Natural resistance to meglumine antimoniate is associated with treatment failure in cutaneous leishmaniasis caused by Leishmania (Viannia) panamensis.

The multifactorial basis of therapeutic response can obscure the relation between antimicrobial drug susceptibility and clinical outcome. To discern the relationship between parasite susceptibility to meglumine antimoniate (SbV) and therapeutic outcome of cutaneous leishmaniasis, risk factors for treatment failure were considered in evaluating this relationship in ninety-one cutaneous leishmaniasis patients and corresponding clinical strains of Leishmania (Viannia) panamensis. Parasite susceptibility to 32 µg SbV/mL (plasma Cmax) was evaluated in primary human macrophages, PBMCs, and U937 macrophages. Early parasitological response to treatment was determined in lesions of a subgroup of patients, and pathogenicity of Sb-resistant and sensitive clinical strains was compared in BALB/c mice. Parasite survival in cell models and patient lesions was determined by qRT-PCR of Leishmania 7SLRNA transcript. Parasite loads in BALB/c mice were quantified by limiting dilution analysis. The disparate Sb-susceptibility of parasite subpopulations distinguished by isoenzyme profiles (zymodemes) was manifest in all cell models. Notably, Sb-resistance defined by parasite survival, was most effectively discerned in U937 macrophages compared with primary human host cells, significantly higher among strains from patients who failed treatment than cured and, significantly associated with treatment failure. Each unit increase in transformed survival rate corresponded to a 10.6-fold rise in the odds of treatment failure. Furthermore, treatment failure was significantly associated with naturally Sb-resistant zymodeme 2.3 strains, which also produced larger lesions and parasite burdens in BALB/c mice than Sb-sensitive zymodeme 2.2 strains. The confounding effect of host risk factors for treatment failure in discerning this association was evidenced in comparing strains from patients with and without the defined risk factors for treatment failure. These results establish the association of natural resistance to meglumine antimoniate with treatment failure, the importance of host risk factors in evaluating drug susceptibility and treatment outcome, and the clinical and epidemiological relevance of natural Sb-resistance in L. (V.) panamensis subpopulations.

Global and cell type-specific immunological hallmarks of severe dengue progression identified via a systems immunology approach.

Severe dengue (SD) is a major cause of morbidity and mortality. To define dengue virus (DENV) target cells and immunological hallmarks of SD progression in children's blood, we integrated two single-cell approaches capturing cellular and viral elements: virus-inclusive single-cell RNA sequencing (viscRNA-Seq 2) and targeted proteomics with secretome analysis and functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion as well as cell-cell communications point towards increased immune cell migration and inflammation in SD progressors. Concurrently, antigen-presenting cells from SD progressors demonstrate intact uptake yet impaired interferon response and antigen processing and presentation signatures, which are partly modulated by DENV. Increased activation, regulation and exhaustion of effector responses and expansion of HLA-DR-expressing adaptive-like NK cells also characterize SD progressors. These findings reveal DENV target cells in human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement.

Co-Infection between Dengue Virus and SARS-CoV-2 in Cali, Colombia.

The co-occurrence of COVID-19 with endemic diseases is a public health concern that may affect patient prognosis and outcomes. The objective of this study was to describe the clinical characteristics of patients with dengue virus (DENV) and SARS-CoV-2 co-infections and compare their outcomes against those of COVID-19 patients without dengue. A cross-sectional study was conducted in patients with SARS-CoV-2 infection who attended a single center in Cali, Colombia, from March 2020 to March 2021. All patients who were tested by both real-time polymerase chain reaction for SARS-CoV-2 and IgM/NS1 for DENV were included. Dengue was diagnosed as having either an IgM- or an NS1- positive test. A total of 90 patients were included (72 with COVID-19 only and 18 with co-infection). Patients with co-infection had more dyspnea (61.1% versus 22.2%; P = 0.003) as well as higher oxygen desaturation (53.3% versus 13.4%; P = 0.002) and neutrophil-to-lymphocyte ratio (5.59 versus 3.84; P = 0.038) than patients with COVID-19 alone. The proportion of patients classified with moderate to severe COVID-19 was higher in the co-infection group (88.3% versus 47.8%; P = 0.002). Also, co-infection was associated with an increased need for mechanical ventilation (P = 0.06), intensive care unit (ICU) initial management (P = 0.02), and ICU admission during hospitalization (P = 0.04) compared with COVID-19 only. The ICU mortality rate was 66.6% in patients with co-infection versus 29.4% in patients infected with only SARS-CoV-2 (P < 0.05). The possibility of DENV and SARS-CoV2 co-infection occurred in the convergence of both epidemic waves. Co-infection was associated with worse clinical outcomes and higher mortality in ICU-admitted patients than in patients with the COVID-19 only.

Sensitivity and Specificity of the Remote Evaluation of Therapeutic Response in Cutaneous Leishmaniasis Using Photographs from a Mobile Application.

Cutaneous leishmaniasis (CL) primarily affects people in remote settings with limited access to health services. mHealth tools offer an opportunity to overcome knowledge gaps about clinical response to treatment. We evaluated the validity of the Guaral+ST mobile application for the remote assessment of therapeutic response in patients with CL, through photographs of lesions captured with the app by community health volunteers. Patients with confirmed CL were followed at weeks 13 and 26 after completion of treatment to assess therapeutic response in two clinical settings in southwest Colombia. Direct evaluation of lesions performed by an experienced physician was considered the reference standard. Photographs of lesions taken by CHV or nurse assistants with the mobile app, were independently evaluated by three physicians to define clinical response. A summary measure of clinical outcome defined by the three physicians was considered the index test. Sensitivity, specificity, and positive and negative predictive values were estimated. Interrater reliability (kappa) was calculated. Among 53 participants with CL who had at least one follow-up visit, the sensitivity of therapeutic response evaluation through photographs taken with the Guaral+ST app, compared with direct evaluation by an expert physician, had high validity with sensitivity of 100% (95% confidence interval: 80.5-100%) and specificity of 97.2% (95% confidence interval: 85.5-99.9%). The chance-adjusted agreement (κ) was > 0.8, which is conventionally characterized as almost perfect. The high accuracy of the remote evaluation of photographs for the assessment of therapeutic response supports the use of mHealth tools for improving access to treatment follow-up for CL.

Alteraciones moleculares implicadas en la fisiopatogenia del cáncer y su utilidad para la investigación en medicina / Molecular changes involved in physiopathogeny of cancer and their utility for research in medicine

La neoplasia es una enfermedad genética que usa mecanismos de progresión e invasión similares a los de los tejidos normales cuando proliferan. Su aparición se debe a la suma de alteraciones genéticas que facilitan la progresión tumoral por fallos en los mecanismos de senescencia celular y apoptosis. Dentro de las principales alteraciones moleculares destacan la expresión aberrante de oncogenes, genes supresores tumorales, enzimas y factores de transcripción que promueven un ciclo celular anómalo. El objetivo de esta revisión es el de conocer algunos de los cambios moleculares implicados en el inicio, promoción y progresión de las neoplasias, con el fin de tener información de los genes útiles para realizar diagnósticos más tempranos del cáncer, que favorezcan el pronóstico de la enfermedad y que sean útiles para la investigación en biotecnología diagnóstica y en terapia génica.

Neoplasia, considered as a genetic disease that uses progression mechanisms similar to the normal tissues' when proliferates. Its presence is due to genetic alterations that facilitate tumor progression by failures in the mechanisms of cellular senescence and apoptosis. Within the main molecular alterations the most important are: aberrant expression of oncogenes, tumor suppressor genes, enzymes and transcription factors that promote abnormal cell cycle. The main objective of this paper is to review some of the molecular changes involved in the initiation, promotion and progression of neoplasms, in order to have genes useful information for earlier diagnosis of cancer, favoring the prognosis of genes disease, for diagnostic research in biotechnology and gene therapy.