ABSTRACT Objective: To evaluate symptoms, lung function, and quality of life of a cohort of patients hospitalized for severe COVID-19 12 months after hospital admission. Methods: This was a cross-sectional study. We included severe COVID-19 survivors hospitalized in one of three tertiary referral hospitals for COVID-19 in the city of Belo Horizonte, Brazil. Participants were submitted to lung function and six-minute walk tests and completed the EQ-5D-3L questionnaire. Results: The whole sample comprised 189 COVID-19 survivors (mean age = 59.6 ± 13.4 years) who had been admitted to a ward only (n = 96; 50.8%) or to an ICU (n = 93; 49.2%). At 12 months of follow-up, 43% of patients presented with dyspnea, 27% of whom had a restrictive ventilatory disorder and 18% of whom presented with impaired DLCO. There were no significant differences in FVC, FEV1, and TLC between the survivors with or without dyspnea. However, those who still had dyspnea had significantly more impaired DLCO (14.9% vs. 22.4%; p < 0.020) and poorer quality of life. Conclusions: After one year, survivors of severe COVID-19 in a middle-income country still present with high symptom burden, restrictive ventilatory changes, and loss of quality of life. Ongoing follow-up is needed to characterize long COVID-19 and identify strategies to mitigate its consequences. Objective symptoms COVID19 COVID 19 COVID-1 1 admission Methods crosssectional cross sectional study Horizonte Brazil sixminute six minute EQ5D3L EQDL EQ 5D 3L D L questionnaire Results 18 mean 596 59 6 59. 134 13 4 13. years n 96 50.8% 508 50 8 93 49.2%. 492 49.2% . 49 2 49.2%) followup, followup follow up, up 43 27 FVC FEV1 FEV However 14.9% 149 14 9 (14.9 vs 22.4% 224 22 0.020 0020 0 020 Conclusions year middleincome middle income burden changes consequences COVID1 COVID- 5 50.8 49.2 14.9 (14. 22.4 0.02 002 02 50. 49. 14. (14 22. 0.0 00 (1 0. (

BACKGROUND Schistosomiasis is a neglected tropical disease caused by trematodes of the genus Schistosoma, with a limited treatment, mainly based on the use of praziquantel (PZQ). Currently, several aspartic proteases genes have already been identified within the genome of Schistosoma species. At least one enzyme encoded from this gene family (SmAP), named SmCD1, has been validated for the development of schistosomicidal drugs, since it has a key role in haemoglobin digestion by worms. OBJECTIVE In this work, we integrated a structure-based virtual screening campaign, enzymatic assays and adult worms ex vivo experiments aiming to discover the first classes of SmCD1 inhibitors. METHODS Initially, the 3D-structures of SmCD1, SmCD2 and SmCD3 were generated using homology modelling approach. Using these models, we prioritised 50 compounds from 20,000 compounds from ChemBridge database for further testing in adult worm aqueous extract (AWAE) and recombinant SmCD1 using enzymatic assays. FINDINGS Seven compounds were confirmed as hits and among them, two compounds representing new chemical scaffolds, named 5 and 19, had IC50 values against SmCD1 close to 100 μM while presenting binding efficiency indexes comparable to or even higher than pepstatin, a classical tight-binding peptide inhibitor of aspartyl proteases. Upon activity comparison against mammalian enzymes, compound 50 was selective and the most potent against the AWAE aspartic protease activity (IC50 = 77.7 μM). Combination of computational and experimental results indicate that compound 50 is a selective inhibitor of SmCD2. Compounds 5, 19 and 50 tested at low concentrations (10 uM) were neither cytotoxic against WSS-1 cells (48 h) nor could kill adult worms ex-vivo, although compounds 5 and 50 presented a slight decrease on female worms motility on late incubations times (48 or 72 h). MAIN CONCLUSION Overall, the inhibitors identified in this work represent promising hits for further hit-to-lead optimisation. treatment PZQ. PZQ . (PZQ) Currently species SmAP, SmAP , (SmAP) SmCD drugs structurebased structure campaign Initially 3Dstructures Dstructures 3D structures D approach models 20000 20 000 20,00 (AWAE them scaffolds IC IC5 10 pepstatin tightbinding tight enzymes (IC5 777 77 7 77. μM. μM) 1 (1 uM WSS1 WSS WSS- 48 (4 h exvivo, exvivo vivo, ex-vivo h. Overall hittolead hit lead optimisation (PZQ (SmAP 2000 2 00 20,0 (IC ( 4 200 0 20,

ABSTRACT Background: COVID-19 has been associated with persistent symptoms and functional changes, especially in those surviving severe disease. Methods: We conducted a prospective multicenter study in patients with severe COVID-19 to determine respiratory sequelae. Patients were stratified into two groups: ward admission (WA) and intensive care unit (ICU) admission. In each follow-up visit, the patients where inquired about cough and dyspnea, and performed spirometry, lung volumes, carbon monoxide diffusion capacity (DLCO), 6-minute walk test (6MWT), and respiratory muscle strength (MIP and MEP). Results of pulmonary function tests at 45 days and 6 months after hospital admission were compared using paired analysis. Results: 211 patients were included, 112 in WA and 99 in ICU. Dyspnea persisted in 64.7% in the WA and 66.7% in the ICU group after 6 months. Lung function measures showed significant improvement between 45 days and 6 months, both in WA and ICU groups in VC, FVC, FEV1, total lung capacity, and 6MW distance measures. The improvement in the proportions of the altered functional parameters was significant in the ICU group for VC (44.2% 45 d; 20.8% 6 m; p = 0,014), FVC (47.6% 45 d; 28% 6 m; p = 0,003), FEV1 (45.1% 45 d; 28% 6 m; p = 0,044), DLCO (33.8% 45 d; 7.7% 6 m; p < 0,0001). Conclusion: Six months follow-up of patients with the severe forms of COVID-19 showed significant improvement in the lung function measures compared to 45 days post hospital discharge. The difference was more evident in those requiring ICU admission.

RESUMO Objetivo: Como a infecção por SARS-CoV-2 pode afetar gravemente os pulmões e podem ocorrer alterações funcionais persistentes após doença grave, nosso objetivo foi determinar os parâmetros de função pulmonar de pacientes com COVID-19, 45 dias após a alta hospitalar e comparar as alterações de acordo com a gravidade da doença. Métodos: Estudo multicêntrico, prospectivo, descritivo e analítico. Os participantes foram alocados em três grupos: grupo internação em enfermaria (IE); grupo internação em UTI sem ventilação mecânica (UTI/VM−); e grupo internação em UTI com VM (UTI/VM+). Volumes pulmonares, DLCO, PImáx, PEmáx e distância percorrida no teste de caminhada de seis minutos (DTC6) foram medidos 45 dias após a alta. Resultados: A amostra foi composta por 242 pacientes (média de idade = 59,4 ± 14,8 anos; 52,1% do sexo masculino), e 232 (96%) apresentavam alteração da função pulmonar. Na coorte total, observou-se distúrbio restritivo em 96%, assim como redução da DLco (em 21,2% dos pacientes), VEF1/CVF (em 39,7%) e PEmáx (em 95,8%), sem diferença entre os grupos para todos. Na comparação entre os grupos, o grupo UTI/VM+ apresentou DLCO reduzida em 50% dos pacientes (p < 0,001) e teve menor média da DTC6 do valor previsto (p = 0,013). Dessaturação de oxigênio no teste de caminhada de seis minutos foi observada em 32,3% da coorte e foi menos frequente no grupo IE. Conclusões: Este é o primeiro estudo sul-americano envolvendo sobreviventes de COVID-19 grave cuja função pulmonar foi avaliada 45 dias após a alta hospitalar. Alterações foram frequentes, principalmente naqueles em VM, o que destaca a importância da avaliação da função pulmonar após COVID-19 grave.

ABSTRACT Objective: Because SARS-CoV-2 infection can severely affect the lungs and persistent functional changes can occur after severe disease, we aimed to determine lung function parameters of COVID-19 patients at 45 days after hospital discharge and compare changes according to the severity of the disease. Methods: This was a prospective descriptive analytical multicenter study. The participants were allocated into three groups: ward admission (WA) group; ICU admission not on mechanical ventilation (ICU/MV−) group; and ICU admission on MV (ICU/MV+) group. Lung volumes, DLco, MIP, MEP, and six-minute walk distance (6MWD) were measured 45 days after discharge. Results: The sample comprised 242 patients (mean age = 59.4 ± 14.8 years; 52.1% of males), and 232 (96%) had altered lung function. In the total cohort, restrictive disorder was observed in 96%, as well as reductions in DLco (in 21.2% of the patients), FEV1/FVC (in 39.7%), and PEmax (in 95.8%), with no differences between the groups. Comparing the groups, the ICU/MV+ group had reduced DLco in 50% of the patients (p < 0.001) and a lower mean 6MWD % of the predicted value (p = 0.013). Oxygen desaturation in the six-minute walk test was observed in 32.3% of the cohort and was less frequent in the IE group. Conclusions: This is the first South American study involving severe COVID-19 survivors whose lung function was assessed 45 days after hospital discharge. Changes were frequent, especially in those on MV, which highlights the importance of lung function evaluation after severe COVID-19.

BACKGROUND Malaria is responsible for 429,000 deaths per year worldwide, and more than 200 million cases were reported in 2015. Increasing parasite resistance has imposed restrictions to the currently available antimalarial drugs. Thus, the search for new, effective and safe antimalarial drugs is crucial. Heterocyclic compounds, such as dihydropyrimidinones (DHPM), synthesised via the Biginelli multicomponent reaction, as well as bicyclic compounds synthesised from DHPMs, have emerged as potential antimalarial candidates in the last few years. METHODS Thirty compounds were synthesised employing the Biginelli multicomponent reaction and subsequent one-pot substitution/cyclisation protocol; the compounds were then evaluated in vitro against chloroquine-resistant Plasmodium falciparum parasites (W2 strain). Drug cytotoxicity in baseline kidney African Green Monkey cells (BGM) was also evaluated. The most active in vitro compounds were evaluated against P. berghei parasites in mice. Additionally, we performed an in silico target fishing approach with the most active compounds, aiming to shed some light into the mechanism at a molecular level. RESULTS The synthetic route chosen was effective, leading to products with high purity and yields ranging from 10-84%. Three out of the 30 compounds tested were identified as active against the parasite and presented low toxicity. The in silico study suggested that among all the molecular targets identified by our target fishing approach, Protein Kinase 3 (PK5) and Glycogen Synthase Kinase 3β (GSK-3β) are the most likely molecular targets for the synthesised compounds. CONCLUSIONS We were able to easily obtain a collection of heterocyclic compounds with in vitro anti-P. falciparum activity that can be used as scaffolds for the design and development of new antiplasmodial drugs.

Few Zika virus (ZIKV) outbreaks had been reported since its first detection in 1947, until the recent epidemics occurred in South America (2014/2015) and expeditiously became a global public health emergency. This arbovirus reached 0.5-1.3 million cases of ZIKV infection in Brazil in 2015 and rapidly spread in new geographic areas such as the Americas. Despite the mild symptoms of the Zika fever, the major concern is related to the related severe neurological disorders, especially microcephaly in newborns. Advances in ZIKV drug discovery have been made recently and constitute promising approaches to ZIKV treatment. In this review, we summarize current computational drug discovery efforts and their applicability to discovery of anti-ZIKV drugs. Lastly, we present successful examples of the use of computational approaches to ZIKV drug discovery.

Abstract Background: Drug repurposing has been an interesting and cost-effective approach, especially for neglected diseases, such as Chagas disease. Methods: In this work, we studied the activity of the antidepressant drug sertraline against Trypanosoma cruzi trypomastigotes and intracellular amastigotes of the Y and Tulahuen strains, and investigated its action mode using cell biology and in silico approaches. Results: Sertraline demonstrated in vitro efficacy against intracellular amastigotes of both T. cruzi strains inside different host cells, including cardiomyocytes, with IC50 values between 1 to 10 μM, and activity against bloodstream trypomastigotes, with IC50 of 14 μM. Considering the mammalian cytotoxicity, the drug resulted in a selectivity index of 17.8. Sertraline induced a change in the mitochondrial integrity of T. cruzi, resulting in a decrease in ATP levels, but not affecting reactive oxygen levels or plasma membrane permeability. In silico approaches using chemogenomic target fishing, homology modeling and molecular docking suggested the enzyme isocitrate dehydrogenase 2 of T. cruzi (TcIDH2) as a potential target for sertraline. Conclusions: The present study demonstrated that sertraline had a lethal effect on different forms and strains of T. cruzi, by affecting the bioenergetic metabolism of the parasite. These findings provide a starting point for future experimental assays and may contribute to the development of new compounds.

Introduction This study evaluated the efficacy of retreatment of pulmonary tuberculosis (TB) with regard to treatment outcomes and antimicrobial susceptibility testing (ST) profiles. Methods This retrospective cohort study analyzed 144 patients treated at a referral hospital in Brazil. All of them had undergone prior treatment, were smear-positive for TB and received a standardized retreatment regimen. Fisher's 2-tailed exact test and the χ2 test were used; RRs and 95% CIs were calculated using univariate and multivariate binary logistic regression. Results The patients were cured in 84 (58.3%) cases. Failure was associated with relapsed treatment and abandonment (n=34). Culture tests were obtained for 103 (71.5%) cases; 70 (48.6%) had positive results. ST results were available for 67 (46.5%) cases; the prevalence of acquired resistance was 53.7%. There were no significant differences between those who achieved or not therapeutic success (p=0.988), despite being sensitive or resistant to 1 or more drugs. Rifampicin resistance was independently associated with therapeutic failure (OR: 4.4, 95% CI:1.12-17.37, p=0.034). For those cases in which cultures were unavailable, a 2nd model without this information was built. In this, return after abandonment was significantly associated with retreatment failure (OR: 3.59, 95% CI:1.17-11.06, p=0.026). Conclusions In this cohort, the general resistance profile appeared to have no influence on treatment outcome, except in cases of rifampicin resistance. The form of reentry was another independent predictor of failure. The use of bacterial culture identification and ST in TB management must be re-evaluated. The recommendations for different susceptibility profiles must also be improved.

O controle do estado de saúde de cada animal que fará parte de um experimento é essencial para prevenir falsa interpretação dos resultados. Sendo assim, o objetivo do presente trabalho foi comparar as condições de saúde de ratos Wistar adultos, machos dos biotérios experimentais da FAFICH (n=10) e do ICB-Bloco C-2 (n=10) provenientes do mesmo biotério de criação (Centro de Bioterismo CEBIO-ICB) com dados da literatura de ratos SPF (livres de patógenos específicos). Foram utilizados para avaliação os seguintes critérios: a) sinais clínicos evidentes (p. ex. alteração no comportamento, queda de pêlos), b) contagem manual de leucócitos, c) exame copro-parasitológico e d) necropsia de pulmão (exame anatomopatológico). Os animais não apresentaram sinais clínicos de doença. No entanto, quando comparados com ratos SPF, a contagem de leucócitos dos ratos provenientes dos dois biotérios foi significativamente diferente (p<0,05). Através dos exames parasitológicos e necropsia de pulmão foram detectados parasitas patogênicos e fungos presentes em processos inflamatórios. Nossos resultados indicam que as condições de saúde dos animais não são satisfatórias e uma das causas prováveis pode ser as atuais condições dos biotérios (talvez as condições do ambiente, alojamentos, população por gaiola, barreiras, divisão interna da área do biotério).

A study was conducted to compare health status of male adult Wistar rats from two Experimental Animal Houses of UFMG with literature data of SPF (free from specific pathogens) and conventional rats. The animals were divided into two groups: Group I (n=10), rats from the experimental animal houses of FAFICH and Group II (n=10) from ICB and following aspects were studied: a) evident clinical signs (behavior modification, hair loss (alopecia), b) leukocyte counts, c) feces exam and d) histological study of the lungs. The rats did not show clinical signs. However, when compared with SPF and conventional rats, both the groups showed a significant increase (p<0,05) of leukocyte count. On feces exam we detected some parasites and on lung histological exam we observed fungus (Group I) and bacteria (Group II). These results showed that the health status of the rats was not satisfactory and required improvements in the conditions of the animal houses.