Leprosy is a chronic infectious disease that may present different clinical forms according to the immune response of the host. Levels of IFN-γ are significantly raised in paucibacillary tuberculoid (T-lep) when compared with multibacillary lepromatous (L-lep) patients. IFN-γ primes macrophages for inflammatory activation and induces the autophagy antimicrobial mechanism. The involvement of autophagy in the immune response against Mycobacterium leprae remains unexplored. Here, we demonstrated by different autophagic assays that LC3-positive autophagosomes were predominantly observed in T-lep when compared with L-lep lesions and skin-derived macrophages. Accumulation of the autophagic receptors SQSTM1/p62 and NBR1, expression of lysosomal antimicrobial peptides and colocalization analysis of autolysosomes revealed an impairment of the autophagic flux in L-lep cells, which was restored by IFN-γ or rapamycin treatment. Autophagy PCR array gene-expression analysis revealed a significantly upregulation of autophagy genes (BECN1, GPSM3, ATG14, APOL1, and TPR) in T-lep cells. Furthermore, an upregulation of autophagy genes (TPR, GFI1B and GNAI3) as well as LC3 levels was observed in cells of L-lep patients that developed type 1 reaction (T1R) episodes, an acute inflammatory condition associated with increased IFN-γ levels. Finally, we observed increased BCL2 expression in L-lep cells that could be responsible for the blockage of BECN1-mediated autophagy. In addition, in vitro studies demonstrated that dead, but not live M. leprae can induce autophagy in primary and lineage human monocytes, and that live mycobacteria can reduce the autophagy activation triggered by dead mycobacteria, suggesting that M. leprae may hamper the autophagic machinery as an immune escape mechanism. Together, these results indicate that autophagy is an important innate mechanism associated with the M. leprae control in skin macrophages.

Covid-19 is a novel infectious disease whose spectrum of presentation ranges from absence of symptoms to widespread interstitial pneumonia associated with severe acute respiratory syndrome (SARS), leading to significant mortality. Given the systemic pattern of Covid-19, there are many factors that can influence patient's functional capacity after acute infection and the identification of such factors can contribute to the development of specific rehabilitation strategies. Pulmonary impairment is the primary cause of hospitalization due to Covid-19, and can progress to SARS as well as increase length of hospitalization. Moreover, cardiac involvement is observed in approximately 30% of hospitalized patients, with an increased risk of acute myocarditis, myocardial injury, and heart failure, which may compromise functional capacity in the long-term. Thromboembolic complications have also been reported in some patients with Covid-19 and are associated with a poor prognosis. Musculoskeletal complications may result from long periods of hospitalization and immobility, and can include fatigue, muscle weakness and polyneuropathy. Studies that address the functional capacity of patients after Covid-19 infection are still scarce. However, based on knowledge from the multiple systemic complications associated with Covid-19, it is reasonable to suggest that most patients, especially those who underwent prolonged hospitalization, will need a multiprofessional rehabilitation program. Further studies are needed to evaluate the functional impact and the rehabilitation strategies for patients affected by Covid-19.

Paracoccidioidomycosis (PCM) is a systemic mycosis endemic to Latin America. Brazil accounts for approximately 80% of cases, where it represents a major public health issue due to its disabling impact and the number of premature deaths it causes. We present a retrospective cohort study that was conducted in order to better understand factors that relate to cure of the infection in the treatment of 200 patients with PCM. We evaluated the influence of sociodemographic and clinical factors as well as therapeutic regimen (trimethoprim-sulfamethoxazole [TMP-SMX] and itraconazole) on the progress of PCM (cure and noncure). There was a higher incidence of cure (83%) among patients who regularly received treatment for their infections and completed the treatment protocol. Moreover, itraconazole (86.4%) was significantly superior to TMP-SMX (51.3%) in terms of cure rate and had a median treatment period that was significantly shorter (12 months) than that for TMP-SMX (23 months). A Cox proportional hazard regression model showed that use of itraconazole increased the hazard of cure, regardless of sex, age, education, clinical form, completion of treatment, and regularity. Although the results of this study show that itraconazole was the best treatment option for PCM patients, a double-blind, randomized, controlled trial is necessary to confirm this conclusion.

Introduction:The benefit of a cardiac rehabilitation (CR) program for patients with Chagas heart failure (CHF) remains unclear. Therefore, we aimed to investigate the effects of CR for CHF patients. Methods: A single-arm pilot study, including 12 patients with CHF, was performed. Patients participated in an 8-month physical exercise intervention, comprising aerobic, strength, and stretching exercises (3 times per week, 60 minutes per session). Nutritional and pharmaceutical counseling were also performed. Functional capacity (cardiopulmonary exercise test), muscle respiratory strength (manovacuometry), and body composition (anthropometry and skinfolds) were evaluated at baseline, and after 4 and 8 months of intervention. Cardiac function (echocardiography), biomarkers (lipid profile, glucose, and glycated hemoglobin) and quality of life (Minnesota Living with Heart Failure Questionnaire) were assessed at baseline and at the end of the intervention. Results: Seven of 12 patients included in the study completed the 8-month follow-up period. Only 2 moderate adverse events occurred during the exercise training. Functional capacity improved after 4 months of CR, while left ventricular ejection fraction (LVEF) and respiratory strength improved after 8 months. Patients with right ventricular (RV) dysfunction at baseline exhibited an improvement in functional capacity after 4 months, and improvements in left ventricular (LV) diastolic pressure, respiratory strength, and quality of life at the end of follow-up. Conversely, those with normal baseline RV function demonstrated LVEF increases that were not observed in patients with RV dysfunction. Conclusions: CR was feasible, safe, and has important clinical benefits for patients with CHF, specifically for cardiac function and muscle respiratory strength.

Benznidazole (BZN) is the main trypanocidal drug used to treat Chagas disease, and the evidence supporting the benefits of BZN use during the chronic phase of the disease will favor its use in millions of individuals. However, more than 30% of patients treated with BZN may suffer adverse drug reactions (ADRs), and the development of tools to identify those patients at risk is highly desirable. In the present study, we aimed to identify predictive factors for ADRs in Chagas disease patients treated with BZN. Among 195 patients included in the study, 48.7% experienced ADRs and 31.3% had ADRs that caused BZN treatment discontinuation. Overall ADRs and ADRs that caused BZN treatment discontinuation were more common among women and in those who graduated from elementary school. Overall ADRs were also less frequent among black individuals. Based on logistic regression analysis, female sex (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.5 to 5.4), graduation from elementary school (OR, 2.0; 95% CI, 1.1 to 3.8), and white (OR, 5.0; 95% CI, 1.0 to 24.1) and mulatto (OR, 5.6; 95% CI, 1.1 to 28.7) races were considered to predict overall ADRs, and female sex (OR, 2.3; 95% CI, 1.2 to 4.3) was considered to predict ADRs that caused BZN treatment discontinuation. Graduation from elementary school also presented a tendency to predict ADRs that caused BZN treatment discontinuation (OR, 1.8; 95% CI, 0.9 to 3.6). The logistic regression (LR) models to predict ADRs to BZN described in this study may become important tools to minimize ADRs and improve patients' compliance and thus assist physicians treating patients with Chagas disease with BZN. E ven 100 years after it was first reported (1), Chagas disease remains a serious public health problem in Latin America, with a high social and economic burden (2, 3). Moreover, the prevalence of Chagas disease is increasing, mainly due to migration, in countries where it is not endemic, such as the United States and European countries (4-7).Benznidazole (BZN) is the main trypanocidal drug used to treat Chagas disease (8, 9), and the parasitological cure rate when patients are treated with BZN during the acute phase of the disease is almost 80% (10, 11). Although BZN effectiveness during the chronic phase of the disease remains uncertain (12)(13)(14), there is compelling evidence supporting the beneficial use of BZN even during the chronic phase of Chagas disease (13, 15), and some international guidelines are now advocating the use of BZN even among adults with chronic disease (16-18). However, adverse drug reactions (ADRs) occur in 30% to 87% of the patients treated with BZN (19-21), and 12% to 29% of patients fail to complete their full course of treatment (19-21). Therefore, the development of tools to identify patients with high probabilities of developing ADRs to BZN is highly desirable, as this strategy would improve compliance to BZN treatment and minimize complications (21,22).Logistic regression (LR) is a method often used to predict outcomes in health studies (23,24), and...

Leprosy reactions are responsible for incapacities in leprosy and represent the major cause of permanent neuropathy. The identification of biomarkers able to identify patients more prone to develop reaction could contribute to adequate clinical management and the prevention of disability. Reversal reaction may occur in unstable borderline patients and also in lepromatous patients. To identify biomarker signature profiles related with the reversal reaction onset, multibacillary patients were recruited and classified accordingly the occurrence or not of reversal reaction during or after multidrugtherapy. Analysis of skin lesion cells at diagnosis of multibacillary leprosy demonstrated that in the group that developed reaction (T1R) in the future there was a downregulation of autophagy associated with the overexpression of TLR2 and MLST8. The autophagy impairment in T1R group was associated with increased expression of NLRP3, caspase-1 (p10) and IL-1β production. In addition, analysis of IL-1β production in serum from multibacillary patients demonstrated that patients who developed reversal reaction have significantly increased concentrations of IL-1β at diagnosis, suggesting that the pattern of innate immune responses could predict the reactional episode outcome. In vitro analysis demonstrated that the blockade of autophagy with 3-methyladenine (3-MA) in Mycobacterium leprae-stimulated human primary monocytes increased the assembly of NLRP3 specks assembly, and it was associated with an increase of IL-1β and IL-6 production. Together, our data suggest an important role for autophagy in multibacillary leprosy patients to avoid exacerbated inflammasome activation and the onset of reversal reaction.

Benznidazole treatment was safe and a large proportion of patients were able to complete a full course of benznidazole treatment under close treatment surveillance. Female sex, skin disorders and mild and moderate ADRs were independently associated with the permanent suspension of benznidazole treatment. In particular, women with moderate skin ADRs had the highest risk of benznidazole treatment interruption.

Most patients with chronic Chagas disease (CD) present the indeterminate form and are at risk to develop the cardiac form. However, the actual rate of progression to the cardiac form is still unknown. Methods: In total, 550 patients with the indeterminate CD form were followed by means of annual electrocardiogram at our outpatient clinic. The studied endpoint was progression to cardiac form defined by the appearance of electrocardiographic changes typical of CD. The progression rate was calculated as the cumulative progression rate and the incidence progression rate per 100 patient years. Results: Thirty-seven patients progressed to the CD cardiac form within a mean of 73 ± 48 months of follow-up, which resulted in a 6.9% cumulative progression rate and incidence rate of 1.48 cases/100 patient years. Patients who progressed were older (mean age 47.8 ± 12.2 years), had a higher prevalence of associated heart diseases (p < 0.0001), positive xenodiagnosis (p = 0.007), and were born in the most endemic Brazilian states (p = 0.018). Previous co-morbidities remained the only variable associated with CD progression after multivariate Cox proportional hazards regression analysis (p = 0.002). Conclusion: The progression rate to chronic CD cardiac form is low and inferior to rates previously reported in other studies.