Home-Use Transcranial Direct Current Stimulation for the Treatment of a Major Depressive Episode: A Randomized Clinical Trial.

Importance: Transcranial direct current stimulation (tDCS) is moderately effective for depression when applied by trained staff. It is not known whether self-applied tDCS, combined or not with a digital psychological intervention, is also effective. Objective: To determine whether fully unsupervised home-use tDCS, combined with a digital psychological intervention or digital placebo, is effective for a major depressive episode. Design, Setting, and Participants: This was a double-blinded, sham-controlled, randomized clinical trial with 3 arms: (1) home-use tDCS plus a digital psychological intervention (double active); (2) home-use tDCS plus digital placebo (tDCS only), and (3) sham home-use tDCS plus digital placebo (double sham). The study was conducted between April 2021 and October 2022 at participants' homes and at Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil. Included participants were aged 18 to 59 years with major depression and a Hamilton Depression Rating Scale, 17-item version (HDRS-17), score above 16, a minimum of 8 years of education, and access to a smartphone and internet at home. Exclusion criteria were other psychiatric disorders, except for anxiety; neurologic or clinical disorders; and tDCS contraindications. Interventions: tDCS was administered in 2-mA, 30-minute prefrontal sessions for 15 consecutive weekdays (1-mA, 90-second duration for sham) and twice-weekly sessions for 3 weeks. The digital intervention consisted of 46 sessions based on behavioral therapy. Digital placebo was internet browsing. Main Outcomes and Measures: Change in HDRS-17 score at week 6. Results: Of 837 volunteers screened, 210 participants were enrolled (180 [86%] female; mean [SD] age, 38.9 [9.3] years) and allocated to double active (n = 64), tDCS only (n = 73), or double sham (n = 73). Of the 210 participants enrolled, 199 finished the trial. Linear mixed-effects models did not reveal statistically significant group differences in treatment by time interactions for HDRS-17 scores, and the estimated effect sizes between groups were as follows: double active vs tDCS only (Cohen d, 0.05; 95% CI, -0.48 to 0.58; P = .86), double active vs double sham (Cohen d, -0.20; 95% CI, -0.73 to 0.34; P = .47), and tDCS only vs double sham (Cohen d, -0.25; 95% CI, -0.76 to 0.27; P = .35). Skin redness and heat or burning sensations were more frequent in the double active and tDCS only groups. One nonfatal suicide attempt occurred in the tDCS only group. Conclusions and Relevance: Unsupervised home-use tDCS combined with a digital psychological intervention or digital placebo was not found to be superior to sham for treatment of a major depressive episode in this trial. Trial Registration: ClinicalTrials.gov Identifier: NCT04889976.

MiRNAs regulate iron homeostasis in Paracoccidioides brasiliensis.

During pathogen interaction with the host, several mechanisms are used to favor or inhibit the infectious process; one is called nutritional immunity, characterized by restriction of micronutrients to pathogens. Several studies on fungi of the Paracoccidioides complex, have demonstrated that these pathogens remodel their metabolic pathways to overcome the hostile condition imposed by the host. However, molecular mechanisms that control the regulation of those metabolic changes are not fully understood. Therefore, this work characterizes the expression profile of miRNAs during iron deprivation and describes metabolic pathways putatively regulated by those molecules. Through analysis of RNAseq, 45 miRNAs were identified and eight presented alterations in the expression profile during iron deprivation. Among the differentially regulated miRNAs, five were more abundant in yeast cells during iron deprivation and interestingly, the analyses of genes potentially regulated by those five miRNAs, pointed to metabolic pathways as oxidative phosphorylation, altered in response to iron deprivation. In addition, miRNAs with more abundance in iron presence, have as target genes encoding transcriptional factors related to iron homeostasis and uptake. Therefore, we suggest that miRNAs produced by Paracoccidioides brasiliensis may contribute to the adaptive responses of this fungus in iron starvation environment.

In silico characterization of microRNAs-like sequences in the genome of Paracoccidioides brasiliensis.

Eukaryotic cells have different mechanisms of post-transcriptional regulation. Among these mechanisms, microRNAs promote regulation of targets by cleavage or degradation of the mRNA. Fungi of the Paracoccidioides complex are the etiological agents of the main systemic mycosis of Latin America. These fungi present a plasticity to adapt and survive in different conditions, and the presence of microRNAs-like molecules could be part of the mechanisms that provide such plasticity. MicroRNAs produced by the host influence the progression of this mycosis in the lungs besides regulating targets involved in apoptosis in macrophage, activation of T and B cells and the production of cytokines. Therefore, this work analyzed the presence of regions in the genome of this fungus with a potential to encode microRNAs-like molecules. Here we show by analysis of sequence similarity the presence of 18 regions, putatively coding for microRNAs-like molecules in the Paracoccidioides brasiliensis genome. We also described the conservation of dicer and argonaut proteins and the cognate transcripts induced in the yeast parasitic phase. This work represents a starting point for the analysis of the presence of those molecules in the morphological stages of the fungus and their role in fungal development.