Exploring novel pyrazole-nitroimidazole hybrids: Synthesis and antiprotozoal activity against the human pathogen trichomonas vaginalis.

Trichomoniasis, a prevalent sexually transmitted infection (STI) caused by the protozoan Trichomonas vaginalis, has gained increased significance globally. Its relevance has grown in recent years due to its association with a heightened risk of acquiring and transmitting the human immunodeficiency virus (HIV) and other STIs. In addition, many publications have revealed a potential link between trichomoniasis and certain cancers. Metronidazole (MTZ), a nitroimidazole compound developed over 50 years ago, remains the first-choice drug for treatment. However, reports of genotoxicity and side effects underscore the necessity for new compounds to address this pressing global health concern. In this study, we synthesized ten pyrazole-nitroimidazoles 1(a-j) and 4-nitro-1-(hydroxyethyl)-1H-imidazole 2, an analog of metronidazole (MTZ), and assessed their trichomonacidal and cytotoxic effects. All compounds 1(a-j) and 2 exhibited IC50 values ≤ 20 µM and ≤ 41 µM, after 24 h and 48 h, respectively. Compounds 1d (IC50 5.3 µM), 1e (IC50 4.8 µM), and 1i (IC50 5.2 µM) exhibited potencies equivalent to MTZ (IC50 4.9 µM), the reference drug, after 24 h. Notably, compound 1i showed high anti-trichomonas activity after 24 h (IC50 5.2 µM) and 48 h (IC50 2.1 µM). Additionally, all compounds demonstrated either non-cytotoxic to HeLa cells (CC50 > 100 µM) or low cytotoxicity (CC50 between 69 and 100 µM). These findings suggest that pyrazole-nitroimidazole derivatives represent a promising heterocyclic system, serving as a potential lead for further optimization in trichomoniasis chemotherapy.

Synthesis and Anti-Trypanosoma cruzi Activity of New Pyrazole-Thiadiazole Scaffolds.

Chagas disease, a silent but widespread disease that mainly affects a socioeconomically vulnerable population, lacks innovative safe drug therapy. The available drugs, benznidazole and nifurtimox, are more than fifty years old, have limited efficacy, and carry harmful side effects, highlighting the need for new therapeutics. This study presents two new series of pyrazole-thiadiazole compounds evaluated for trypanocidal activity using cellular models predictive of efficacy. Derivatives 1c (2,4-diCl) and 2k (4-NO2) were the most active against intracellular amastigotes. Derivative 1c also showed activity against trypomastigotes, with the detachment of the flagellum from the parasite body being a predominant effect at the ultrastructural level. Analogs have favorable physicochemical parameters and are predicted to be orally available. Drug efficacy was also evaluated in 3D cardiac microtissue, an important target tissue of Trypanosoma cruzi, with derivative 2k showing potent antiparasitic activity and a significant reduction in parasite load. Although 2k potentially reduced parasite load in the washout assay, it did not prevent parasite recrudescence. Drug combination analysis revealed an additive profile, which may lead to favorable clinical outcomes. Our data demonstrate the antiparasitic activity of pyrazole-thiadiazole derivatives and support the development of these compounds using new optimization strategies.

Function of a multimodal signal: A multiple hypothesis test using a robot frog.

Multimodal communication may evolve because different signals may convey information about the signaller (content-based selection), increase efficacy of signal processing or transmission through the environment (efficacy-based selection), or modify the production of a signal or the receiver's response to it (inter-signal interaction selection). To understand the function of a multimodal signal (aggressive calls + toe flags) emitted by males of the frog Crossodactylus schmidti during territorial contests, we tested two hypotheses related to content-based selection (quality and redundant signal), one related to efficacy-based selection (efficacy backup), and one related to inter-signal interaction selection (context). For each hypothesis we derived unique predictions based on the biology of the study species. In a natural setting, we exposed resident males to a robot frog simulating aggressive calls (acoustic stimulus) and toe flags (visual stimulus), combined and in isolation, and measured quality-related traits from males and local levels of background noise and light intensity. Our results provide support to the context hypothesis, as toe flags (the context signal) are insufficient to elicit a receiver's response on their own. However, when toe flags are emitted together with aggressive calls, they evoke in the receiver qualitatively and quantitatively different responses from that evoked by aggressive calls alone. In contrast, we found no evidence that toe flags and aggressive calls provide complementary or redundant information about male quality, which are key predictions of the quality and redundant signal hypotheses respectively. Finally, the multimodal signal did not increase the receiver's response across natural gradients of light and background noise, a key prediction of the efficacy backup hypothesis. Toe flags accompanying aggressive calls seem to provide contextual information that modify the receiver's response in territorial contests. We suggest this contextual information is increased motivation to escalate the contest, and discuss the benefits to the signallers and receivers of adding a contextual signal to the aggressive display. Examples of context-dependent multimodal signals are rare in the literature, probably because most studies focus on single hypotheses assuming content- or efficacy-based selection. Our study highlights the importance of considering multiple selective pressures when testing multimodal signal function.

Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against Trypanosoma cruzi.

Chagas disease, a chronic and silent disease caused by Trypanosoma cruzi, is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and nifurtimox, two nitroheterocyclic drugs that show limited efficacy and severe side effects. The failure of potential drug candidates in Chagas disease clinical trials highlighted the urgent need to identify new effective chemical entities and more predictive tools to improve translational success in the drug development pipeline. In this study, we designed a small library of pyrazole derivatives (44 analogs) based on a hit compound, previously identified as a T. cruzi cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds 3g, 3j, and 3m as promising candidates, with IC50 values of 6.09 ± 0.52, 2.75 ± 0.62, and 3.58 ± 0.25 µM, respectively, against intracellular amastigotes. All pyrazole derivatives have good oral bioavailability prediction. The structure-activity relationship (SAR) analysis revealed increased potency of 1-aryl-1H-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the para-position. The 3m compound stands out for its trypanocidal efficacy in 3D microtissue, which mimics tissue microarchitecture and physiology, and abolishment of parasite recrudescence in vitro. Our findings encourage the progression of the promising candidate for preclinical in vivo studies.

Recently reported biological activities of pyrazole compounds.

The pyrazole nucleus is an aromatic azole heterocycle with two adjacent nitrogen atoms. Pyrazole derivatives have exhibited a broad spectrum of biological activities, and approved pyrazole-containing drugs include celecoxib, antipyrine, phenylbutazone, rimonabant, and dipyrone. Many research groups have synthesized and evaluated pyrazoles against several biological agents. This review examines recent publications relating the structures of pyrazoles with their corresponding biological activities.

Identification of influential events concerning the Antarctic ozone hole over southern Brazil and the biological effects induced by UVB and UVA radiation in an endemic treefrog species.

The increased incidence of solar ultraviolet radiation (UV) due to ozone depletion has been affecting both terrestrial and aquatic ecosystems and it may help to explain the enigmatic decline of amphibian populations in specific localities. In this work, influential events concerning the Antarctic ozone hole were identified in a dataset containing 35 years of ozone measurements over southern Brazil. The effects of environmental doses of UVB and UVA radiation were addressed on the morphology and development of Hypsiboas pulchellus tadpole (Anura: Hylidae), as well as on the induction of malformation after the conclusion of metamorphosis. These analyzes were complemented by the detection of micronucleus formation in blood cells. 72 ozone depletion events were identified from 1979 to 2013. Surprisingly, their yearly frequency increased three-fold during the last 17 years. The results clearly show that H. pulchellus tadpole are much more sensitive to UVB than UVA light, which reduces their survival and developmental rates. Additionally, the rates of micronucleus formation by UVB were considerably higher compared to UVA even after the activation of photolyases enzymes by a further photoreactivation treatment. Consequently, a higher occurrence of malformation was observed in UVB-irradiated individuals. These results demonstrate the severe genotoxic impact of UVB radiation on this treefrog species and its importance for further studies aimed to assess the impact of the increased levels of solar UVB radiation on declining species of the Hylidae family.

The new pyrazolyltetrazole derivative MSN20 is effective via oral delivery against cutaneous leishmaniasis.

An orally delivered, safe and effective treatment for leishmaniasis is an unmet medical need. Azoles and the pyrazolylpyrimidine allopurinol present leishmanicidal activity, but their clinical efficacies are variable. Here, we describe the activity of the new pyrazolyltetrazole hybrid, 5-[5-amino-1-(4'-methoxyphenyl)1H-pyrazole-4-yl]1H-tetrazole (MSN20). MSN20 showed a 50% inhibitory concentration (IC50) of 22.3 µM against amastigotes of Leishmania amazonensis and reduced significantly the parasite load in infected mice, suggesting its utility as a lead compound for the development of an oral treatment for leishmaniasis.

A Review of the Synthesis of Oxazoline Derivatives.

Oxazolines are important heterocyclic systems due to their biological activities, such as antibacterial, antimalarial, anticancer, antiviral, anti-inflammatory, antifungal, antipyretic, and antileishmanial. They have been widely applied as chiral auxiliaries, polymers, catalysts, protecting groups, building blocks, and ligands in asymmetric synthesis. Due to their importance, many synthetic routes to prepare oxazoline moieties have been investigated and developed by researchers around the world. In this review, we summarized several synthetic methodologies published in the literature. The main substrates are nitriles, carboxylic acids, and acid derivatives, which react with a variety of reactants under conventional heating, microwave irradiation or ultrasound irradiation conditions. Syntheses via intramolecular cyclisation from amides have also been reported. Many publications have highlighted procedures based on solvent-free conditions using eco-friendly, reusable, and easy-availability catalysts.

Microwave extraction and molecular imprinted polymer isolation of bergenin applied to the dendrochronological chemical study of Peltophorum dubium.

This study describes methodologies for extracting and isolating bergenin, a C-glucoside of 4-O-methylgallic acid found in some plants and it presents various in vitro and in vivo biological activities. Bergenin was previously obtained from the Pelthophorum dubim (Fabaceae) roots with a good yield. Conventional chromatographic procedures of the CHCl3 soluble fraction of the MeOH extract gave 3.62% of this glucoside. An HPLC/DAD method was also developed and validated for bergenin and its precursor, gallic acid quantifications. Microwave extractions with different solvents were tested to optimize the extraction of bergenin, varying the temperature and time. MAE (Microwave Assisted Extraction) was more efficient than conventional extraction procedures, giving a higher yield of bergenin per root mass (0.45% vs. 0.0839%). Molecularly imprinted polymer (MIP) and non-imprinted polymer (NIP) based on bergenin as the template molecule, methacrylic acid, and ethylene glycol dimethacrylate were synthesized and characterized by FTIR and SEM (Scanning Electron Microscopy). Bergenin adsorption experiments using MIP and NIP followed by molecular imprinted solid phase extraction (MISPE) showed that MIP had a higher selectivity for bergenin than NIP. A dendrochronological study using the proposed method for detection and quantification of gallic acid and bergenin in five P. dubium growth rings of a 31-year-old heartwood and in the phelloderm and barks indicated that bergenin was more abundant in the 11-14th growth rings of the heartwood and decreased from the heartwood to the barks.

Ecological modeling, biogeography, and phenotypic analyses setting the tiger cats' hyperdimensional niches reveal a new species.

Recently, the tiger-cat species complex was split into Leopardus tigrinus and Leopardus guttulus, along with other proposed schemes. We performed a detailed analysis integrating ecological modeling, biogeography, and phenotype of the four originally recognized subspecies-tigrinus, oncilla, pardinoides, guttulus-and presented a new multidimensional niche depiction of the species. Species distribution models used > 1400 records from museums and photographs, all checked for species accuracy. Morphological data were obtained from institutional/personal archives. Spotting patterns were established by integrating museum and photographic/camera-trap records. Principal component analysis showed three clearly distinct groups, with the Central American specimens (oncilla) clustering entirely within those of the Andes, namely the pardinoides group of the cloud forests of the southern Central-American and Andean mountain chains (clouded tiger-cat); the tigrinus group of the savannas of the Guiana Shield and central/northeastern Brazil (savanna tiger-cat); and the guttulus group in the lowland forests of the Atlantic Forest domain (Atlantic Forest tiger-cat). This scheme is supported by recent genetic analyses. All species displayed different spotting patterns, with some significant differences in body measurements/proportions. The new distribution presented alarming reductions from the historic range of - 50.4% to - 68.2%. This multidimensional approach revealed a new species of the elusive and threatened tiger-cat complex.

Synthesis and activity of novel tetrazole compounds and their pyrazole-4-carbonitrile precursors against Leishmania spp.

A new series of 5-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1H-tetrazole derivatives (4a-m) and their precursor 1-aryl-3-methyl-1H-pyrazole-4-carbonitriles (3a-m) were synthesized and evaluated as antileishmanials against Leishmania braziliensis and Leishmania amazonensis promastigotes in vitro. In parallel, the cytotoxicity of these compounds was evaluated on the RAW 264.7 cell line. The results showed that among the assayed compounds the substituted 3-chlorophenyl (4a) (IC50/24h=15±0.14 µM) and 3,4-dichlorophenyl tetrazoles (4d) (IC50/24h=26±0.09 µM) were the most potent against L. braziliensis promastigotes, as compared the reference drug pentamidine, which presented IC50=13±0.04 µM. In addition, 4a and 4d derivatives were less cytotoxic than pentamidine. However, these tetrazole derivatives (4) and pyrazole-4-carbonitriles precursors (3) differ against each of the tested species and were more effective against L.braziliensis than on L. amazonensis.

Diversity and associations between coastal habitats and anurans in southernmost Brazil.

This study aimed to verify the relationship between habitat and the composition of anuran species in dune and restinga habitats in southernmost Brazil. The habitats were sampled between April 2009 and March 2010 using pitfalls with drift fence. We have captured 13,508 individuals of 12 anuran species. Species richness was lower in the dunes and dominance was higher in the resting. Apparently the less complex plant cover, water availability, and wide daily thermal variation in dunes act as an environmental filter for frogs. This hypothesis is reinforced by the fact that the most abundant species (Physalaemus biligonigerus and Odonthoprynus maisuma) bury themselves in the sand, minimizing these environmental stresses. Despite being in the Pampa biome, the studied community was more similar to those of coastal restinga environment of southeast Brazil than with other of the Pampa biome. The number of recorded species is similar to those observed in other open habitats in Brazil, showing the importance of adjacent ones to the shoreline for the maintenance of the diversity of anurans in southernmost Brazil.

A new thioglycolic ester ß-cyclodextrin/PdCl2 in water: An accessible catalyst for the Suzuki-Miyaura coupling reaction.

A novel, easily prepared and accessible water-soluble supramolecular catalyst for the Suzuki-Miyaura CC coupling reaction was synthesized and characterized by FTIR, NMR, XRD, SEM, and HR-TEM. An inexpensive Pd(II) source added to the resulting aqueous solution of thioglycolic ester ß-cyclodextrin (1-TGA-SH-ß-CD/PdCl2) showed Pd nanoclusters and efficient catalytic activity for Suzuki-Miyaura CC coupling reactions of aryl halides with aryl boronic acids, employing K2CO3 as base, in an environmentally benign aqueous solution prepared in open flasks. Organic aryl halides including chlorides can produce moderate to excellent yields with aryl boronic acids and a small catalytic amount (0.01 mol%) of 1-TGA-SH-ß-CD/PdCl2. This hydro-soluble catalyst stock solution was stable for long periods (more than three months) and could be reused in two runs until showing loss of catalytic activity. Some experiments to understand the mechanism were performed, with the results suggesting incorporation of aryl halide in the catalytic cavity.

Synthesis by Microwave Irradiation, Molecular Structural Analysis and Trypanocidal Activity of Novel Pyrazole-tetrahydropyrimidine Derivatives.

BACKGROUND: A series of new eight 2-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1,4,5,6-tetrahydropyrimidines 1(a-h) were synthesized by microwave irradiation technique. In vitro phenotypic screening was performed to evaluate the effect of these compounds on intracellular amastigotes forms of Trypanosoma cruzi, the etiological agent of Chagas disease. METHODS: Compounds 1(a-h) were synthesized from pyrazole-carbonitriles 2(a-h) employing microwave irradiation (50W) for 10-20 minutes. Physicochemical properties were calculated using OSIRIS DataWarrior. The toxic effect on mammalian cells (Vero Cells) and the trypanocidal activity against Trypanosoma cruzi (Dm28c-Luc) were also evaluated. RESULTS: Compounds 1(a-h) were obtained in 24-94% yields. They were completely characterized by Fourier Transform Infrared (FT-IR), Nuclear Magnetic Resonance (NMR) and High-Resolution Mass Spectrometry (HRMS) analyses. The derivatives showed low trypanocidal activity, with IC50 ranging from 47.16 to > 100 µM, with lower activity than benznidazole (1.93 µM) used as reference drug. CONCLUSION: The attractive features of this synthetic methodology are mild conditions, short reaction time, and low power. All derivatives showed low toxicity in mammalian cells, good oral bioavailability, and did not violate Lipinski´s rule of 5.

Temporal pattern of humoral immune response in mild cases of COVID-19.

BACKGROUND: Understanding the humoral response pattern of coronavirus disease 2019 (COVID-19) is one of the essential factors to better characterize the immune memory of patients, which allows understanding the temporality of reinfection, provides answers about the efficacy and durability of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and consequently helps in global public health and vaccination strategy. Among the patients who became infected with SARS-CoV-2, the majority who did not progress to death were those who developed the mild COVID-19, so understanding the pattern and temporality of the antibody response of these patients is certainly relevant. AIM: To investigate the temporal pattern of humoral response of specific immunoglobulin G (IgG) in mild cases of COVID-19. METHODS: Blood samples from 191 COVID-19 real-time reverse transcriptase-polymerase chain reaction (RT-qPCR)-positive volunteers from the municipality of Toledo/ Paraná/Brazil, underwent two distinct serological tests, enzyme-linked immunosorbent assay, and detection of anti-nucleocapsid IgG. Blood samples and clinicoepidemiological data of the volunteers were collected between November 2020 and February 2021. All assays were performed in duplicate and the manufacturers' recommendations were strictly followed. The data were statistically analyzed using multiple logistic regression; the variables were selected by applying the P < 0.05 criterion. RESULTS: Serological tests to detect specific IgG were performed on serum samples from volunteers who were diagnosed as being positive by RT-qPCR for COVID-19 or had disease onset in the time interval from less than 1 mo to 7 mo. The time periods when the highest number of participants with detectable IgG was observed were 1, 2 and 3 mo. It was observed that 9.42% of participants no longer had detectable IgG antibodies 1 mo only after being infected with SARS-CoV-2 and 1.57% were also IgG negative at less than 1 mo. At 5 mo, 3.14% of volunteers were IgG negative, and at 6 or 7 mo, 1 volunteer (0.52%) had no detectable IgG. During the period between diagnosis by RT-qPCR/symptoms onset and the date of collection for the study, no statistical significance was observed for any association analyzed. Moreover, considering the age category between 31 and 59 years as the exposed group, the P value was 0.11 for the category 31 to 59 years and 0.32 for the category 60 years or older, showing that in both age categories there was no association between the pair of variables analyzed. Regarding chronic disease, the exposure group consisted of the participants without any comorbidity, so the P value of 0.07 for the category of those with at least one chronic disease showed no association between the two variables. CONCLUSION: A temporal pattern of IgG response was not observed, but it is suggested that immunological memory is weak and there is no association between IgG production and age or chronic disease in mild COVID-19.

Tuberculosis preventive treatment in children and adolescents: an observational study of secondary data.

OBJECTIVE: To analyze the effectiveness, safety, outcomes, and associated factors of tuberculosis preventive treatment (TPT) in children and adolescents in Paraná, southern Brazil. METHOD: This was an observational cohort study with a retrospective collection of secondary data from the TPT information systems of the state of Paraná from 2009 to 2016, and tuberculosis in Brazil from 2009 to 2018. RESULTS: In total, 1,397 people were included. In 95.4% of the individuals, the indication for TPT was a history of patient-index contact with pulmonary tuberculosis. Isoniazid was used in 99.9% of the cases with TPT, and 87.7% completed the treatment. The TPT protection was 98.7%. Among the 18 people who had TB, 14 (77.8%) became ill after the second year of treatment, and four (22.2%) in the first two years (p < 0.001). Adverse events were reported in 3.3% of cases, most of them were gastrointestinal and medication was discontinued in only 2 (0.1%) patients. No risk factors associated with the illness were observed. CONCLUSIONS: The authors observed a low rate of illness in pragmatics routine conditions in TPT for children and adolescents, especially within the first two years after the end of treatment, with good tolerability and a good percentage of adherence to the treatment. TPT should be encouraged to achieve the goals of the End TB Strategy of the World Health Organization as an essential strategy to reduce the incidence rate of the disease, but studies with new schemes must continue to be carried out in real-life scenarios.

Intensification of high cell-density cultivations of rE. coli for production of S. pneumoniae antigenic surface protein, PspA3, using model-based adaptive control.

This work proposes an innovative methodology to control high density fed-batch cultures of E. coli, based on measurements of the concentration of dissolved oxygen and on estimations of the cellular specific growth rate (µ), of the yield of biomass/limiting substrate (Y (xs)) and of the maintenance coefficient (m). The underlying idea is to allow cells to grow according to their metabolic capacity, without the constraints inherent to pre-set growth rates. Cellular concentration was assessed on-line through a capacitance probe. Three configurations of the control system were compared: (1) pre-set value for the three control parameters; (2) continuously updating µ; (3) updating µ, Y (xs) and m. Implementation of an efficient noise filter for the signal of the capacitance probe was essential for a good performance of the control system. The third control strategy, within the framework of an adaptive model-based control, led to the best results, with biomass productivity reaching 9.2 g(DCW)/L/h.

Bioactivity of Novel Pyrazole-Thiazolines Scaffolds against Trypanosoma cruzi: Computational Approaches and 3D Spheroid Model on Drug Discovery for Chagas Disease.

Chagas disease, a century-old disease that mainly affects the impoverished population in Latin America, causes high morbidity and mortality in endemic countries. The available drugs, benznidazole (Bz) and nifurtimox, have limited effectiveness and intense side effects. Drug repurposing, and the development of new chemical entities with potent activity against Trypanosoma cruzi, are a potential source of therapeutic options. The present study describes the biological activity of two new series of pyrazole-thiazoline derivatives, based on optimization of a hit system 5-aminopyrazole-imidazoline previously identified, using structure−activity relationship exploration, and computational and phenotype-based strategies. Promising candidates, 2c, 2e, and 2i derivatives, showed good oral bioavailability and ADMET properties, and low cytotoxicity (CC50 > 100 µM) besides potent activity against trypomastigotes (0.4−2.1 µM) compared to Bz (19.6 ± 2.3 µM). Among them, 2c also stands out, with greater potency against intracellular amastigotes (pIC50 = 5.85). The selected pyrazole-thiazoline derivatives showed good permeability and effectiveness in the 3D spheroids system, but did not sustain parasite clearance in a washout assay. The compounds' mechanism of action is still unknown, since the treatment neither increased reactive oxygen species, nor reduced cysteine protease activity. This new scaffold will be targeted to optimize in order to enhance its biological activity to identify new drug candidates for Chagas disease therapy.

Association of the "Weekend Warrior" and Other Leisure-time Physical Activity Patterns With All-Cause and Cause-Specific Mortality: A Nationwide Cohort Study.

Importance: It is unclear whether the weekly recommended amount of moderate to vigorous physical activity (MVPA) has the same benefits for mortality risk when activity sessions are spread throughout the week vs concentrated in fewer days. Objective: To examine the association of weekend warrior and other patterns of leisure-time physical activity with all-cause and cause-specific mortality. Design, Setting, and Participants: This large nationwide prospective cohort study included 350 978 adults who self-reported physical activity to the US National Health Interview Survey from 1997 to 2013. Participant data were linked to the National Death Index through December 31, 2015. Exposures: Participants were grouped by self-reported activity level: physically inactive (<150 minutes per week [min/wk] of MVPA) or physically active (≥150 min/wk of moderate or ≥75 min/wk of vigorous activity). The active group was further classified by pattern: weekend warrior (1-2 sessions/wk) or regularly active (≥3 session/wk); and then, by frequency, duration/session, and intensity of activity. Main Outcomes and Measures: All-cause, cardiovascular disease (CVD), and cancer mortality. Statistical analyses were performed in April 2022. Results: A total of 350 978 participants (mean [SD] age, 41.4 [15.2] years; 192 432 [50.8%] women; 209 432 [67.8%] Non-Hispanic White) were followed during a median of 10.4 years (3.6 million person-years). There were 21 898 deaths documented, including 4130 from CVD and 6034 from cancer. Compared with physically inactive participants, hazard ratios (HR) for all-cause mortality were 0.92 (95% CI, 0.83-1.02) for weekend warrior and 0.85 (95% CI, 0.83-0.88) for regularly active participants; findings for cause-specific mortality were similar. Given the same amount of total MVPA, weekend warrior participants had similar all-cause and cause-specific mortality rates as regularly active participants. The HRs for weekend warrior vs regularly active participants were 1.08 (95% CI, 0.97-1.20) for all-cause mortality; 1.14 (95% CI, 0.85-1.53) for CVD mortality; and 1.07 (95% CI, 0.87-1.31) for cancer mortality. Conclusions and Relevance: The findings of this large prospective cohort study suggest that individuals who engage in active patterns of physical activity, whether weekend warrior or regularly active, experience lower all-cause and cause-specific mortality rates than inactive individuals. Significant differences were not observed for all-cause or cause-specific mortality between weekend warriors and regularly active participants after accounting for total amount of MVPA; therefore, individuals who engage in the recommended levels of physical activity may experience the same benefit whether the sessions are performed throughout the week or concentrated into fewer days.

MAOA uVNTR Genetic Variant and Major Depressive Disorder: A Systematic Review.

Major Depressive Disorder (MDD) is a highly prevalent multifactorial psychopathology affected by neurotransmitter levels. Monoamine Oxidase A (MAOA) influences several neural pathways by modulating these levels. This systematic review (per PRISMA protocol and PECOS strategy) endeavors to understand the MAOA uVNTR polymorphism influence on MDD and evaluate its 3R/3R and 3R* genotypic frequencies fluctuation in MDD patients from different populations. We searched the Web of Science, PubMed, Virtual Health Library, and EMBASE databases for eligible original articles that brought data on genotypic frequencies related to the MAOA uVNTR variant in patients with MDD. We excluded studies with incomplete data (including statistical data), reviews, meta-analyses, and abstracts. Initially, we found 43 articles. After removing duplicates and applying the inclusion/exclusion criteria, seven articles remained. The population samples studied were predominantly Asians, with high 3R and 4R allele frequencies. Notably, we observed higher 3R/3R (female) and 3R* (male) genotype frequencies in the healthy control groups and higher 4R/4R (female) and 4R* (male) genotype frequencies in the MDD groups in the majority of different populations. Despite some similarities in the articles analyzed, there is still no consensus on the MAOA uVNTR variant's role in MDD pathogenesis.