Determination of Inhibitory Effect of PKM2 Enzyme and Antitumoral Activity of Novel Coumarin-Naphthoquinone Hybrids.

BACKGROUND: Oral squamous cell carcinoma (OSCC) represents the primary form of oral cancer, posing a significant global health threat. The existing chemotherapy options are accompanied by notable side effects impacting patient treatment adherence. Consequently, the exploration and development of novel substances with enhanced anticancer effects and fewer side effects have become pivotal in the realms of biological and chemical science. OBJECTIVE: This work presents the pioneering examples of naphthoquinone-coumarin hybrids as a new category of highly effective cytotoxic substances targeting oral squamous cell carcinoma (OSCC). METHODS: Given the significance of both naphthoquinones and coumarins as essential pharmacophores/ privileged structures in the quest for anticancer compounds, this study focused on the synthesis and evaluation of novel naphthoquinones/coumarin hybrids against oral squamous cell carcinoma. RESULTS: By several in vitro, in silico, and in vivo approaches, we demonstrated that compound 6e was highly cytotoxic against OSCC cells and several other cancer cell types and was more selective than current chemotherapeutic drugs (carboplatin) and the naphthoquinone lapachol. Furthermore, compound 6e was non-hemolytic and tolerated in vivo at 50 mg/kg with an LD50 of 62.5 mg/kg. Furthermore, compound 6e did not induce apoptosis and cell cycle arrest but led to intracellular vesicle formation with LC3 aggregation in autophagosomes, suggesting an autophagic cell death. Additionally, 6e had a high-affinity potential for PKM2 protein, higher than the known ligands, such as lapachol or shikonin, and was able to inhibit this enzyme activity in vitro. CONCLUSION: We assert that compound 6e shows promise as a potential lead for a novel chemotherapeutic drug targeting OSCC, with potential applicability to other cancer types.

Randomized, Multicenter Study to Assess the Effects of Different Doses of Sildenafil on Mortality in Adults With Pulmonary Arterial Hypertension.

BACKGROUND: Sildenafil, approved for pulmonary arterial hypertension (PAH), has a recommended adult dose of 20 mg TID, with a previously approved 5-mg TID dose by the US Food and Drug Administration. Safety concerns arose because of common off-label use of higher doses, particularly after pediatric data linked higher doses to increased mortality. To assess this, the Food and Drug Administration mandated a study evaluating the effects of various sildenafil doses on mortality in adults with PAH. METHODS: This randomized, double-blind study compared sildenafil at doses of 5, 20, or 80 mg TID in adults with PAH. The primary objective was noninferiority of 80 mg of sildenafil versus 5 mg for all-cause mortality. Secondary end points included time to clinical worsening and change in 6-minute walk distance at 6 months. Interim analyses were planned at 50% and 75% of the anticipated mortality events. Safety and tolerability were assessed in the intention-to-treat population. RESULTS: The study was halted after the first interim analysis, demonstrating noninferiority for 80 mg of sildenafil versus 5 mg. Of 385 patients enrolled across all dose groups, 78 died. The primary analysis showed a hazard ratio of 0.51 (99.7% CI, 0.22-1.21; P<0.001 for noninferiority) for overall survival comparing 80 mg of sildenafil with 5 mg. Time to clinical worsening favored 80 mg of sildenafil compared with 5 mg (hazard ratio, 0.44 [99.7% CI, 0.22-0.89]; P<0.001). Sildenafil at 80 mg improved 6-minute walk distance from baseline at 6 months compared with 5 mg (least square mean change, 18.9 m [95% CI, 2.99-34.86]; P=0.0201). No significant differences were found between 80 mg of sildenafil and 20 mg in mortality, clinical worsening, and 6-minute walk distance. Adverse event-related drug discontinuations were numerically higher with 80 mg of sildenafil. CONCLUSIONS: Sildenafil at 80 mg was noninferior to sildenafil at 5 mg when examining all-cause mortality in adults with PAH. Secondary efficacy end points favored 80 mg of sildenafil over 5 mg. On the basis of these findings, the Food and Drug Administration recently revoked the approval of 5 mg of sildenafil for adults with PAH, reinforced 20 mg TID as the recommended dose, and now allows dose titration up to 80 mg TID, if needed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060487.

Spider's Silk as a Potential Source of Antibiotics: An Integrative Review.

Spiders produce webs, which are still a largely unexplored source of antibacterial compounds, although the reports of its application in the medical field. Therefore, this study aims to present an integrative review of the antibacterial activity of spider webs. The research was conducted using Google Scholar, Scielo, Web of Science, PubMed, ScienceDirect, Medline EBSCO, LILACS, and Embase. The inclusion criteria were original articles written in English that studied the antibiotic properties of the web or isolated compounds tested. The studies were compared according to the spider species studied, the type of web, treatment of the sample, type of antimicrobial test, and the results obtained. Nine hundred and seventy-three publications were found, and after applying the inclusion and exclusion criteria, sixteen articles were selected. Bacterial inhibition was found in seven studies against various species of bacteria such as Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Salmonella Typhi, Bacillus megaterium, Listeria monocytogenes, Acinetobacter baumannii, Streptococcus pneumoniae, Pasteurella multocida, and Bacillus subtilis. Additionally, there was no apparent relationship between the proximity of the spider species evaluated in the studies and the presence or absence of activity. Methodological problems detected may affected the reproducibility and reliability of the results in some studies, such as the lack of description of the web or microorganism strain, as well as the absence of adequate controls and treatments to sterilize the sample. Spider webs can be a valuable source of antibiotics; however, more studies are needed to confirm the real activity of the web or components involved.

N, N'-disubstituted Ureas as Novel Antiplatelet Agents: Synthesis, Pharmacological Evaluation and In Silico Studies.

INTRODUCTION: Thrombotic disorders are among the leading causes of morbidity and mortality worldwide. Drugs used in the prevention and treatment of atherothrombosis have pharmacokinetic limitations and adverse effects such as hemorrhagic conditions, highlighting the importance of developing more effective antiplatelet agents. ethod: In this work, we synthesized N,N'-disubstituted ureas 3a-3j and evaluated their antiplatelet profiles through in vitro, ex vivo, and in silico studies. The synthesized derivatives exhibited a selective inhibitory profile against platelet aggregation induced by arachidonic acid (AA) in vitro, without significantly affecting other aspects of primary hemostasis and blood coagulation. The compounds that showed inhibition greater than 85% were submitted to the analysis of their potency by calculating the concentration required to inhibit 50% of platelet aggregation induced by AA (IC50). Urea derivative 3a was the most potent with IC50 of 1.45 µM. Interestingly, this derivative inhibited more than 90% of platelet aggregation induced by AA ex vivo, with a similar effect to acetylsalicylic acid. In the hemolysis assay, most of the urea derivatives presented values below 10% suggesting good hemocompatibility. Additionally, the compounds tested at 100 µM also showed no cytotoxic effects in HepG2 and Vero cells. RESULT: The in silico results suggested that compound 3a may bind to the key residue of COX-1 similar to AA and known COX-1 inhibitors, and the results are also in agreement with our SAR, which suggests that the inhibition of this enzyme is the most likely mechanism of antiplatelet activity. CONCLUSION: Therefore, these results demonstrated that N,N'-disubstituted ureas are promising candidates for the development of novel antiplatelet agents.

Antiviral evaluation of 1,4-disubstituted-1,2,3-triazole derivatives against Chikungunya virus.

Aim: This work aimed to investigate the antiviral activity of two 1,4-disubstituted-1,2,3-triazole derivatives (1 and 2) against Chikungunya virus (CHIKV) replication. Materials & methods: Cytotoxicity was analyzed using colorimetric assays and the antiviral potential was evaluated using plaque assays and computational tools. Results: Compound 2 showed antiviral activity against CHIKV 181-25 in BHK-21 and Vero cells. Also, this compound presented a higher activity against CHIKV BRA/RJ/18 in Vero cells, like compound 1. Compound 2 exhibited virucidal activity and inhibited virus entry while compound 1 inhibited virus release. Molecular docking suggested that these derivatives inhibit nsP1 protein while compound 1 may also target capsid protein. Conclusion: Both compounds exhibit promising antiviral activity against CHIKV by blocking different steps of virus replication.

Social protection as a right of people affected by tuberculosis: a scoping review and conceptual framework.

BACKGROUND: Tuberculosis is an infectious disease strongly influenced by social determinants closely associated with cycles of poverty and social exclusion. Within this context, providing social protection for people affected by the disease constitutes a powerful instrument for reducing inequalities and enhancing inclusion and social justice. This study aimed to identify and synthesize strategies and measures aimed at ensuring social protection as a right of people affected by tuberculosis. METHODS: This is a scoping review, with searches conducted in six databases in February 2023. We included publications from 2015 onwards that elucidate strategies and measures of social protection aimed at safeguarding the rights to health, nutrition, employment, income, housing, social assistance, and social security for people affected by tuberculosis. These strategies could be implemented through policies, programs, and/or governmental agreements in any given context. The data extracted from the articles underwent descriptive analysis and a narrative synthesis of findings based on the dimensions of social protection. Additionally, we developed a conceptual framework illustrating the organizational and operational aspects of measures and strategies related to each dimension of social protection identified in this review. RESULTS: A total of 9317 publications were retrieved from the databases, of which sixty-three publications were included. The study's results highlighted measures and strategies concerning the social protection of people affected by tuberculosis. These measures and strategies revolved around the rights to proper nutrition and nourishment, income, housing, and health insurance, as well as expanded rights encompassing social assistance and social welfare. It was reported that ensuring these rights contributes to improving nutritional status and the quality of life for individuals with tuberculosis, along with reducing catastrophic costs, expanding access to healthcare interventions and services, and fostering TB treatment adherence, thereby leading to higher rates of TB cure. CONCLUSIONS: Our findings identify social protection measures as a right for people affected by tuberculosis and have the potential to guide the development of evidence-based social and health policies through collaboration between tuberculosis control programs and governmental entities.

Anticancer Activity and Molecular Targets of Piper cernuum Substances in Oral Squamous Cell Carcinoma Models.

Oral squamous cell carcinoma (OSCC) is a worldwide public health problem, with high morbidity and mortality rates. The development of new drugs to treat OSCC is paramount. Piper plant species have shown many biological activities. In the present study, we show that dichloromethane partition of Piper cernuum (PCLd) is nontoxic in chronic treatment in mice, reduces the amount of atypia in tongues of chemically induced OSCC, and significantly increases animal survival. To identify the main active compounds, chromatographic purification of PCLd was performed, where fractions 09.07 and 14.05 were the most active and selective. These fractions promoted cell death by apoptosis characterized by phosphatidyl serine exposition, DNA fragmentation, and activation of effector caspase-3/7 and were nonhemolytic. LC-DAD-MS/MS analysis did not propose matching spectra for the 09.07 fraction, suggesting compounds not yet known. However, aporphine alkaloids were annotated in fraction 14.05, which are being described for the first time in P. cernuum and corroborate the observed cytotoxic activity. Putative molecular targets were determined for these alkaloids, in silico, where the androgen receptor (AR), CHK1, CK2, DYRK1A, EHMT2, LXRß, and VEGFR2 were the most relevant. The results obtained from P. cernuum fractions point to promising compounds as new preclinical anticancer candidates.

Chloroquinolone Carboxamide Derivatives as New Anti-HSV-1 Promising Drugs.

BACKGROUND: Since the emergence of HSV resistant strains, new antiviral agents have emerged and still are urgently needed, especially those with alternative targets. OBJECTIVE: In this work, we evaluated new quinolone derivatives as anti-HSV. METHODS: For this study, cells were infected and treated with different components to evaluate the profile of HSV replication in vitro. In addition, studies were performed to determine the pharmacokinetic toxicity and profile of the compound. RESULTS: Indeed the EC50 values of these promising molecules ranged between 8 µM and 32 µM. We have also showed that all compounds inhibited the expression of ICP27 viral proteins, which gives new insights in the search for new target for antiherpetic therapy. Chlorine in positions C6 and phosphonate in position C1 have shown to be important for viral inhibition. The chloroquinolone carboxamide derivatives fulfilled "Lipinsky Rule of Five" for good oral bioavailability and showed higher intestinal absorption and blood brain barrier penetration, as well as lower toxicity profile. CONCLUSION: Although the inhibition activities of chloroquinolone carboxamide derivatives were lower than acyclovir, they showed different modes of action in comparison to the drugs currently available. These findings encourage us to continue pre-clinical studies for the development of new anti-HSV-1 agents.

Tecnologias educacionais em saúde para adolescentes e jovens lgbti+: revisão integrativa / Tecnologías educativas en salud para adolescentes y jóvenes lgbti+: revisión integradora / Educational technologies in health for adolescent and young lgbti+: integrative review

RESUMO Objetivo: analisar o desenvolvimento e o uso de tecnologias educacionais em saúde para adolescentes e jovens lésbicas, gays, bissexuais, travestis, transexuais, pessoas intersexo e mais da diversidade sexual e de gênero (LGBTI+). Método: revisão integrativa de literatura, conduzida pela estratégia PICo, com busca nas bases de dados: MEDLINE via PubMed, CINAHL, Embase, Scopus, LILACS e Web of Scienceatualizadaem abril e maio de 2023. Na etapa de seleção, o levantamento bibliográfico foi organizado pelo gerenciador de referências Mendeley® com auxílio do software colaborativo em revisões Rayyan®. Resultados: onze artigos compuseram a amostra final, evidenciando o uso de programas de intervenções virtuais, do vídeo interativo e a utilização de grupos focais e fóruns de discussão virtual como recursos significativos desenvolvidos como intervenções em saúde digital para adolescentes e jovens LGBTI+. Considerações Finais: as tecnologias analisadas têm potencial para lhes alcançar de modo consistente, apoiando seus processos de conhecimento e as tomadas de decisões sobre sua saúde, sendo fontes significativas de informação e aprendizagem, com o acesso virtual representando uma oportunidade-chave no contexto da saúde digital. Recomendam-se fontes digitais de base científica nos cuidados à saúde de adolescentes e jovens LGBTI+.

RESUMEN Objetivo: analizar el desarrollo y uso de tecnologías educativas en salud para adolescentes y jóvenes lesbianas, gays, bisexuales, travestís, transexuales, personas intersexuales y más de la diversidad sexual y de género (LGBTI+). Método: revisión integradora de la literatura, conducida por la estrategia PICo, con búsqueda en las bases de datos: MEDLINE vía PubMed, CINAHL, Embase, Scopus, LILACS y Web ofScience actualizada en abril y mayo de 2023. En la etapa de selección, el estudio bibliográfico fue organizado por el gestor de referencias Mendeley® con ayuda del software colaborativo en revisiones Rayyan®. Resultados: once artículos compusieron la muestra final, evidenciando el uso de programas de intervenciones virtuales, del vídeo interactivo y la utilización de grupos focales y foros de discusión virtual como recursos significativos desarrollados como intervenciones en salud digital para adolescentes y jóvenes LGBTI+. Consideraciones finales: las tecnologías analizadas tienen potencial para alcanzarles de manera consistente, apoyando sus procesos de conocimiento y las decisiones sobre su salud, siendo fuentes significativas de información y aprendizaje, con el acceso virtual representando una oportunidad clave en el contexto de la salud digital. Se recomiendan fuentes digitales de base científica en el cuidado de la salud de adolescentes y jóvenes LGBTI+.

ABSTRACT Objective: to analyze the development and use of educational health technologies for adolescent and young lesbians, gays, bisexuals, transvestites, transsexuals, intersex people and more of sexual and gender diversity (LGBTI+). Method: integrative literature review, conducted by the PICo strategy, with search in the databases: MEDLINE via PubMed, CINAHL, Embase, Scopus, LILACS and Web of Science updated in April and May 2023. In the selection stage, the bibliographic survey was organized by the reference manager Mendeley® with the aid of collaborative software in Rayyan®. Results: eleven articles composed the final sample, evidencing the use of virtual the use of focus groups and virtual discussion forums as significant resources developed as digital health interventions for adolescent and young LGBTI+. Final Thoughts: the technologies analyzed have the potential to reach them consistently, supporting their knowledge processes and decision making about their health, being significant sources of information and learning, with virtual access representing a key opportunity in the context of digital health. Scientific-based digital sources are recommended in the health care of adolescent and young LGBTI+.

Integral health care for transgender adolescents: subsidies for nursing practice.

OBJECTIVE: to analyze the integral health care for transgender adolescents from the perspective of their guardians. METHOD: qualitative research based on the Social Network framework proposed by Lia Sanicola, developed with 22 guardians of transgender adolescents in Brazil through semi-structured individual online interviews. The empirical material was analyzed using the content analysis technique, thematic modality. RESULTS: lack of ambience was observed, in addition to technical unpreparedness of health professionals in relation to the theme at all levels of care, transphobia, centralization of care in scarce qualified services for transgender children and youth, absence of family support, lack of health promotion actions within the community, especially in the school environment, and the common support from non-governmental initiatives. CONCLUSION: the centralization of actions in scarce specialized services in the country, and the structural transphobia can compromise the integral health care for transgender adolescents. There is an urgent need for a network of care capable of assisting the joint action by multi and interdisciplinary teams, with greater proactivity of the nurse with the transgender adolescent and their guardians in individual and collective actions; ambience; health promotion in schools for visibility and support in Primary Health Care since childhood. HIGHLIGHTS: (1) Need for a network of care concerning integral health care for transgender adolescents.(2) Centralization and scarce qualified services for transgender children and youth.(3) Invisible families, lack of health promotion within the community.(4) Unpreparedness of health professionals and disarticulation of the health care network.(5) Need for qualification of nurses when caring for transgender people.

26-Week Open-Label Extension Study Evaluating the Safety and Tolerability of Flexible Doses of Oral Ziprasidone in Children and Adolescents with Bipolar I Disorder (Most Recent Episode Manic).

Objective: To describe the longer-term effectiveness, safety, and tolerability of open-label ziprasidone in children and adolescents with bipolar I disorder (BD-I). Methods: A subset of 23 participants aged 10-17 years, who were previously treated in a multi-site, 4-week randomized controlled trial received open-label ziprasidone (20-80 mg twice a day) for up to 26 weeks. Results: The most common adverse events (AEs) were fatigue (30%), somnolence (17%), and nausea (13%). Effects on weight, body mass index, and metabolic parameters (glucose, cholesterol, and triglycerides) were minimal. No participant had a Fridericia-corrected QT interval ≥ 460 msec or a change from baseline of ≥60 msec, and there were no cardiac-related AEs. Both the participants who continued ziprasidone and those who initiated ziprasidone in the open-label extension showed improvements in their symptoms of mania. Conclusions: The overall findings of the study are consistent with the accumulating knowledge on the safety profile of ziprasidone in the acute and long-term treatment of children and adolescents with BD-I, in the midst of a manic episode. ClinicalTrial.gov ID: NCT03768726.

Technology for nursing consultation with transsexual women in the light of Leininger's transcultural theory.

OBJECTIVE: to describe the construction and validation of a nursing consultation technology for transgender women. METHODS: a methodological study developed in three stages with construction based on the Leininger's Cross-Cultural Theory, content validation performed by experts in transgender sexual health and evaluation by nurses of care for transgender women. Items with a minimum agreement of 80% were considered validated, according to the Content Validity Index and binomial test. RESULTS: the technology contains 59 items in three blocks: the first, for identification of the transsexual woman; the second, with the Clinical Data; and the third, regarding the Propaedeutics of Care. All items reached agreement higher than 0.8 and an overall Validity Index of 80%. CONCLUSIONS: the technology was content-validated and evaluated by nurses and can be applicable in clinical and outpatient practice as well as in academia to promote quality care for transgender women.

Structural insights into the inhibition of the nsP2 protease from Chikungunya virus by molecular modeling approaches.

Chikungunya virus (CHIKV) is the etiological agent of the Chikungunya fever which has spread worldwide. Clinically, this disease may lead to prolonged incapacitating joint pain that can compromise remarkably the patients' quality of life. However, there are no licensed vaccines or specific drugs to fight this infection yet, making the search for novel therapies an imperative need. In this scenario, the CHIKV nsP2 protease emerged as an attractive therapeutic target once this protein plays a pivotal role in viral replication and pathogenesis. Hence, we investigated the structural basis for the inhibition of this enzyme by using molecular docking and dynamics simulations. Compounds with inhibitory activities against CHIKV nsP2 protease determined experimentally were selected from the literature. Docking studies with a set of stereoisomers showed that trans isomers, but not cis ones, bound close to the catalytic dyad which may explain isomerism requirements to the enzyme's inhibition. Further, binding mode analyses of other known inhibitors revealed highly conserved contacts between inhibitors and enzyme residues like N1011, C1013, A1046, Y1079, N1082, W1084, L1205, and M1242. Molecular dynamics simulations reinforced the importance of some of these interactions and pointed to nonpolar interactions as the main forces for inhibitors' binding. Finally, we observed that true inhibitors exhibited lower structural fluctuation, higher ligand efficiency and did not induce significant changes in protein correlated motions. Collectively, our findings might allow discerning true inhibitors from false ones and can guide drug development efforts targeting the nsP2 protease to fight CHIKV infections in the future.

Pro-Apoptotic Antitumoral Effect of Novel Acridine-Core Naphthoquinone Compounds against Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in combination, usually lead to important side effects. Thus, the discovery and development of new antineoplastic drugs are essential to improve disease prognosis and reduce toxicity. In the present study, acridine-core naphthoquinone compounds were synthesized and evaluated for their antitumor activity in OSCC cells. The mechanism of action, pharmacokinetics, and toxicity parameters of the most promising compound was further analyzed using in silico, in vitro, and in vivo methods. Among the derivatives, compound 4e was highly cytotoxic (29.99 µM) and selective (SI 2.9) at levels comparable and generally superior to chemotherapeutic controls. Besides, compound 4e proved to be non-hemolytic, stable, and well tolerated in animals at all doses tested. Mechanistically, compound 4e promoted cell death by apoptosis in the OSCC cell, and molecular docking studies suggested this compound possibly targets enzymes important for tumor progression, such as RSK2, PKM2, and topoisomerase IIα. Importantly, compound 4e presented a pharmacological profile within desirable parameters for drug development, showing promise for future preclinical trials.

Support for Mothers, Fathers, or Guardians of Transgender Children and Adolescents: A Systematic Review on the Dynamics of Secondary Social Networks.

Mothers', fathers', or guardians' support for disclosures of diverse gender identity has significant relationships with decreased suicidality for transgender children and adolescents. They play an essential role in facing transphobia, protecting trans children, and strengthening the expression of their identity. These guardians need structural, emotional, and informative support; they need to be prepared to recognize and manage of their own feelings, as well as deal with the challenges that come with new social contexts of transphobia in schools, health institutions, and other community spaces. This study aimed to analyze the scientific evidence on the dynamics of secondary social networks to support mothers, fathers, or guardians of transgender children and adolescents. This is a systematic review of qualitative studies, guided by PRISMA guidelines. Controlled and free vocabularies were used to survey the primary studies in the following databases: EMBASE; Scopus; MEDLINE; Cumulative Index to Nursing and Allied Health Literature (CINAHL); PsycInfo; Latin American and Caribbean Literature in Health Sciences (LILACS); and Web of Science. A total of 28 articles made up the final sample of this review. Secondary social networks were described as fragile, characterized by conflicting and broken ties with healthcare services and professionals, isolation and unpreparedness from schools, and emotional and informational support from peer groups and some qualified healthcare professionals. The literature shows the potential of the dynamics of secondary social support networks; however, it presented the unpreparedness of professionals and institutional policies for welcoming transgender children and adolescents and their families, with the peer group being the main emotional and informative support network.

Dynamics of Primary Social Networks to Support Mothers, Fathers, or Guardians of Transgender Children and Adolescents: A Systematic Review.

Mothers, fathers, or guardians of children and adolescents who do not identify with the gender they were assigned at birth face barriers in their social network to recognize their children's gender identity. This study aimed to analyze the scientific evidence on the dynamics of primary social networks to support mothers, fathers, or guardians of transgender children and adolescents. This is a systematic review of qualitative studies guided by the PRISMA guidelines. Controlled and free vocabulary were used to survey the studies in the EMBASE, Scopus, MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo, Latin American and Caribbean Literature in Health Sciences (LILACS), and Web of Science databases. A total of 21 studies composed the final sample. Primary social networks were described as fragile and conflicting family/blood relationship ties with disapproval, isolation, rejection, a lack of understanding, and feelings of exclusion were expressed. Some have lost friends, reported tension in marriage and with relatives, and were commonly treated with hostility and harassment. Social transition does take place in the mutual context of struggle and resistance which demands a support network for parents or guardians.

Efficacy, Safety, and Tolerability of Flexibly Dosed Ziprasidone in Children and Adolescents with Mania in Bipolar I Disorder: A Randomized Placebo-Controlled Replication Study.

Objective: To evaluate the acute efficacy, safety, and tolerability of flexibly dosed ziprasidone in children and adolescents with Bipolar I Disorder (BD-I). Methods: Participants, 10-17 years of age, meeting The Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria, were randomized 1:1 in a 4-week double-blind (DB) study, to receive ziprasidone (20-80 mg/twice a day) or placebo. Some were then enrolled in a 26-week open-label extension (OLE) study. The primary efficacy measure was the Young Mania Rating Scale (YMRS) total score. Results: A total of 171 participants entered this randomized DB study and 23 continued into the OLE study. The mean (SD) age of the combined sample was 13.4 (2.1) years, 44.4% were male, and 66.7% were white. The demographic characteristics of participants who received ziprasidone (n = 86) or placebo (n = 85) were similar. The primary objective was met: the mean difference for ziprasidone versus placebo in the YMRS total score was -4.23 (95% confidence interval: -7.14 to -1.32; p = 0.005) indicating an effect size of 0.58. The most common adverse events (AEs) in the ziprasidone group were somnolence (31.4%), fatigue (22.1%), and nausea (14%). The mean Fridericia-corrected QT interval (QTcF) intervals in the ziprasidone group were moderately prolonged relative to the placebo group at all study visits. No participants had QTcF intervals ≥480 msec or an increase from baseline ≥60 msec. No AEs indicative of QT prolongation occurred. Weight, body mass index (BMI), and BMI z-scores, and metabolic measures were similar in both treatment groups. The data from the OLE study will be reported separately. Conclusions: Ziprasidone was effective in children and adolescents with BD-I in a manic episode, replicating the results of a previous study with a similar design (Findling et al. 2013). Overall, ziprasidone was safe and well tolerated with no meaningful effects on weight or metabolic parameters. Trial registration: ClinicalTrials.gov. NCT02075047 and NCT03768726.

Gender violence perpetrated against trans women.

OBJECTIVES: to identify scientific evidence on gender violence perpetrated against trans women. METHODS: integrative review, carried out in June 2020, without time frame, in the Scopus, MEDLINE, Embase, CINAHL, WoS, PsycInfo and LILACS databases. The controlled descriptors of DeCS, MeSH and their entry terms were used: "Transgender People", "Transgender", "Gender Identity", "Transsexuality", "Gender Violence", "Aggression", "Sexual Offenses", "Rape", "Violence", "Domestic Violence". The presentation and synthesis of the results were presented in the PRISMA-2009 flowchart. RESULTS: the final sample, consisting of 16 articles, identified different types of violence (sexual, physical, verbal, psychological and financial), perpetrated by family members, strangers, police officers, intimate partners, health professionals, acquaintances, or friends. CONCLUSIONS: trans women suffer violence and social exclusion that result from stigma and discrimination due to gender identity and result in unrestricted damage to physical health.

Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19.

BACKGROUND: Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan-human-coronavirus activity in vitro. METHODS: We conducted a phase 2-3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19-related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. RESULTS: A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], -9.04 to -3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of -5.81 percentage points (95% CI, -7.78 to -3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmatrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. CONCLUSIONS: Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.).

Prognostic relevance of magnesium alterations in patients with a myocardial infarction and left ventricular dysfunction: insights from the EPHESUS trial.

AIMS: Magnesium changes are common in myocardial infarction (MI) complicated with left ventricular systolic dysfunction (LVSD) and/or heart failure (HF). The relation between serum magnesium and clinical outcomes is insufficiently elucidated in this population. METHODS AND RESULTS: The EPHESUS trial randomized 6632 patients to either eplerenone or placebo. Hypomagnesemia and hypermagnesemia were defined as a serum magnesium <0.66 and >1.10 mmol/L, respectively. Linear mixed models and time-dependent Cox regression analysis were used to determine the effect of eplerenone on magnesium changes and the prognostic importance of magnesium. The co-primary outcomes were all-cause mortality and a composite of cardiovascular (CV) mortality and CV hospitalization. A total of 5371 patients had a post-baseline magnesium measurement. At baseline, 231 (4.3%) patients had hypomagnesemia and 271 (5.0%) patients had hypermagnesemia. During a median follow-up of 16 months, 682 (13%) developed hypomagnesemia and 512 (9.5%) hypermagnesemia. Eplerenone treatment did not result in a different magnesium level during follow-up (P = 0.14). After covariate adjustment hypo- and hypermagnesemia were not associated with a higher risk of CV events. Magnesium levels did not modulate the effect of a high potassium (>5 mmol/L) or low potassium (<4 mmol/L) on the clinical outcome. Baseline magnesium levels did not influence the treatment effect of eplerenone (P-interaction > 0.1 for all primary and secondary endpoints). CONCLUSION: In patients with MI complicated by LVSD or HF, magnesium alterations were not associated with clinical outcomes nor did they influence the effect of eplerenone. Serum magnesium did not modulate the effect of potassium changes on clinical outcome or the treatment effect of eplerenone. CLINICALTRIALS.GOV IDENTIFIER: NCT00232180.