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OBJECTIVE: To evaluate the effect of the basilar invagination (BI) type B on cervical spine. METHODS: The research protocol used head magnetic resonance imaging (MRI) exams from 41 participants with BI type B and 158 controls. The criterion for BI was the distance of the odontoid apex to Chamberlain's line (DOCL) equal to or greater than 7 mm. The clivus length (CLI), clivus canal angle (CCA), Welcker's basal angle (WBA), Boogaard's angle (BOA), upper cervical lordosis angle (UCL), and total cervical lordosis angle (CL) were evaluated. The descriptive analysis, group comparisons, and correlations between skull base and cervical spine parameters were performed at the 95% confidence interval. RESULTS: Participants with BI type B showed shorter clivus length (CLI: 25.7mm±7.3); greater angulation of the skull base (WBA: 126.5±10.4); greater inclination foramen magnum (BOA: 151.5±14.5); decrease in the value of the (CCA: 131.6±15); and greater angulations of UCL (17.9 ±13.8) and CL (29.7 ±19.9) in comparison to the control group (P < 0.05). Clivus length and CCA correlated inversely with UCL and CL, while BOA correlated directly with UCL and CL. The WBA did not correlate with CL (P < 0.05). CONCLUSION: The deformation of skull base in the BI of type B caused, on average, a hyperlordosis of almost 30 degrees in the C2-C6 segment. This change was approximately 17º in the C2-C4, with the clivus hypoplasia being a risk factor for cervical hyperlordosis.

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BACKGROUND: Exercise training may reduce whole-body fat mass and percentage. However, whether exercise improves fat distribution assessed by fat mass ratio (FMR) and regional fat percentage in men living with HIV (MLHIV) is still unclear. The aim of this study was to compare the FMR and total and regional body fat between physically active and inactive MLHIV and HIV-uninfected men. METHODS: Using a cross­sectional design, total and regional body fat assessed by dual x-ray absorptiometry (DXA) were compared between 19 MLHIV (ACT-MLHIV, 52±7 y, 23.8±4.1 kg.m-2) enrolled in a multimodal training program (aerobic, strength and flexibility exercises) for at least 12 months (60­min sessions; 3 times/wk with moderate intensity) vs. 19 inactive MLHIV (IN-MLHIV, 51±7 y, 25.9±3.3 kg.m-2) and 19 HIV-uninfected men (HIV-, 51±8 y, 26.0±3.3 kg.m-2). FMR was calculated as the ratio between the percentage of fat in the trunk and the lower limbs. RESULTS: The ACT-MLHIV showed a lower trunk fat percentage (24.1±17.9% vs. 34.4±11.9%; P=0.02) and FMR (1.5±0.6 vs.1.9±0.5; P=0.02) than the IN-MLHIV, with no difference between them in lower limbs fat percentage (IN-MLHIV: 16.3±5.9 vs. ACT-MLHIV: 15.9±9.6%; P=0.98). HIV- showed a lower FMR (1.2±0.2; P<0.02) and superior lower limb fat percentage (24.1±8.0%; P<0.0001) than IN-MLHIV and ACT-MLHIV, as well as a higher total fat percentage than ACT-MLHIV (27.3±6.2 vs. 21.8±6.9%; P=0.02). CONCLUSIONS: Physical exercise seems to attenuate HIV-associated lipodystrophy by reducing trunk fat percentage while preserving lower limb fat mass. FMR and total fat percentage should not be used alone as markers of exercise-induced changes in lipodystrophy.

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BACKGROUND: Leishmaniasis is a significant global public health issue that is caused by parasites from Leishmania genus. With limited treatment options and rising drug resistance, there is a pressing need for new therapeutic approaches. Molecular chaperones, particularly Hsp90, play a crucial role in parasite biology and are emerging as promising targets for drug development. OBJECTIVE: This study evaluates the efficacy of 17-DMAG in treating BALB/c mice from cutaneous leishmaniasis through in vitro and in vivo approaches. MATERIALS AND METHODS: We assessed 17-DMAG's cytotoxic effect on bone marrow-derived macrophages (BMMΦ) and its effects against L. braziliensis promastigotes and intracellular amastigotes. Additionally, we tested the compound's efficacy in BALB/c mice infected with L. braziliensis via intraperitoneal administration to evaluate the reduction in lesion size and the decrease in parasite load in the ears and lymph nodes of infected animals. RESULTS: 17-DMAG showed selective toxicity [selective index = 432) towards Leishmania amastigotes, causing minimal damage to host cells. The treatment significantly reduced lesion sizes in mice and resulted in parasite clearance from ears and lymph nodes. It also diminished inflammatory responses and reduced the release of pro-inflammatory cytokines (IL-6, IFN-γ, TNF) and the regulatory cytokine IL-10, underscoring its dual leishmanicidal and anti-inflammatory properties. CONCLUSIONS: Our findings confirm the potential of 17-DMAG as a viable treatment for cutaneous leishmaniasis and support further research into its mechanisms and potential applications against other infectious diseases.

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Paracoccidioidomycosis (PCM) is an endemic fungal disease that occurs in Latin America and primarily affects humans. The disease has been rarely documented in non-human primates. This report details a disseminated and fatal case of PCM caused by Paracoccidioides brasiliensis in a western black-handed tamarin (Saguinus niger) under human care. Histopathological examination revealed extensive pyogranulomatous inflammation in the lungs, spleen, liver, lymph nodes, kidneys, epididymis, right testicle, heart, adrenal gland and intestines, associated with characteristic yeast forms consistent with Paracoccidioides spp and confirmed by immunohistochemistry. Molecular analysis indicated a high nucleotide similarity with P. brasiliensis sequences for both the 18S rRNA and gp43 genes. This naturally occurring infection highlights the susceptibility of these animals to PCM and their role in ecoepidemiology warrants further investigation.

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Lynch syndrome is the most common cause of hereditary colorectal cancer. It usually develops asymptomatically until symptoms related to colorectal carcinoma appear, such as gastrointestinal bleeding, abdominal pain, and changes in bowel habits and/or stool characteristics. Oftentime, when these clinical signs and symptoms are not present, the diagnosis becomes challenging. We present the clinical case of a 69-year-old woman, adopted, with no known previous history, who presented to the emergency department with low back pain, without irradiation, that had been going on for three days, associated with inflammatory signs in the right hip region. There were no urinary or sensory alterations and no recent trauma. She was initially discharged with antibiotherapy with the diagnosis of hip cellulitis. As the symptoms continued and the inflammation spread to the right lower limb, she returned to the emergency department. A CT scan revealed an abscess (17 cm) in the right buttock, complicated by necrotizing fasciitis due to fistulization from a tumor in the right colon. She underwent an exploratory laparotomy, which identified a neoplasm of the ascending colon, adherent to the abdominal wall, in the right lumbar region. Right hemicolectomy and drainage of the right buttock/thigh abscess were performed. The histology was compatible with invasive adenocarcinoma, with high-grade dysplasia but well differentiated, pT3G1N0. The immunohistochemistry was suggestive of Lynch syndrome.

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In the New World, dogs are considered the main reservoir of visceral leishmaniasis (VL). Due to inefficacies in existing treatments and the lack of an efficient vaccine, dog culling is one of the main strategies used to control disease, making the development of new therapeutic interventions mandatory. We previously showed that Tanespimycin (17-AAG), a Hsp90 inhibitor, demonstrated potential for use in leishmaniasis treatment. The present study aimed to test the safety of 17-AAG in dogs by evaluating plasma pharmacokinetics, dose-proportionality, and the tolerability of 17-AAG in response to a dose-escalation protocol and multiple administrations at a single dose in healthy dogs. Two protocols were used: Study A: four dogs received variable intravenous (IV) doses (50, 100, 150, 200, or 250 mg/m2) of 17-AAG or a placebo (n = 4/dose level), using a cross-over design with a 7-day "wash-out" period; Study B: nine dogs received three IV doses of 150 mg/m2 of 17-AAG administered at 48 h intervals. 17-AAG concentrations were determined by a validated high-performance liquid chromatographic (HPLC) method: linearity (R2 = 0.9964), intra-day precision with a coefficient of variation (CV) ≤ 8%, inter-day precision (CV ≤ 20%), and detection and quantification limits of 12.5 and 25 ng/mL, respectively. In Study A, 17-AAG was generally well tolerated. However, increased levels of liver enzymes-alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)-and bloody diarrhea were observed in all four dogs receiving the highest dosage of 250 mg/m2. After single doses of 17-AAG (50-250 mg/m2), maximum plasma concentrations (Cmax) ranged between 1405 ± 686 and 9439 ± 991 ng/mL, and the area under the curve (AUC) plotting plasma concentration against time ranged between 1483 ± 694 and 11,902 ± 1962 AUC 0-8 h µg/mL × h, respectively. Cmax and AUC parameters were dose-proportionate between the 50 and 200 mg/m2 doses. Regarding Study B, 17-AAG was found to be well tolerated at multiple doses of 150 mg/m2. Increased levels of liver enzymes-ALT (28.57 ± 4.29 to 173.33 ± 49.56 U/L), AST (27.85 ± 3.80 to 248.20 ± 85.80 U/L), and GGT (1.60 ± 0.06 to 12.70 ± 0.50 U/L)-and bloody diarrhea were observed in only 3/9 of these dogs. After the administration of multiple doses, Cmax and AUC 0-48 h were 5254 ± 2784 µg/mL and 6850 ± 469 µg/mL × h in plasma and 736 ± 294 µg/mL and 7382 ± 1357 µg/mL × h in tissue transudate, respectively. In conclusion, our results demonstrate the potential of 17-AAG in the treatment of CVL, using a regimen of three doses at 150 mg/m2, since it presents the maintenance of high concentrations in subcutaneous interstitial fluid, low toxicity, and reversible hepatotoxicity.

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Background and Objectives: As the gaming industry experiences exponential growth, concerns about gaming disorder (GD) also grow. It is crucial to understand the structural features of games that can interact with individual characteristics of gamers to promote GD. This research consolidates the views of an international body of panelists to create an assessment tool for gauging the addictive potential of distinct games. Methods: Utilizing the iterative and structured Delphi method, an international panel of researchers, clinicians, and people with lived experience were recruited to offer a multifaceted viewpoint on the addictive risk associated with specific structural elements in games. Two rounds of surveys facilitated consensus. Results: The panel initially included 40 members-ten from research, eight from clinical settings, and 22 with lived experiences. The second round included 27 panelists-seven from research, eight from clinical settings, and 11 with lived experiences. The study identified 25 structural features that contribute to potentially addictive gaming patterns. Discussion and Conclusions: Consensus was found for 25 features, which were distilled into a 23-item evaluation tool. The Saini-Hodgins Addiction Risk Potential of Games Scale (SHARP-G) consists of five overarching categories: 'Social,' 'Gambling-Like Features,' 'Personal Investment,' 'Accessibility,' and 'World Design.' SHARP-G yields a total score indicating level of addiction risk. A case study applying the scale to three games of differing perceived risk levels demonstrated that that score corresponded to game risk as expected. While the SHARP-G scale requires further validation, it provides significant promise for evaluating gaming experiences and products.

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Background: Salmonella enterica serovar Infantis (Salmonella Infantis) is a zoonotic, ubiquitous and foodborne pathogen of worldwide distribution. Despite Brazil's relevance as a major meat exporter, few studies were conducted to characterize strains of this serovar by genomic analyses in this country. Therefore, this study aimed to assess the diversity of 80 Salmonella Infantis strains isolated from veterinary, food and human sources in Brazil between 2013 and 2018 by comparative genomic analyses. Additional genomes of non-Brazilian countries (n = 18) were included for comparison purposes in some analyses. Methods: Analyses of whole-genome multi-locus sequence typing (wgMLST), using PGAdb-builder, and of fragmented genomes, using Gegenees, were conducted to compare the 80 Brazilian strains to the 18 non-Brazilian genomes. Pangenome analyses and calculations were performed for all Salmonella Infantis genomes analyzed. The presence of prophages was determined using PHASTER for the 80 Brazilian strains. The genome plasticity using BLAST Ring Image Generator (BRIG) and gene synteny using Mauve were evaluated for 20 selected Salmonella Infantis genomes from Brazil and ten from non-Brazilian countries. Unique orthologous protein clusters were searched in ten selected Salmonella Infantis genomes from Brazil and ten from non-Brazilian countries. Results: wgMLST and Gegenees showed a high genomic similarity among some Brazilian Salmonella Infantis genomes, and also the correlation of some clusters with non-Brazilian genomes. Gegenees also showed an overall similarity >91% among all Salmonella Infantis genomes. Pangenome calculations revealed an open pangenome for all Salmonella Infantis subsets analyzed and a high gene content in the core genomes. Fifteen types of prophages were detected among 97.5% of the Brazilian strains. BRIG and Mauve demonstrated a high structural similarity among the Brazilian and non-Brazilian isolates. Unique orthologous protein clusters related to biological processes, molecular functions, and cellular components were detected among Brazilian and non-Brazilian genomes. Conclusion: The results presented using different genomic approaches emphasized the significant genomic similarity among Brazilian Salmonella Infantis genomes analyzed, suggesting wide distribution of closely related genotypes among diverse sources in Brazil. The data generated contributed to novel information regarding the genomic diversity of Brazilian and non-Brazilian Salmonella Infantis in comparison. The different genetically related subtypes of Salmonella Infantis from Brazil can either occur exclusively within the country, or also in other countries, suggesting that some exportation of the Brazilian genotypes may have already occurred.

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The yeast-encapsulated orange oil (YEOO) is a novel larvicide under development against vector mosquitoes. Despite its efficiency against Aedes aegypti (L.) in small scale experiments, its applicability in vector control can be influenced by other effects on mosquito behaviour or physiology. For this reason, the impact of YEOO particles in mosquito oviposition was evaluated in laboratory and semi-field conditions. Oviposition assays with one gravid Aedes aegypti female were carried under laboratory and semi-field conditions with natural light and temperature fluctuation. For all ovitraps, the number of eggs was manually counted in the wooden paddle and in the solution of each ovitrap. The proportion of eggs between substrates (wooden paddle and solution) varied between conditions, with females in laboratory presenting a lower preference to lay eggs in paddles when compared with studies in semi-field. This behaviour shifts in laboratory can create challenges to extrapolate results from laboratory to the field. Here, studies in both conditions indicate a similar impact of YEOO particles in Aedes aegypti oviposition. The potential treatment concentration of YEOO particles presents a strong repellent/deterrent effect (-0.559 > OAI > -0.760) within the initial 72h of application when compared with water, and weak repellent/deterrent signal (OAI = -0.220) when compared against inactivated yeast. Control ovitraps with water were more positive for egg presence than treated ovitraps, while ovitraps with YEOO particles and inactivated yeast present similar number of positive ovitraps. It is possible that the repellent/deterrent action is partially driven by the delivery system, since most times Citrus sinensis EO oviposition repellent/deterrent signal is weak, and it seem influenced by solvent/delivery used. However, it is unclear how the yeast wall that protect/surrounds the orange oil will negatively affect oviposition since live yeast are normally consider an attractant for mosquito oviposition.

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Functional signal in an interaction network is a phenomenon in which species resembling each other in their traits interact with similar partners. We tested the functional signal concept in realm-specific and regional flea-host networks from four biogeographic realms and asked whether the species composition of (a) host spectra and (b) flea assemblages is similar between functionally similar flea and host species, respectively. Analogously to testing for phylogenetic signal, we applied Mantel tests to investigate the correlation between flea or host functional distances calculated from functional dendrograms and dissimilarities in sets of interacting partners. In all realm-specific networks, functionally similar fleas tended to exploit similar hosts often belonging to the same genus, whereas functionally similar hosts tended to harbour similar fleas, again often belonging to the same genus. The strength of realm-specific functional signals and the frequency of detecting a significant functional signal in the regional networks differed between realms. The frequency of detecting a significant functional signal in the regional networks correlated positively with the network size for fleas and with the number of hosts in a network for hosts. A functional signal in the regional networks was more frequently found for hosts than for fleas. We discuss the mechanisms behind the functional signal in both fleas and their hosts, relate geographic functional signal patterns to the historic biogeography of fleas and conclude that functional signals in the species composition of host spectra for fleas and of flea assemblages for hosts result from the interplay of evolutionary and ecological processes.

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A black skimmer (Rynchops niger) and a brown booby (Sula leucogaster) were rescued and gross, histopathological, immunohistochemical and polymerase chain reaction evaluations were conducted to investigate the cause of death. There were neoplastic infiltrations of CD3+ PAX5- lymphocytes in the black skimmer and CD3- PAX5+ lymphocytes in the brown booby. Molecular assays for viral agents were negative in both cases. This is the first report of disseminated lymphoma as the cause of stranding and death in these species in Brazil.

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We searched for common patterns in parasite ecology by investigating species and host contributions to the beta-diversity of infracommunities (=assemblages of parasites harboured by a host individual) in helminths of three species of South African ungulates and fleas of 11 species of South American rodents, assuming that a comparison of patterns in distinctly different parasites and hosts would allow us to judge the generality or, at least, commonness of these patterns. We used data on species' composition and numbers of parasites and asked whether (i) parasite species' attributes (life cycle, transmission mode, and host specificity in helminths; possession of sclerotized combs, microhabitat preference, and host specificity in fleas) or their population structure (mean abundance and/or prevalence) and (ii) host characteristics (sex and age) affect parasite and host species' contributions to parasite beta-diversity (SCBD and HCBD, respectively). We found that parasite species' morphological and ecological attributes were mostly not associated with their SCBD. In contrast, parasite SCBD, in both ungulates and rodents, significantly increased with either parasite mean abundance or prevalence or both. The effect of host characteristics on HCBD was detected in a few hosts only. In general, parasite infracommunities' beta-diversity appeared to be driven by variation in parasite species rather than the uniqueness of the assemblages harboured by individual hosts. We conclude that some ecological patterns (such as the relationships between SCBD and parasite abundance/prevalence) appear to be common and do not differ between different host-parasite associations in different geographic regions, whereas other patterns (the relationships between SCBD and parasite species' attributes) are contingent and depend on parasite and host identities.

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The Terminalia catappa L. tree is an ornamental and shade tree producter of a large amount of biological waste sent to landfills. Therefore, this plant constitutes so-called municipal solid wood waste (MSWW), which causes undesirable impacts on the environment, such as the generation of methane through the action of microorganisms. Sustainable solutions for the proper use and disposal of MSWW are a topic that has assumed great relevance at present due to the high quantities of MSWW generated worldwide. Pyrolysis constitutes an attractive alternative for the sustainable use of MSWW to produce higher value-added products. This study investigated the slow pyrolysis of Terminalia catappa L. fruit and the use of the aqueous fraction produced for bovine mastitis control. We obtained four fractions from the pyrolysis process, with average yields of the aqueous phase (36.22 ± 2.0 %), bio-oil (5.52 ± 0.4 %), biochar (37.55 ± 2.8 %) and gas (20.71 ± 2.0 %). The aqueous fraction was extracted with organic solvents and analyzed by gas chromatography coupled to mass spectrometry (GC‒MS). The extracts were composed mainly of phenols (50 %), furan derivatives, cyclic ketones, and others with lower contents, such as alcohols and esters. The aqueous fraction had bactericidal activity against Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli, which are responsible for bovine mastitis. In addition, the fraction showed low cytotoxicity against a murine melanoma cell line from a C57BL/6J mouse, B16F10 cells and mouse peritoneal cells.

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The pursuit of novel treatment alternatives to address the accumulated resistance to antimicrobials over the years has prompted the scientific community to explore biodiversity, particularly animal venom, as a potential source of new antimicrobial drugs. Snake venoms, with their complex mixtures of components, are particularly promising targets for investigation in this regard. The search for novel molecules exhibiting antimicrobial activity against multidrug-resistant strains is of paramount importance for public health and numerous research groups worldwide. High expectations within the healthcare field are supported by the scientific literature, which highlights the potential development of innovative drugs through in vivo and in vitro application, depending on dose titration. Snake venoms and their molecules and peptides offer exponential possibilities for biotechnological applications as antimicrobial agents. However, many uncertainties and unexplored avenues remain, presenting opportunities for discoveries and research.

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We studied the relationships between functional alpha and beta diversities of fleas and their small mammalian hosts in 4 biogeographic realms (the Afrotropics, the Nearctic, the Neotropics and the Palearctic), considering 3 components of alpha diversity (functional richness, divergence and regularity). We asked whether (a) flea alpha and beta diversities are driven by host alpha and beta diversities; (b) the variation in the off-host environment affects variation in flea alpha and beta diversities; and (c) the pattern of the relationship between flea and host alpha or beta diversities differs between geographic realms. We analysed alpha diversity using modified phylogenetic generalized least squares and beta diversity using modified phylogenetic generalized dissimilarity modelling. In all realms, flea functional richness and regularity increased with an increase in host functional richness and regularity, respectively, whereas flea functional divergence correlated positively with host functional divergence in the Nearctic only. Environmental effects on the components of flea alpha diversity were found only in the Holarctic realms. Host functional beta diversity was invariantly the best predictor of flea functional beta diversity in all realms, whereas the effects of environmental variables on flea functional beta diversity were much weaker and differed between realms. We conclude that flea functional diversity is mostly driven by host functional diversity, whereas the environmental effects on flea functional diversity vary (a) geographically and (b) between components of functional alpha diversity.

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Leishmaniases, a group of diseases caused by the species of the protozoan parasite Leishmania, remains a significant public health concern worldwide. Host immune responses play a crucial role in the outcome of Leishmania infections, and several mediators that regulate inflammatory responses are potential targets for therapeutic approaches. Annexin A1 (AnxA1), an endogenous protein endowed with anti-inflammatory and pro-resolving properties, has emerged as a potential player. We have shown that during L. braziliensis infection, deficiency of AnxA1 exacerbates inflammatory responses but does not affect parasite burden. Here, we have investigated the role of AnxA1 in L. amazonensis infection, given the non-healing and progressive lesions characteristic of this infectious model. Infection of AnxA1 KO BALB/c mice resulted in increased lesion size and tissue damage associated with higher parasite burdens and enhanced inflammatory response. Notably, therapeutic application of the AnxA1 peptidomimetic Ac2-26 improves control of parasite replication and increases IL-10 production in vivo and in vitro, in both WT and AnxA1 KO mice. Conversely, administration of WRW4, an inhibitor of FPR2/3, resulted in larger lesions and decreased production of IL-10, suggesting that the effects of AnxA1 during L. amazonensis infection are associated with the engagement of these receptors. Our study illuminates the role of AnxA1 in L. amazonensis infection, demonstrating its impact on the susceptibility phenotype of BALB/c mice. Furthermore, our results indicate that targeting the AnxA1 pathway by using the Ac2-26 peptide could represent a promising alternative for new treatments for leishmaniasis.

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Antifungal therapy, especially with the azoles, could promote the incidence of less susceptible isolates of Cryptococcus neoformans and C. gattii species complexes (SC), mostly in developing countries. Given that these species affect mostly the immunocompromised host, the infections are severe and difficult to treat. This review encompasses the following topics: 1. infecting species and their virulence, 2. treatment, 3. antifungal susceptibility methods and available categorical endpoints, 4. genetic mechanisms of resistance, 5. clinical resistance, 6. fluconazole minimal inhibitory concentrations (MICs), clinical outcome, 7. environmental influences, and 8. the relevance of host factors, including pharmacokinetic/pharmacodynamic (PK/PD) parameters, in predicting the clinical outcome to therapy. As of now, epidemiologic cutoff endpoints (ECVs/ECOFFs) are the most reliable antifungal resistance detectors for these species, as only one clinical breakpoint (amphotericin B and C. neoformans VNI) is available.

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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.

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We studied spatial variation in the effects of environment and network size on species positions and roles in multiple flea-mammal networks from four biogeographic realms. We asked whether species positions (measured as species strength [SS], the degree of interaction specialization [d'], and the eigenvector centrality [C]) or the roles of fleas and their hosts in the interaction networks: (a) are repeatable/conserved within a flea or a host species; (b) vary in dependence on environmental variables and/or network size; and (c) the effects of environment and network size on species positions or roles in the networks depend on species traits. The repeatability analysis of species position indices for 441 flea and 429 host species, occurring in at least two networks, demonstrated that the repeatability of SS, d', and C within a species was significant, although not especially high, suggesting that the indices' values were affected by local factors. The majority of flea and host species in the majority of networks demonstrated a peripheral role. A value of at least one index of species position was significantly affected by environmental variables or network size in 41 and 36, respectively, of the 52 flea and 52 host species that occurred in multiple networks. In both fleas and hosts, the occurrence of the significant effect of environment or network size on at least one index of species position, but not on a species' role in a network, was associated with some species traits.