = 0.49; I2 = 55.3%; two trials; very low certainty). The fixed-effect meta-analyses showed indications of beneficial effects. Trial sequential analyses showed that the required information size for all three analyses was not reached. Meta-analysis (RR 0.93; 95% CI 0.82 to 1.07; p = 0.31; I2 = 0%; four trials; moderate certainty) and trial sequential analysis (boundary for futility crossed) showed that we could reject that remdesivir versus control reduced the risk of death by 20%. Meta-analysis (RR 0.82; 95% CI 0.68 to 1.00; p = 0.05; I2 = 38.9%; four trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of difference between remdesivir versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of remdesivir on serious adverse events. Meta-analysis (RR 0.40; 95% CI 0.19 to 0.87; p = 0.02; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of intravenous immunoglobulin versus control on all-cause mortality, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analysis (RR 0.63; 95% CI 0.35 to 1.14; p = 0.12; I2 = 77.4%; five trials; very low certainty) and trial sequential analysis (required information size not reached) showed no evidence of a difference between tocilizumab versus control on serious adverse events. Fixed-effect meta-analysis showed indications of a beneficial effect of tocilizumab on serious adverse events. Meta-analysis (RR 0.70; 95% CI 0.51 to 0.96; p = 0.02; I2 = 0%; three trials; very low certainty) showed evidence of a beneficial effect of tocilizumab versus control on mechanical ventilation, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm of reject realistic intervention effects. Meta-analysis (RR 0.32; 95% CI 0.15 to 0.69; p < 0.00; I2 = 0%; two trials; very low certainty) showed evidence of a beneficial effect of bromhexine versus standard care on non-serious adverse events, but trial sequential analysis (required information size not reached) showed that the result was severely underpowered to confirm or reject realistic intervention effects. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that hydroxychloroquine versus control reduced the risk of death and serious adverse events by 20%. Meta-analyses and trial sequential analyses (boundary for futility crossed) showed that we could reject that lopinavir-ritonavir versus control reduced the risk of death, serious adverse events, and mechanical ventilation by 20%. All remaining outcome comparisons showed that we did not have enough information to confirm or reject realistic intervention effects. Nine single trials showed statistically significant results on our outcomes, but were underpowered to confirm or reject realistic intervention effects. Due to lack of data, it was not relevant to perform network meta-analysis or possible to perform individual patient data meta-analyses. CONCLUSIONS: No evidence-based treatment for COVID-19 currently exists. Very low certainty evidence indicates that corticosteroids might reduce the risk of death, serious adverse events, and mechanical ventilation; that remdesivir might reduce the risk of serious adverse events; that intravenous immunoglobin might reduce the risk of death and serious adverse events; that tocilizumab might reduce the risk of serious adverse events and mechanical ventilation; and that bromhexine might reduce the risk of non-serious adverse events. More trials with low risks of bias and random errors are urgently needed. This review will continuously inform best practice in treatment and clinical research of COVID-19. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020178787.


Assuntos
COVID-19/terapia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Corticosteroides/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Bromoexina/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/mortalidade , Ensaios Clínicos como Assunto , Expectorantes/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Respiração Artificial , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/isolamento & purificação , Resultado do Tratamento
8.
Artigo em Inglês | MEDLINE | ID: mdl-33685900

RESUMO

Plasmodium falciparum from the Greater Mekong subregion has evolved resistance to the artemisinin-based combination therapy dihydroartemisinin and the partner drug piperaquine. To monitor the potential westward spread or independent evolution of piperaquine resistance, we evaluated the in vitro susceptibility of 120 P. falciparum isolates collected at the China-Myanmar border during 2007-2016. The parasite isolates displayed a relatively wide range of piperaquine susceptibility estimates. While 56.7% of the parasites showed bimodal drug response curves, all but five generated area-under-the-curve (AUC) estimates consistent with a susceptible phenotype. Using the piperaquine survival assay (PSA), 5.6% parasites showed reduced susceptibility. Of note, parasites from 2014-2016 showed the highest AUC value and the highest proportion with a bimodal curve, suggesting falling effectiveness in these later years. Unsupervised K-mean analysis of the combined data assigned parasites into three clusters and identified significant correlations between IC50, IC90, and AUC values. No parasites carried the E415G mutation in a putative exo-nuclease, new mutations in PfCRT, or amplification of the plasmepsin 2/3 genes, suggesting mechanisms of reduced piperaquine susceptibility that differ from those described in other countries of the region. The association of increased AUC, IC50, and IC90 values with major PfK13 mutations (F446I and G533S) suggests that piperaquine resistance may evolve in these PfK13 genetic backgrounds. Additionally, the Pfmdr1 F1226Y mutation was associated with significantly higher PSA values. Further elucidation of piperaquine resistance mechanisms and continuous surveillance are warranted.

9.
Syst Rev ; 9(1): 262, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33218366

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) which has rapidly spread worldwide. Several human randomized clinical trials assessing potential vaccines are currently underway. There is an urgent need for a living systematic review that continuously assesses the beneficial and harmful effects of all available vaccines for COVID-19. METHODS/DESIGN: We will conduct a living systematic review based on searches of major medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify relevant randomized clinical trials. We will update the literature search once a week to continuously assess if new evidence is available. Two review authors will independently extract data and conduct risk of bias assessments. We will include randomized clinical trials comparing any vaccine aiming to prevent COVID-19 (including but not limited to messenger RNA; DNA; non-replicating viral vector; replicating viral vector; inactivated virus; protein subunit; dendritic cell; other vaccines) with any comparator (placebo; "active placebo;" no intervention; standard care; an "active" intervention; another vaccine for COVID-19) for participants in all age groups. Primary outcomes will be all-cause mortality; a diagnosis of COVID-19; and serious adverse events. Secondary outcomes will be quality of life and non-serious adverse events. The living systematic review will include aggregate data meta-analyses, trial sequential analyses, network meta-analyses, and individual patient data meta-analyses. Within-study bias will be assessed using Cochrane risk of bias tool. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) and Confidence in Network Meta-Analysis (CINeMA) approaches will be used to assess certainty of evidence. Observational studies describing harms identified during the search for trials will also be included and described and analyzed separately. DISCUSSION: COVID-19 has become a pandemic with substantial mortality. A living systematic review assessing the beneficial and harmful effects of different vaccines is urgently needed. This living systematic review will regularly inform best practice in vaccine prevention and clinical research of this highly prevalent disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020196492.


Assuntos
Vacinas contra COVID-19 , COVID-19/prevenção & controle , COVID-19/mortalidade , COVID-19/virologia , Vacinas contra COVID-19/efeitos adversos , Humanos , Metanálise como Assunto , Metanálise em Rede , Pandemias , Qualidade de Vida , Projetos de Pesquisa , SARS-CoV-2 , Revisões Sistemáticas como Assunto , Resultado do Tratamento
10.
Saudi Med J ; 41(9): 938-946, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32893275

RESUMO

OBJECTIVES: To find reference data for the time of appearance of ossification centers in carpal bones and the lower ends of the radius and ulna in the Saudi population. In addition, to check the sequence of appearance of carpal bones and the relation of this sequence to the appearance of distal epiphyses of the radius and ulna. Methods: A retrospective radiological study was carried out between 2012 to 2020 at King Fahad Hospital of the University, Al-Khobar, Saudi Arabia. A sample of 279 hand/wrist plain radiographs of Saudi children was analyzed. RESULTS: The first bones at the wrist region to appear in Saudi children are the capitate, hamate, and distal epiphysis of the radius, and these appear during the first year of life. The other bones develop subsequently at yearly intervals, and the last one to appear is the pisiform, which arises at the end of the first decade of life. CONCLUSION: The sequence of appearance of carpal bones in the Saudi population is similar to what is described in the literature. However, the time of appearance of some of these bones is earlier than that in other populations.


Assuntos
Desenvolvimento Ósseo/fisiologia , Ossos do Carpo/diagnóstico por imagem , Ossos do Carpo/fisiologia , Osteogênese , Adolescente , Ossos do Carpo/anatomia & histologia , Criança , Pré-Escolar , Epífises , Feminino , Humanos , Lactente , Masculino , Rádio (Anatomia)/anatomia & histologia , Rádio (Anatomia)/diagnóstico por imagem , Estudos Retrospectivos , Arábia Saudita , Caracteres Sexuais , Ulna/anatomia & histologia , Ulna/diagnóstico por imagem
11.
PLoS Med ; 17(9): e1003293, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32941437

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. METHODS AND FINDINGS: This is the first edition of a living systematic review of randomized clinical trials comparing the effects of all treatment interventions for participants in all age groups with COVID-19. We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review is based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Cochrane guidelines, and our 8-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and nonserious adverse events. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until August 7, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 33 randomized clinical trials enrolling a total of 13,312 participants. All trials were at overall high risk of bias. We identified one trial randomizing 6,425 participants to dexamethasone versus standard care. This trial showed evidence of a beneficial effect of dexamethasone on all-cause mortality (rate ratio 0.83; 95% confidence interval [CI] 0.75-0.93; p < 0.001; low certainty) and on mechanical ventilation (risk ratio [RR] 0.77; 95% CI 0.62-0.95; p = 0.021; low certainty). It was possible to perform meta-analysis of 10 comparisons. Meta-analysis showed no evidence of a difference between remdesivir versus placebo on all-cause mortality (RR 0.74; 95% CI 0.40-1.37; p = 0.34, I2 = 58%; 2 trials; very low certainty) or nonserious adverse events (RR 0.94; 95% CI 0.80-1.11; p = 0.48, I2 = 29%; 2 trials; low certainty). Meta-analysis showed evidence of a beneficial effect of remdesivir versus placebo on serious adverse events (RR 0.77; 95% CI 0.63-0.94; p = 0.009, I2 = 0%; 2 trials; very low certainty) mainly driven by respiratory failure in one trial. Meta-analyses and trial sequential analyses showed that we could exclude the possibility that hydroxychloroquine versus standard care reduced the risk of all-cause mortality (RR 1.07; 95% CI 0.97-1.19; p = 0.17; I2 = 0%; 7 trials; low certainty) and serious adverse events (RR 1.07; 95% CI 0.96-1.18; p = 0.21; I2 = 0%; 7 trials; low certainty) by 20% or more, and meta-analysis showed evidence of a harmful effect on nonserious adverse events (RR 2.40; 95% CI 2.01-2.87; p < 0.00001; I2 = 90%; 6 trials; very low certainty). Meta-analysis showed no evidence of a difference between lopinavir-ritonavir versus standard care on serious adverse events (RR 0.64; 95% CI 0.39-1.04; p = 0.07, I2 = 0%; 2 trials; very low certainty) or nonserious adverse events (RR 1.14; 95% CI 0.85-1.53; p = 0.38, I2 = 75%; 2 trials; very low certainty). Meta-analysis showed no evidence of a difference between convalescent plasma versus standard care on all-cause mortality (RR 0.60; 95% CI 0.33-1.10; p = 0.10, I2 = 0%; 2 trials; very low certainty). Five single trials showed statistically significant results but were underpowered to confirm or reject realistic intervention effects. None of the remaining trials showed evidence of a difference on our predefined outcomes. Because of the lack of relevant data, it was not possible to perform other meta-analyses, network meta-analysis, or individual patient data meta-analyses. The main limitation of this living review is the paucity of data currently available. Furthermore, the included trials were all at risks of systematic errors and random errors. CONCLUSIONS: Our results show that dexamethasone and remdesivir might be beneficial for COVID-19 patients, but the certainty of the evidence was low to very low, so more trials are needed. We can exclude the possibility of hydroxychloroquine versus standard care reducing the risk of death and serious adverse events by 20% or more. Otherwise, no evidence-based treatment for COVID-19 currently exists. This review will continuously inform best practice in treatment and clinical research of COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/terapia , Cuidados Críticos/métodos , Gerenciamento Clínico , Pandemias , Pneumonia Viral/terapia , Qualidade de Vida , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/psicologia , Hospitalização/tendências , Humanos , Pneumonia Viral/epidemiologia , Pneumonia Viral/psicologia , SARS-CoV-2
12.
PLoS Negl Trop Dis ; 14(6): e0008255, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32530913

RESUMO

BACKGROUND: Vivax malaria is an important public health problem in the Greater Mekong Subregion (GMS), including the China-Myanmar border. Previous studies have found that Plasmodium vivax has decreased sensitivity to antimalarial drugs in some areas of the GMS, but the sensitivity of P. vivax to antimalarial drugs is unclear in the China-Myanmar border. Here, we investigate the drug sensitivity profile and genetic variations for two drug resistance related genes in P. vivax isolates to provide baseline information for future drug studies in the China-Myanmar border. METHODOLOGY/PRINCIPAL FINDINGS: A total of 64 P. vivax clinical isolates collected from the China-Myanmar border area were assessed for ex vivo susceptibility to eight antimalarial drugs by the schizont maturation assay. The medians of IC50 (half-maximum inhibitory concentrations) for chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate, artemether, dihydroartemisinin were 84.2 nM, 34.9 nM, 4.0 nM, 22.3 nM, 41.4 nM, 2.8 nM, 2.1 nM and 2.0 nM, respectively. Twelve P. vivax clinical isolates were found over the cut-off IC50 value (220 nM) for chloroquine resistance. In addition, sequence polymorphisms in pvmdr1 (P. vivax multidrug resistance-1), pvcrt-o (P. vivax chloroquine resistance transporter-o), and difference in pvmdr1 copy number were studied. Sequencing of the pvmdr1 gene in 52 samples identified 12 amino acid substitutions, among which two (G698S and T958M) were fixed, M908L were present in 98.1% of the isolates, while Y976F and F1076L were present in 3.8% and 78.8% of the isolates, respectively. Amplification of the pvmdr1 gene was only detected in 4.8% of the samples. Sequencing of the pvcrt-o in 59 parasite isolates identified a single lysine insertion at position 10 in 32.2% of the isolates. The pvmdr1 M908L substitutions in pvmdr1 in our samples was associated with reduced sensitivity to chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate and dihydroartemisinin. CONCLUSIONS: Our findings depict a drug sensitivity profile and genetic variations of the P. vivax isolates from the China-Myanmar border area, and suggest possible emergence of chloroquine resistant P. vivax isolates in the region, which demands further efforts for resistance monitoring and mechanism studies.


Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos , Malária Vivax/parasitologia , Proteínas de Membrana Transportadoras/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium vivax/efeitos dos fármacos , Polimorfismo Genético , Proteínas de Protozoários/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , China , Feminino , Genótipo , Humanos , Lactente , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Mianmar , Testes de Sensibilidade Parasitária , Plasmodium vivax/isolamento & purificação , Análise de Sequência de DNA , Adulto Jovem
13.
mBio ; 11(1)2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32098812

RESUMO

Mutations in the Plasmodium falciparum Kelch 13 (PfK13) protein are associated with artemisinin resistance. PfK13 is essential for asexual erythrocytic development, but its function is not known. We tagged the PfK13 protein with green fluorescent protein in P. falciparum to study its expression and localization in asexual and sexual stages. We used a new antibody against PfK13 to show that the PfK13 protein is expressed ubiquitously in both asexual erythrocytic stages and gametocytes and is localized in punctate structures, partially overlapping an endoplasmic reticulum marker. We introduced into the 3D7 strain four PfK13 mutations (F446I, N458Y, C469Y, and F495L) identified in parasites from the China-Myanmar border area and characterized the in vitro artemisinin response phenotypes of the mutants. We found that all the parasites with the introduced PfK13 mutations showed higher survival rates in the ring-stage survival assay (RSA) than the wild-type (WT) control, but only parasites with N458Y displayed a significantly higher RSA value (26.3%) than the WT control. After these PfK13 mutations were reverted back to the WT in field parasite isolates, all revertant parasites except those with the C469Y mutation showed significantly lower RSA values than their respective parental isolates. Although the 3D7 parasites with introduced F446I, the predominant PfK13 mutation in northern Myanmar, did not show significantly higher RSA values than the WT, they had prolonged ring-stage development and showed very little fitness cost in in vitro culture competition assays. In comparison, parasites with the N458Y mutations also had a prolonged ring stage and showed upregulated resistance pathways in response to artemisinin, but this mutation produced a significant fitness cost, potentially leading to their lower prevalence in the Greater Mekong subregion.IMPORTANCE Artemisinin resistance has emerged in Southeast Asia, endangering the substantial progress in malaria elimination worldwide. It is associated with mutations in the PfK13 protein, but how PfK13 mediates artemisinin resistance is not completely understood. Here we used a new antibody against PfK13 to show that the PfK13 protein is expressed in all stages of the asexual intraerythrocytic cycle as well as in gametocytes and is partially localized in the endoplasmic reticulum. By introducing four PfK13 mutations into the 3D7 strain and reverting these mutations in field parasite isolates, we determined the impacts of these mutations identified in the parasite populations from northern Myanmar on the ring stage using the in vitro ring survival assay. The introduction of the N458Y mutation into the 3D7 background significantly increased the survival rates of the ring-stage parasites but at the cost of the reduced fitness of the parasites. Introduction of the F446I mutation, the most prevalent PfK13 mutation in northern Myanmar, did not result in a significant increase in ring-stage survival after exposure to dihydroartemisinin (DHA), but these parasites showed extended ring-stage development. Further, parasites with the F446I mutation showed only a marginal loss of fitness, partially explaining its high frequency in northern Myanmar. Conversely, reverting all these mutations, except for the C469Y mutation, back to their respective wild types reduced the ring-stage survival of these isolates in response to in vitro DHA treatment.


Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Resistência a Medicamentos/genética , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Ásia Sudeste , Resistência a Medicamentos/efeitos dos fármacos , Humanos , Malária Falciparum/parasitologia , Mutação , Organismos Geneticamente Modificados
14.
Parasit Vectors ; 13(1): 67, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051017

RESUMO

BACKGROUND: The malaria elimination plan of the Greater Mekong Subregion (GMS) is jeopardized by the increasing number of Plasmodium vivax infections and emergence of parasite strains with reduced susceptibility to the frontline drug treatment chloroquine/primaquine. This study aimed to determine the evolution of the P. vivax multidrug resistance 1 (Pvmdr1) gene in P. vivax parasites isolated from the China-Myanmar border area during the major phase of elimination. METHODS: Clinical isolates were collected from 275 P. vivax patients in 2008, 2012-2013 and 2015 in the China-Myanmar border area and from 55 patients in central China. Comparison was made with parasites from three border regions of Thailand. RESULTS: Overall, genetic diversity of the Pvmdr1 was relatively high in all border regions, and over the seven years in the China-Myanmar border, though slight temporal fluctuation was observed. Single nucleotide polymorphisms previously implicated in reduced chloroquine sensitivity were detected. In particular, M908L approached fixation in the China-Myanmar border area. The Y976F mutation sharply decreased from 18.5% in 2008 to 1.5% in 2012-2013 and disappeared in 2015, whereas F1076L steadily increased from 33.3% in 2008 to 77.8% in 2015. While neutrality tests suggested the action of purifying selection on the pvmdr1 gene, several likelihood-based algorithms detected positive as well as purifying selections operating on specific amino acids including M908L, T958M and F1076L. Fixation and selection of the nonsynonymous mutations are differently distributed across the three border regions and central China. Comparison with the global P. vivax populations clearly indicated clustering of haplotypes according to geographic locations. It is noteworthy that the temperate-zone parasites from central China were completely separated from the parasites from other parts of the GMS. CONCLUSIONS: This study showed that P. vivax populations in the China-Myanmar border has experienced major changes in the Pvmdr1 residues proposed to be associated with chloroquine resistance, suggesting that drug selection may play an important role in the evolution of this gene in the parasite populations.


Assuntos
Antimaláricos/farmacologia , Variação Genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium vivax/genética , Proteínas de Protozoários/genética , China , Cloroquina/farmacologia , Erradicação de Doenças , Evolução Molecular , Haplótipos , Humanos , Malária Vivax/epidemiologia , Malária Vivax/parasitologia , Mutação , Mianmar , Plasmodium vivax/efeitos dos fármacos , Análise de Sequência de DNA , Tailândia
15.
Cureus ; 11(10): e5923, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31857919

RESUMO

Introduction Tibial fractures with nonunion are frequently managed with Ilizarov external fixation. Living with an external frame has some psychological impact which is readily neglected from the literature. We conducted a study to evaluate the status of limb functionality in patients managed with the Ilizarov external ring fixator technique and assess their self-esteem while living with the frame. Materials and methods This is a prospective observational study conducted in the Orthopedic Department of Dr. Ruth KM Phau Civil Hospital, Karachi, Pakistan, from June 2018 to June 2019. A total of 26 patients consecutively managed with Ilizarov external fixation for infected nonunion, with unilateral tibial fractures, were included. To assess the postoperative functionality status, lower extremity functional scale (LEFS) was used. To assess and evaluate the impact of the external frame application on the self-esteem of these patients, Rosenberg's self-esteem (RSE) scale was used. For each patient, LEFS and RSE scales were administered at the time of hospital discharge, after six months of frame application, and at the time of removal of the frame. Results The mean duration of hospital stay was 4.11 ± 1.23 weeks. The mean LEFS scores increased by 47% from hospital discharge until the time of frame removal. The differences were highly significant (p < 0.001). There was a 12% decline in the mean score of self-esteem from the time of discharge till the time of removal of the Ilizarov frame and these differences were highly significant (p < 0.001). Conclusion Ilizarov technique improves the limb functionality status significantly in participants with a unilateral tibial fracture. However, it also reduces their self-esteem during the period of frame application. Psychological support is recommended for participants living with an external fixation frame to protect their self-esteem.

16.
Cureus ; 11(10): e5854, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31754588

RESUMO

Background Anemia is one of the most common conditions that affect pregnancies, with dietary iron deficiency being its most common cause. Maternal anemia has been associated with increased risks of both maternal and neonatal adverse outcomes. This study aimed to analyze the maternal and neonatal outcomes in women with third-trimester anemia. Methods This was a retrospective report from a Pakistani public hospital. It included data records of the childbirths in the hospital, with at least one record that documented the hemoglobin (Hb) level in women in the first or second trimester and one in the third trimester. The duration of the study was from January 1, 2019 to June 30, 2019. Women with Hb level of <10mg/dL in the third trimester were categorized as anemic, and those with Hb level of >10mg/dL were categorized as non-anemic. Pregnancy outcomes were assessed for both mothers and babies. All data were processed through SPSS version 21.0 for Windows (IBM Corp., Armonk, NY). Results The study evaluated 235 (37.8%) anemic and 387 (62.2%) non-anemic women. Adverse maternal outcomes were compared between the two groups. In anemic women, gestational hypertension (56% vs. 27%; p: <0.0001), preeclampsia (65% vs. 25%; p: <0.0001), antepartum hemorrhage (32% vs. 19%; p: =0.0001), postpartum hemorrhage (79% vs. 28%; p: <0.0001), transfusions (94% vs. 5%; p: <0.0001), prolonged/obstructed labor (49% vs. 20%; p: <0.000), urgent induction of labor (24% vs. 2%; p: <0.0001), and urgent caesarean section (CS) (45% vs. 29%; p: 0.0001) were significantly more common as compared to non-anemic women. Adverse neonatal outcomes such as low birth weight (LBW) (59% vs. 29%; p: <0.0001), small-for-gestational-age (SGA) (73% vs. 23%; p: <0.0001), preterm delivery (39% vs. 15%; p: <0.0001), stillbirth (8% vs. 3%; p: 0.01), and early neonatal death (9% vs. 2%; p: 0.000) were associated more with anemia. There was no report of maternal mortality in either group. Conclusion: Anemia in the third trimester of pregnancy is associated with adverse maternal and neonatal outcomes including neonatal death. Efforts are required to ensure adequate maternal nutritional status in order to prevent poor outcomes.

17.
PLoS Negl Trop Dis ; 13(11): e0007850, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31730621

RESUMO

Plasmodium ovale accounts for a disproportionate number of travel-related malaria cases. This parasite is understudied since there is a reliance on clinical samples. We collected a P. ovale curtisi parasite isolate from a clinical case in western Thailand and performed RNA-seq analysis on the blood stage transcriptomes. Using both de novo assembly and alignment-based methods, we detected the transcripts for 6628 out of 7280 annotated genes. For those lacking evidence of expression, the vast majority belonged to the PIR and STP1 gene families. We identified new splicing patterns for over 2500 genes, and mapped at least one untranslated region for over half of all annotated genes. Our analysis also detected a notable presence of anti-sense transcripts for over 10% of P. ovale curtisi genes. This transcriptomic analysis provides new insights into the blood-stage biology of this neglected parasite.


Assuntos
Sangue/parasitologia , Perfilação da Expressão Gênica , Malária/parasitologia , Plasmodium ovale/crescimento & desenvolvimento , Plasmodium ovale/genética , Biologia Computacional , Humanos , Plasmodium ovale/isolamento & purificação , Análise de Sequência de RNA , Tailândia
18.
J Clin Transl Sci ; 3(2-3): 97-104, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31660232

RESUMO

Introduction: There are few longitudinal studies about South Asians (SAs) and little information about recruitment and retention approaches for this ethnic group. Methods: We followed 906 SAs enrolled in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort for 5 years. Surviving participants were invited for a second clinical exam from 2015 to 2018. A new wave of participants was recruited during 2017-2018. We assessed the yields from different methods of recruitment and retention. Results: A total of 759 (83%) completed the second clinical exam, and 258 new participants were enrolled. Providing a nearby community hospital location for the study exam, offering cab/shared ride reimbursement, and conducting home visits were the most effective methods for enhancing retention. New participant recruitment targeted women and individuals with lower socioeconomic status, and we found that participant referrals and active community engagement were most effective. Mailing invitational letters to those identified by electronic health records had very low yield. Conclusion: Recruitment and retention strategies that address transportation barriers and increase community engagement will help increase the representation of SAs in health research.

19.
BMJ Open ; 9(10): e028076, 2019 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-31630098

RESUMO

OBJECTIVE: The prevalence of type 2 diabetes (T2D) among Iraqi immigrants to Sweden is high and partly related to sedentary physical activity and calorie dense food. The aim of the present study was to explore perceptions, experiences and barriers concerning lifestyle modifications (LSM) in Iraqi immigrants to Sweden at risk for T2D. DESIGN: A qualitative thematic analysis was conducted on data collected from gender-specific focus group interviews which took place during a culturally adapted randomised controlled intervention study addressing motivation to lifestyle change, self-empowerment, behavioural modifications and sociocultural barriers to LSM. Seven focus groups were held, with an interval of 1-4 weeks between January and May of 2015; each session lasted approximately 1.5 hours. SETTING: The city of Malmö, Sweden. PARTICIPANTS: Out of 27 women and 23 men assigned to the intervention group, 19 women and 14 men who attended at least one focus group session were included in the study. RESULTS: Participants expressed awareness of the content of healthy lifestyle practices. They also expressed numerous social and cultural barriers to LSM connected to irregular meals, overeating, food and drinking preferences and family expectations. Overeating was described as a consequence of social and cultural norms and expectations and of poor mental well-being. Facilitators for reaching successful LSM were connected to family involvement and support. CONCLUSION: Our study reports that facilitators for LSM are connected to presence of family support. Preventive actions addressing family involvement may benefit Middle Eastern immigrants at high risk for T2D to consider healthier lifestyles practices. Identification of sociocultural barriers and facilitators for LSM are crucial for successful health promotion in minority populations at risk for T2D. TRIAL REGISTRATION: Trial registration number: NCT01420198 for the MEDIM-study; Pre-results.


Assuntos
Emigrantes e Imigrantes , Comportamentos Relacionados com a Saúde/etnologia , Estilo de Vida Saudável , Adulto , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/prevenção & controle , Família , Comportamento Alimentar/etnologia , Feminino , Grupos Focais , Preferências Alimentares/etnologia , Humanos , Masculino , Pessoa de Meia-Idade , Oriente Médio/etnologia , Apoio Social , Suécia/epidemiologia
20.
Genes (Basel) ; 10(9)2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505774

RESUMO

The emergence and spread of drug resistance is a problem hindering malaria elimination in Southeast Asia. In this study, genetic variations in drug resistance markers of Plasmodium falciparum were determined in parasites from asymptomatic populations located in three geographically dispersed townships of Myanmar by PCR and sequencing. Mutations in dihydrofolate reductase (pfdhfr), dihydropteroate synthase (pfdhps), chloroquine resistance transporter (pfcrt), multidrug resistance protein 1 (pfmdr1), multidrug resistance-associated protein 1 (pfmrp1), and Kelch protein 13 (k13) were present in 92.3%, 97.6%, 84.0%, 98.8%, and 68.3% of the parasites, respectively. The pfcrt K76T, pfmdr1 N86Y, pfmdr1 I185K, and pfmrp1 I876V mutations were present in 82.7%, 2.5%, 87.5%, and 59.8% isolates, respectively. The most prevalent haplotypes for pfdhfr, pfdhps, pfcrt and pfmdr1 were 51I/59R/108N/164L, 436A/437G/540E/581A, 74I/75E/76T/220S/271E/326N/356T/371I, and 86N/130E/184Y/185K/1225V, respectively. In addition, 57 isolates had three different point mutations (K191T, F446I, and P574L) and three types of N-terminal insertions (N, NN, NNN) in the k13 gene. In total, 43 distinct haplotypes potentially associated with multidrug resistance were identified. These findings demonstrate a high prevalence of multidrug-resistant P. falciparum in asymptomatic infections from diverse townships in Myanmar, emphasizing the importance of targeting asymptomatic infections to prevent the spread of drug-resistant P. falciparum.


Assuntos
Antimaláricos/farmacologia , Resistência a Múltiplos Medicamentos , Malária/parasitologia , Plasmodium falciparum/genética , Polimorfismo Genético , Di-Hidropteroato Sintase/genética , Humanos , Malária/epidemiologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Mianmar , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade , Proteínas de Protozoários/genética , Tetra-Hidrofolato Desidrogenase/genética
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