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HIV-1 antiretroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses, leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here, we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 100-10,000× less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir, thereby influencing cytopathic effects and proviral immune evasion.
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Infecções por HIV , HIV-1 , Provírus , Transcrição Gênica , Integração Viral , Latência Viral , HIV-1/genética , HIV-1/fisiologia , Humanos , Provírus/genética , Latência Viral/genética , Integração Viral/genética , Infecções por HIV/virologia , Infecções por HIV/genética , Regulação Viral da Expressão Gênica , Regiões Promotoras Genéticas/genética , Linfócitos T CD4-Positivos/virologia , Linfócitos T/virologia , Linfócitos T/imunologia , Linhagem CelularRESUMO
Skeletal muscle atrophy is a morbidity and mortality risk factor that happens with disuse, chronic disease, and aging. The tissue remodeling that happens during recovery from atrophy or injury involves changes in different cell types such as muscle fibers, and satellite and immune cells. Here, we show that the previously uncharacterized gene and protein Zfp697 is a damage-induced regulator of muscle remodeling. Zfp697/ZNF697 expression is transiently elevated during recovery from muscle atrophy or injury in mice and humans. Sustained Zfp697 expression in mouse muscle leads to a gene expression signature of chemokine secretion, immune cell recruitment, and extracellular matrix remodeling. Notably, although Zfp697 is expressed in several cell types in skeletal muscle, myofiber-specific Zfp697 genetic ablation in mice is sufficient to hinder the inflammatory and regenerative response to muscle injury, compromising functional recovery. We show that Zfp697 is an essential mediator of the interferon gamma response in muscle cells and that it functions primarily as an RNA-interacting protein, with a very high number of miRNA targets. This work identifies Zfp697 as an integrator of cell-cell communication necessary for tissue remodeling and regeneration.
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Músculo Esquelético , Proteínas de Ligação a RNA , Animais , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/genética , Camundongos Knockout , Atrofia Muscular/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Camundongos Endogâmicos C57BL , Interferon gama/metabolismoRESUMO
Renal cell carcinoma is the most common adult renal solid tumor and the deadliest urological cancer, with clear cell renal cell carcinoma (ccRCC) being the predominant subtype. The PI3K/AKT signaling pathway assumes a central role in ccRCC tumorigenesis, wherein its abnormal activation confers a highly aggressive phenotype, leading to swift resistance against current therapies and distant metastasis. Thus, treatment resistance and disease progression remain a persistent clinical challenge in managing ccRCC effectively. PTEN, an antagonist of the PI3K/AKT signaling axis, emerges as a crucial factor in tumor progression, often experiencing loss or inactivation in ccRCC, thereby contributing to elevated mortality rates in patients. Therefore, understanding the molecular mechanisms underlying PTEN suppression in ccRCC tumors holds promise for the discovery of biomarkers and therapeutic targets, ultimately enhancing patient monitoring and treatment outcomes. The present review aims to summarize these mechanisms, emphasizing their potential prognostic, predictive, and therapeutic value in managing ccRCC.
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Stressful situations lead to change in or damage to the central nervous system, the hypothalamic-pituitary-adrenal axis, and autonomic function. Techniques for reducing stress such as yoga and mindfulness meditation have been reported to improve emotional regulation and mindfulness skill, as well as stress response. Mindfulness skill relies on intense focus to quiet the mind and bring concentration to the present moment. The present study was a randomized control trial to investigate the effects of an 8-week training program (three 45-minute sessions/week, one session with an instructor and two sessions as home practice) in mindfulness meditation or in yoga on stress and related variables in healthy people. Forty-four healthy participants were randomly allocated to one of three groups: a mindfulness group (n = 16), a yoga group (n = 13), and a control group (n = 15). The yoga training significantly modified heart rate variability, contributing to decreased relative power of the low-frequency band; the relative power of the high-frequency band increased after training. The mindfulness meditation training significantly improved mindfulness skill and concentration performance. In the present study, yoga was associated with increased heart rate variability and mindfulness meditation was associated with an increase in mindfulness skill and concentration performance.
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Meditação , Atenção Plena , Estresse Psicológico , Yoga , Humanos , Atenção Plena/métodos , Masculino , Estresse Psicológico/terapia , Feminino , Adulto , Frequência Cardíaca , Adulto JovemRESUMO
BACKGROUND: Continuous kidney replacement therapy (CKRT) has recently become the preferred kidney replacement modality for children with acute kidney injury (AKI). We hypothesise that CKRT technical parameters and treatment settings in addition to the clinical characteristics of patients may influence the circuit lifetime in children. METHODS: The study involved children included in the EurAKId registry (NCT02960867), who underwent CKRT treatment. We analysed patient characteristics and CKRT parameters. The primary end point was mean circuit lifetime (MCL). Secondary end points were number of elective circuit changes and occurrence of dialysis-related complications. RESULTS: The analysis was composed of 247 children who underwent 37,562 h of CKRT (median 78, IQR 37-165 h per patient). A total of 1357 circuits were utilised (3, IQR 2-6 per patient). MCL was longer in regional citrate anticoagulation (RCA), compared to heparin (HA) and no anticoagulation (NA) (42, IQR 32-58 h; 24, IQR 14-34 h; 18, IQR 12-24 h, respectively, p < 0.001). RCA was associated with longer MCL regardless of the patient's age or dialyser surface. In multivariate analysis, MCL correlated with dialyser surface area (beta = 0.14, p = 0.016), left internal jugular vein vascular access site (beta = -0.37, p = 0.027), and the use of HA (beta = -0.14, p = 0.038) or NA (beta = -0.37, p < 0.001) vs. RCA. RCA was associated with the highest ratio of elective circuit changes and the lowest incidence of complications. CONCLUSION: Anticoagulation modality, dialyser surface, and vascular access site influence MCL. RCA should be considered when choosing first-line anticoagulation for CKRT in children. Further efforts should focus on developing guidelines and clinical practice recommendations for paediatric CKRT.
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Aim: To develop a ß-AgVO3 gel and evaluate its physicochemical stability and antifungal activity against Candida albicans. Materials & methods: The gel was prepared from the minimum inhibitory concentration (MIC) of ß-AgVO3. The physicochemical stability was evaluated by centrifugation, accelerated stability (AS), storage (St), pH, syringability, viscosity and spreadability tests and antifungal activity by the agar diffusion. Results: The MIC was 62.5 µg/ml. After centrifugation, AS and St gels showed physicochemical stability. Lower viscosity and higher spreadability were observed for the higher ß-AgVO3 concentration and the minimum force for extrusion was similar for all groups. Antifungal effect was observed only for the ß-AgVO3 gel with 20xMIC. Conclusion: The ß-AgVO3 gel showed physicochemical stability and antifungal activity.
We used silver and vanadium to make a gel that can kill fungi in the mouth. We looked at the color of the gel, it's smell and also checked how well it lasted. The gel turned yellow and had no smell and did not spoil for at least 2 months. When we tested the gel against a type of fungus, it worked as well as another medicine called chlorhexidine, which is sold in pharmacies. But when we compared it with another medicine called nystatin, our gel was not as effective in killing the fungus.
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PURPOSE: This systematic review with meta-analysis aims to analyze the effects of different types of exercise on cognition, neuroprotective and neuroinflammatory blood markers in older adults with mild cognitive impairment (MCI). METHODS: Relevant studies were identified using PubMED, SPORTDiscuss, Web of Science, Scopus, and PsycInfo databases. Methodological quality assessment of the studies was done with modified Downs and Black checklist. Data obtained from the included studies was analyzed using Comprehensive Meta-Analysis 4.0 software and results were reported using the random effects method. RESULTS: A total of twenty-three studies were identified. The findings were summarized as change in cognitive function after the exercise interventions in general and after each type of exercise. On average, the exercise intervention revealed an effect size (ES): 1.165; 0.741 to 1.589 (95% Confidence Interval (CI); p < 0.001); aerobic exercise ES: 1.442; 0.624 to 2.260 (95 %CI); p = 0.001; Multimodal ES: 0,856; 0.366 to 1.346 (95 % CI); p = 0.001 and resistance exercise ES: 1.229; 0.339 to 2.120 (95 % CI); p = 0.007. In addition, we observed significant small ES: -0.475; -0.817 to -0.134 (95 %CI); p = 0.006, I2= 0 %; τ2 = 0 of exercise effects on Tumor Necrosis Factor-α (TNF-α) and non-significant large ES:0.952; -0.238 to 2.142 (95 %CI); p = 0.117 on Brain Derived Neurotrophic Factor (BDNF) in persons with MCI. CONCLUSION: The present study revealed the existence of a large positive effect of overall exercise intervention on cognitive function and a small effect on TNF-α in old people with MCI. Additionally, this study demonstrates that aerobic and resistance exercises had similar larger positive effects and were better than multimodal exercise on increasing cognition in older persons with MCI.
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To evaluate the microstructural characterization, mechanical properties and antimicrobial activity of acrylic resins incorporated with different concentrations of reduced graphene oxide (rGO). Specimens were made of self-cured and heat-cured acrylic resins for the control group and concentrations of 0.5%, 1%, and 3%. The microstructural characterization was evaluated by scanning electron microscopy (SEM) and energy-dispersive X-ray (EDS). For mechanical testing, flexural strength, and Knoop hardness tests were performed. Microbiological evaluations were performed by colony forming units (CFU) analysis, tetrazolium salt reduction (XTT), and SEM images. The modified acrylic resins showed increased mechanical properties at low concentrations (p < 0.05) and with reduced S. mutans (p < 0.05). Reduced graphene oxide interfered with the mechanical performance and microbiological properties of acrylic resins depending on the concentration of rGO, and type of polymerization and microorganism evaluated. The incorporation of graphene compounds into acrylic resins is an alternative to improve the antimicrobial efficacy and performance of the material.
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OBJECTIVES: Describe the characteristics and changes in the profile of women who sought care after experiencing sexual violence (SV) during the first six months of the COVID-19 pandemic in a Brazilian city. METHODS: This is a cross-sectional retrospective study. Data from emergency care and legal abortion requests of women assisted at the Women's Health Care Center Hospital (School of Medical Sciences, University of Campinas, Brazil) due to SV experienced between March 23 and August 23, 2020 (Quarantine Group, QG), were collected and compared with data from the same period of the previous biennium (Comparison Group, CG). χ2 and Fisher's exact tests were used to compare groups; the significance level was 5%. RESULTS: Data for 236 women were analyzed; 70 women were included in the QG and 166 in the CG. In the QG, there was a restriction in the area of origin of women, with a higher proportion of women who lived in Campinas (P = 0.0007) and a higher frequency of chronic SV (P = 0,035). There were no rapes associated with the use of social media or apps in the QG, but 9.8% of women in the CG experienced rape associated with the use of social media or apps. There were higher rates of domestic violence (P = 0.022) and intimidation through physical force (P = 0.011) in the first two months. CONCLUSION: The COVID-19 quarantine affected the profile of women who sought care after experiencing SV. The quarantine resulted in changes in the area of origin of patients, hindering access to health services and leading to higher rates of chronic and domestic SV, particularly in the first 2 months of the pandemic.
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Esta coletânea nos conduz por experiências trilhadas por educandos (as) e educadores (as) à colheita da Especialização e Aperfeiçoamento em Educação Popular e Promoção de Territórios Saudáveis na Convivência com o Semiárido com participantes do Ceará e do Rio Grande do Norte. Esse processo formativo se desenvolveu como uma das estratégias da Política Nacional de Educação Popular em Saúde (PNEPS-SUS) em uma profícua articulação entre movimentos de educação popular em saúde e movimentos que atuam no campo das lutas do campo e da cidade. No primeiro volume desta coletânea intitulada "Entrelaçando arte, cultura e saúde: possibilidades de coracionar o cuidado com a vida" estão as produções construídas por esse conjunto de sujeitos sociais durante o curso nos trabalhos de conclusão do curso, articulados na temática da arte, cultura e saúde. Neste segundo volume das produções advindas desses trabalhos de conclusão de curso tem como foco a participação popular a partir das experiências nos territórios. Assim, essa obra intitulada "Vozes que vem dos territórios: a participação popular que emerge do cotidiano" evidencia a diversidade de trilhas que advêm dessa questão geral a fim de que os leitores (as) possam refletir sobre as diversas formas de participação social e popular presente nas comunidades e territórios. Esta obra está organizada em três seções, a saber: "Lutas e Organização Popular em Territórios Urbanos, do Campo e das Águas"; "Educação do campo e promoção da saúde" e "A força das mulheres, das juventudes e do controle social em contextos urbanos e comunidades tradicionais". Ao trilhar essa obra esperamos que as reflexões aqui trazidas possam contribuir para fomentar, pensar e construir novas possibilidades e perspectivas de ampliação da participação popular, do protagonismo dos diferentes sujeitos sociais, na radicalização da democracia onde todas as decisões possam ter a voz e as diversas vozes presentes nos territórios onde os processos de saúde-adoecimento-cuidado e a defesa da vida acontecem no cotidiano.
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Humanos , Masculino , Feminino , Educação em Saúde , Promoção da Saúde , Aprendizagem Baseada em ProblemasRESUMO
In the search for alternatives to overcome the challenge imposed by drug resistance development in cancer treatment, the modulation of autophagy has emerged as a promising alternative that has achieved good results in clinical trials. Nevertheless, most of these studies have overlooked a novel and selective type of autophagy: chaperone-mediated autophagy (CMA). Following its discovery, research into CMA's contribution to tumor progression has accelerated rapidly. Therefore, we now understand that stress conditions are the primary signal responsible for modulating CMA in cancer cells. In turn, the degradation of proteins by CMA can offer important advantages for tumorigenesis, since tumor suppressor proteins are CMA targets. Such mutual interaction between the tumor microenvironment and CMA also plays a crucial part in establishing therapy resistance, making this discussion the focus of the present review. Thus, we highlight how suppression of LAMP2A can enhance the sensitivity of cancer cells to several drugs, just as downregulation of CMA activity can lead to resistance in certain cases. Given this panorama, it is important to identify selective modulators of CMA to enhance the therapeutic response.
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PURPOSE: We investigated the effects of a 16-week combined exercise training on body composition, metabolic and inflammatory markers in sedentary middle-aged workers. We also assessed whether significant alterations in metabolic markers were associated with changes in health-related outcomes. METHODS: This randomized controlled trial involved 46 participants randomly allocated into control and exercise groups. The exercise group performed 16-week combined aerobic and resistance training for 75 min/session, 3 times/week. Fasting blood samples were collected at baseline and after 16-week intervention to determine lipid profile, metabolic and inflammatory markers as primary outcomes. RESULTS: A total of 36 participants completed the intervention (53.70 ± 6.92 years old) (n = 18 in each group). Waist circumference (interaction effect: F = 7.423, p = 0.002), fat mass (interaction effect: F = 5.070, p = 0.011), and muscle mass (interaction effect: F = 5.420, p = 0.007) were improved in the exercise group compared to the control group. Fasting glucose increased after the 16-week follow-up (time effect: F = 73.253, p < 0.001), without an intergroup difference. Insulin levels were greater in the control compared to exercise group (group effect: F = 6.509, p = 0.015). The control group tended to increase the HOMA-IR index (interaction effect: F = 3.493, p = 0.070) and to decrease the QUICKI index (interaction effect: F = 3.364, p = 0.075) to a greater extent compared to the exercise group. Exercise group reduced leptin (interaction effect: F = 11.175, p = 0.002) and adiponectin (interaction effect: F = 4.437, p = 0.043) concentrations in a greater magnitude than control group. IL-6 (time effect: F = 17.767, p < 0.001) and TNF-α (time effect: F = 9.781, p = 0.004) concentrations decreased after the intervention, without an intergroup difference. IL-17A levels increased in the control compared to exercise group (interaction effect: F = 5.010, p = 0.033). Effects on adiponectin, IL-6 and IL-17A levels seem to depend on baseline BMI, age, and sex. Percentage changes in leptin correlated positively with changes in HOMA-IR index in the exercise (r = 0.565, p = 0.015) and control (r = 0.670, p = 0.002) groups. CONCLUSIONS: A combined training program can be an effective strategy to improve body composition and inflammatory markers and prevent marked reductions in insulin sensitivity among middle-aged workers.
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This study aimed to incorporate ß-AgVO3 and rGO into self-curing (SC) and heat-curing (HC) acrylic resins and to evaluate their physicochemical, mechanical, and antimicrobial properties while correlating them with the characterized material structure. Acrylic resin samples were prepared at 0 % (control), 0.5 %, 1 %, and 3 % for both nanoparticles. The microstructural characterization was assessed by scanning electron microscopy (SEM) (n = 1) and energy dispersive X-ray spectroscopy (EDS) (n = 1). The physicochemical and mechanical tests included flexural strength (n = 10), Knoop hardness (n = 10), roughness (n = 10), wettability (n = 10), sorption (n = 10), solubility (n = 10), porosity (n = 10), and color evaluation (n = 10). The microbiological evaluation was performed by counting colony-forming units (CFU/mL) and cell viability (n = 8). The results showed that the ß-AgVO3 samples showed lower counts of Candida albicans, Pseudomonas aeruginosa, and Streptococcus mutans due to their promising physicochemical properties. The mechanical properties were maintained with the addition of ß-AgVO3. The rGO samples showed higher counts of microorganisms due to the increase in physicochemical properties. It can be concluded that the incorporation of ß-AgVO3 into acrylic resins could be an alternative to improve the antimicrobial efficacy and performance of the material.
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Synthetic biology aims to contribute to the development of next-generation patient-specific cell-based therapies for chronic diseases especially through the construction of sophisticated synthetic gene switches to enhance the safety and spatiotemporal controllability of engineered cells. Indeed, switches that sense and process specific cues, which may be either externally administered triggers or endogenous disease-associated molecules, have emerged as powerful tools for programming and fine-tuning therapeutic outputs. Living engineered cells, often referred to as designer cells, incorporating such switches are delivered to patients either as encapsulated cell implants or by infusion, as in the case of the clinically approved CAR-T cell therapies. Here, we review recent developments in synthetic gene switches responsive to molecular stimuli, spanning regulatory mechanisms acting at the transcriptional, translational, and posttranslational levels. We also discuss current challenges facing clinical translation of cell-based therapies employing these devices.
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The CardioMEMS™ system remotely monitors changes in pulmonary artery pressures, which allows for early detection of heart failure worsening. It is a safe and reliable invasive monitoring system. We report a case in which there was a late migration of the device at 6 months of follow-up to the contralateral pulmonary artery. The mechanisms, consequences, and management of device migration are discussed. To our knowledge, there are very few published data on late sensor migration.
The CardioMEMS™ system keeps track of changes in lung artery pressure from a distance. This helps spot early signs of heart failure getting worse. It is a safe and dependable way to keep an eye on things inside the body. We describe a situation where the sensor moved to the opposite lung artery 6 months later. We talk about why this happens, what it means, and how to handle it. There is not much info out there about sensors moving late, as far as we know.
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Despite the array of mammalian transgene switches available for regulating therapeutic protein expression in response to small molecules or physical stimuli, issues remain, including cytotoxicity of chemical inducers and limited biocompatibility of physical cues. This study introduces gene switches driven by short peptides comprising eight or fewer amino acid residues. Utilizing a competence regulator (ComR) and sigma factor X-inducing peptide (XIP) from Streptococcus vestibularis as the receptor and inducer, respectively, this study develops two strategies for a peptide-activated transgene control system. The first strategy involves fusing ComR with a transactivation domain and utilizes ComR-dependent synthetic promoters to drive expression of the gene-of-interest, activated by XIP, thereby confirming its membrane penetrability and intracellular functionality. The second strategy features an orthogonal synthetic receptor exposing ComR extracellularly (ComREXTRA), greatly increasing sensitivity with exceptional responsiveness to short peptides. In a proof-of-concept study, peptides are administered to type-1 diabetic mice with microencapsulated engineered human cells expressing ComREXTRA for control of insulin expression, restoring normoglycemia. It is envisioned that this system will encourage the development of short peptide drugs and promote the introduction of non-toxic, orthogonal, and highly biocompatible personalized biopharmaceuticals for gene- and cell-based therapies.
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Peptídeos , Animais , Camundongos , Humanos , Peptídeos/genética , Peptídeos/farmacologia , Peptídeos/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/terapia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , TransgenesRESUMO
HIV-1 anti-retroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 10010,000X less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir thereby influencing cytopathic effects and proviral immune evasion.
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(1) Background: Psoriasis is a common chronic inflammatory skin disease with different manifestations, affecting the quality of life at social, emotional, and professional dimensions and requiring long-term treatment. This study aimed to investigate the effect of psychosocial and clinical factors on adherence to topical treatment in psoriasis. (2) Methods: Self-reported measures and weighing the medicines were used to assess adherence. Psychopathological symptoms were measured using the Brief Symptoms Inventory (BSI). Social and clinical factors were assessed by a sociodemographic and clinical questionnaire. Adherence to treatment with topical medication was assessed using a sample of 102 psoriasis patients. (3) Results: The explanatory models of adherence to topical treatment in psoriasis translated into positive associations between adherence and the education level (higher education) (p = 0.03; φ = 0.23), the single-family household (p = 0.01; φ = 0.44), active employment status (p = 0.05; φ = -0.19), familiar history of psoriasis (p = 0.04; φ = -0.21), and the presence of obsessive-compulsive symptoms (p = 0.01; d = 0.29). (4) Conclusions: In patients who present the characteristics identified that influence non-adherence, instructions should be reinforced to increase adherence. The experimental mortality (39.6%) reduced the sample size, representing a limitation of the study.
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BACKGROUND: Adolescent solitude was drastically impacted by the COVID-19 pandemic. As solitude is crucial for adolescent development through its association with both positive and negative developmental outcomes, it is critical to understand how adolescents' daily-life solitary experiences changed as a result of the pandemic. METHODS: Using three waves of Experience Sampling Method data from a longitudinal study, we compared adolescents' daily-life solitary experiences in the early (nT1=100; MAge=16.1; SDAge=1.9; 93% girls) and mid-pandemic (nT2=204; MAge=16.5; SDAge=2.0; 79% girls) to their pre-pandemic experiences. RESULTS: We found that adolescents with lower levels of pre-pandemic social support and social skills reported wanting to be alone less and feeling like an outsider more at both time points during the pandemic. In the mid-pandemic wave, adolescents with higher levels of pre-pandemic social support and social skills reported decreases in positive affect compared to the pre-pandemic wave. CONCLUSION: This study shows that adolescents' daily-life solitary experiences worsened throughout the COVID-19 pandemic. There should be continued concern for the wellbeing of all adolescents, not only those already at risk, as effects of the pandemic on mental health might only manifest later.