Genome-wide signatures of complex introgression and adaptive evolution in the big cats.

The great cats of the genus Panthera comprise a recent radiation whose evolutionary history is poorly understood. Their rapid diversification poses challenges to resolving their phylogeny while offering opportunities to investigate the historical dynamics of adaptive divergence. We report the sequence, de novo assembly, and annotation of the jaguar (Panthera onca) genome, a novel genome sequence for the leopard (Panthera pardus), and comparative analyses encompassing all living Panthera species. Demographic reconstructions indicated that all of these species have experienced variable episodes of population decline during the Pleistocene, ultimately leading to small effective sizes in present-day genomes. We observed pervasive genealogical discordance across Panthera genomes, caused by both incomplete lineage sorting and complex patterns of historical interspecific hybridization. We identified multiple signatures of species-specific positive selection, affecting genes involved in craniofacial and limb development, protein metabolism, hypoxia, reproduction, pigmentation, and sensory perception. There was remarkable concordance in pathways enriched in genomic segments implicated in interspecies introgression and in positive selection, suggesting that these processes were connected. We tested this hypothesis by developing exome capture probes targeting ~19,000 Panthera genes and applying them to 30 wild-caught jaguars. We found at least two genes (DOCK3 and COL4A5, both related to optic nerve development) bearing significant signatures of interspecies introgression and within-species positive selection. These findings indicate that post-speciation admixture has contributed genetic material that facilitated the adaptive evolution of big cat lineages

Evaluation of cytotoxic effect of the combination of a pyridinyl carboxamide derivative and oxaliplatin on NCI-H1299 human non-small cell lung carcinoma cells.

Even with all improvements in both diagnostic and therapeutic techniques, lung cancer remains as the most lethal and prevalent cancer in the world. Therefore, new therapeutic drugs and new strategies of drug combination are necessary to provide treatments that are more efficient. Currently, standard therapy regimen for lung cancer includes platinum drugs, such as cisplatin, oxaliplatin, and carboplatin. Besides of the better toxicity profile of oxaliplatin when compared with cisplatin, peripheral neuropathy remains as a limitation of oxaliplatin dose. This study presents LabMol-12, a new pyridinyl carboxamide derivative with antileishmanial and antichagasic activity, as a new hit for lung cancer treatment, which induces apoptosis dependent of caspases in NCI-H1299 lung cancer cells both in monolayer and 3D culture. Moreover, LabMol-12 allows a reduction of oxaliplatin dose when they are combined, thereby, it is a relevant strategy for reducing the side effects of oxaliplatin with the same response. Molecular modeling studies corroborated the biological findings and suggested that the combined therapy can provide a better therapeutically profile effects against NSCLC. All these findings support the fact that the combination of oxaliplatin and LabMol-12 is a promising drug combination for lung cancer

Síndrome de Ramsay Hunt: relato de caso / Ramsay Hunt Syndrome: a case report

A Síndrome de Ramsay Hunt ocorre pela reativação do vírus varicela zoster latente no gânglio geniculado do nervo facial, sendo caracterizada por paralisia facial periférica e lesões vesiculares em pavilhão auricular. O diagnóstico é essencialmente clinico, baseado na história e exame físico do paciente. O tratamento com antiviral e corticoide, de forma precoce, tem demonstrado bom prognóstico

VIOLÊNCIA CONTRA A MULHER: O CUIDADO PRÉ-NATAL E A IMPORTÂNCIA DA ATUAÇÃO HUMANIZADA

Objective: We aimed to analyze and identify the behaviors and strategies used by health professionals in the face of domestic violence during prenatal care. Results: It was observed in the literature that up to 59% of women, in various socioeconomic and cultural situations, will experience some moment of violence at least once in their lives, and it may be during the pregnancy period. It has been shown that the prevalence of physical violence in Brazil was 8% in the city of São Paulo and 11% in the Zona da Mata of the state of Pernambuco. According to the United Nations (UN), in 2016, Brazil was in 5th place in the world ranking of countries with the highest rates of violence against women. Final Considerations: Violence against women, in itself, is a complex and impactful social problem; when this violence happens during pregnancy, it is even more traumatic, with physical and psychological consequences not only for her but also for her children. The study demonstrated the importance of the humanized and holistic performance of health professionals who will accompany this pregnant woman, being fundamental to detect and intervene, aiming at a better quality of life.Objetivo: Se pretende analizar e identificar las conductas y estrategias utilizadas por los profesionales de la salud ante la violencia doméstica durante el prenatal. Resultados: Se observó en la literatura que hasta el 59% de las mujeres, en diversas situaciones socioeconómicas y culturales, experimentarán algún momento de violencia al menos una vez en su vida, y puede ser durante el período de embarazo. Se demostró que la prevalencia de la violencia física en Brasil era del 8% en la ciudad de São Paulo y del 11% en la Zona da Mata del Estado de Pernambuco. Según la Organización de las Naciones Unidas (ONU), en 2016, Brasil ocupó el 5º lugar en el ranking mundial de países con mayor índice de violencia contra las mujeres. Consideraciones finales: La violencia contra la mujer, en sí misma, es un problema social complejo y de gran impacto; cuando esta violencia ocurre durante el embarazo, es aún más traumática, con consecuencias físicas y psicológicas no sólo para ella sino también para sus hijos. El estudio demostró la importancia de la actuación humanizada y holística de los profesionales de la salud que van a acompañar a esta gestante, siendo esencial para detectar e intervenir, buscando una mejor calidad de vida.Objetivo: Objetiva-se analisar e identificar as condutas e estratégias utilizadas pelos profissionais de saúde diante da violência doméstica durante o pré-natal. Resultados: Observou-se na literatura que até 59% das mulheres, em várias situações socioeconômicas e culturais, passarão por algum momento de violência pelo menos uma vez na vida, podendo ser durante o período de gravidez.  Demonstrou-se que a prevalência de violência física no Brasil, foi de 8% na cidade de São Paulo e 11% na Zona da Mata do Estado de Pernambuco. De acordo com a Organização Nações Unidas (ONU), em 2016, o Brasil encontrava-se em 5º lugar ranking mundial dos países com maior índice de violência contra as mulheres.  Considerações Finais: A violência contra a mulher, por si só, é um problema social, complexo e impactante, quando essa violência acontece no decorrer do período gestacional é ainda mais traumático, com consequências físicas e psicológicas não só para ela como também para os filhos. O estudo demonstrou a importância da atuação humanizada e holística dos profissionais da saúde que acompanharão essa gestante, sendo fundamental para detectar e intervir, visando uma melhor qualidade de vida.Objetivo: Objetiva-se analisar e identificar as condutas e estratégias utilizadas pelos profissionais de saúde diante da violência doméstica durante o pré-natal. Resultados: Observou-se na literatura que até 59% das mulheres, em várias situações socioeconômicas e culturais, passarão por algum momento de violência pelo menos uma vez na vida, podendo ser durante o período de gravidez.  Demonstrou-se que a prevalência de violência física no Brasil, foi de 8% na cidade de São Paulo e 11% na Zona da Mata do Estado de Pernambuco. De acordo com a Organização Nações Unidas (ONU), em 2016, o Brasil encontrava-se em 5º lugar ranking mundial dos países com maior índice de violência contra as mulheres.  Considerações Finais: A violência contra a mulher, por si só, é um problema social, complexo e impactante, quando essa violência acontece no decorrer do período gestacional é ainda mais traumático, com consequências físicas e psicológicas não só para ela como também para os filhos. O estudo demonstrou a importância da atuação humanizada e holística dos profissionais da saúde que acompanharão essa gestante, sendo fundamental para detectar e intervir, visando uma melhor qualidade de vida

Dexmedetomidina versus outros sedativos na prevenção de Delirium nos adultos em ventilação mecânica

Delirium é uma síndrome neurocognitiva aguda relativamente comum e grave que se caracteriza por desatenção, consciência alterada, disfunção cognitiva e curso flutuante, e pode levar à mortalidade, declínio funcional, institucionalização e demência, com maior incidência nos pacientes mais velhos. Pacientes hospitalizados na Unidade de Terapia Intensiva (UTI) e em uso de ventilação mecânica (VM), quando sedados em excesso, possuem maior duração de permanência na UTI, aumento da duração da VM, maior incidência de delirium e mortalidade. Estudos apontam que a dexmedetomidina reduz a incidência de delirium em pacientes adultos hospitalizados na UTI e em uso de ventilação mecânica quando comparada com outros sedativos. Desse modo, o objetivo do estudo é comparar a dexmedetomidina e outros sedativos na prevenção de delirium nos adultos em ventilação mecânica. Trata-se de uma revisão bibliográfica integrativa, do tipo quantitativa, que utilizou as plataformas do PubMed, SciELO e Cochrane Library como bases de dados para seleção dos artigos, todos na língua inglesa. Foram utilizadas literaturas publicadas com recorte temporal de 2017 a 2022. De acordo com as literaturas analisadas, conclui-se que, quando comparado com outros sedativos gabaminérgicos, como os benzodiazepínicos e o propofol, a dexmedetomidina diminui significativamente a incidência de delirium nos pacientes adultos em ventilação mecânica na UTI, com melhora da capacidade de despertar do paciente, preservação do desempenho cognitivo e redução do risco de depressão respiratória. Desse modo, pesquisas futuras sobre as propriedades farmacológicas da dexmedetomidina podem ajudar a determinar se esta droga possui propriedades neuroprotetoras intrínsecas, sendo assim, tal descoberta facilitaria o desenvolvimento de análogos com menos efeitos colaterais cardiorrespiratórios, tendo em vista seu efeito hemodinâmico, com bradicardia e possível hipotensão associadas

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir