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OBJECTIVE: Video-based eye tracking was used to investigate saccade, pupil, and blink abnormalities among patients with Huntington's disease (HD) who watched sequences of short videos. HD, an autosomal dominant neurodegenerative disorder resulting from a CAG mutation on chromosome 4, produces motor and cognitive impairments including slow or irregular eye movements, which have been studied using structured tasks. METHODS: To explore how HD affects eye movements under instruction free conditions, we assessed 22 HD patients and their age matched controls in a 10-minute video-based free viewing task. RESULTS: Patients with HD experienced a significant reduction in saccade exploration rate following video clip transitions, an increase in pupil reactions to luminance changes after clip transitions, and a significant higher blink rate throughout the task compared to the control group. CONCLUSIONS: These results show that HD has a significant impact on how patients visually explore and respond to their environment under unconstrained and ecologically natural conditions. SIGNIFICANCE: Eye tracking in HD patients revealed saccadic, pupil, and blink abnormalities in early HD patients, suggestive of brain circuitry abnormalities that probably involve brain stem deficits. Further research should explore the impact of these changes on the quality of life of the patients affected by the disease.
Assuntos
Piscadela , Doença de Huntington , Pupila , Movimentos Sacádicos , Humanos , Movimentos Sacádicos/fisiologia , Doença de Huntington/fisiopatologia , Doença de Huntington/genética , Piscadela/fisiologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Pupila/fisiologia , Idoso , Estimulação Luminosa/métodos , Tecnologia de Rastreamento Ocular , Reflexo Pupilar/fisiologiaRESUMO
Steroid hormones bind to specific receptors that act as transcription factors to modify gene expression in the brain to regulate physiological and behavioural processes. The specific genes controlled by steroid hormones in the brain are not fully known. Identifying these genes is integral to establishing a comprehensive understanding of how hormones impact physiology and behaviour. A popular organism for answering this question is the cichlid fish Astatotilapia burtoni. Recently, CRISPR/Cas9 was used to engineer A. burtoni that lack functional androgen receptor (AR) genes encoding ARα. ARα mutant male A. burtoni produced fewer aggressive displays and possessed reduced expression of the gene encoding brain-specific aromatase, cyp19a1, in the ventromedial hypothalamus (VMH), an aggression locus. As a follow-up, we investigated whether ARα deficiency affected cyp19a1 expression in female A. burtoni using the same genetic line. We find that female A. burtoni possessing one or two non-functional ARα alleles had much higher expression of cyp19a1 in the preoptic area (POA), while females with one non-functional ARα allele possessed lower expression of cyp19a1 in the putative fish homologue of the bed nucleus of the stria terminalis (BNST). Thus, ARα may have a sex-specific role in modifying cyp19a1 expression in the teleost POA and BNST, regions that underlie sex differences across vertebrates.
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Introdução: A voz é um indicador de estados emocionais, influenciada por fatores como o tônus vagal, a respiração e a variabilidade da frequência cardíaca. O estudo explora esses fatores e a relação com a regulação emocional e a prática meditativa como técnica de autorregulação. Objetivo: Investigar a diferença nas características vocais e na variação da frequência cardíaca em meditadores experientes (EM) e novatos (NM) antes e depois de uma prática meditativa e em não praticantes de meditação grupo controle (CG), antes e depois de um teste controle. Métodos: Estudo quase-fatorial 3 x 2. Três grupos foram avaliados (meditadores experientes EM; meditadores novatos NM; e grupo controle CG, não praticantes de meditação) em dois momentos da manipulação experimental antes e depois de uma sessão meditativa para praticantes de meditação, e antes e depois de uma tarefa de busca de palavras para o grupo controle. A frequência fundamental, jitter, shimmer, relação harmônico-ruído e o primeiro (F1), o segundo (F2) e terceiro (F3) formantes da vogal [a]; a variação da frequência cardíaca (SDNN, RMSSD, LF/HF, SD1 and SD2); estado de ansiedade e autopercepção vocal, foram investigados, antes e após a intervenção. Resultados: O grupo EM alcançou ótimo relaxamento do trato vocal. Os grupos NM e CG apresentaram mudanças em F1. Prática meditativa, de longa duração, está associado com grande diferença em F3, SDNN e SD2 na variação da frequência cardíaca. Conclusão: Os resultados sugerem que prática meditativa influencia a expressão vocal e reação emocional, e que a experiência em prática meditativa favorece esta relação. (AU)
Introduction: The voice is an indicator of emotional states, influenced by factors such as vagal tone, breathing and heart rate variability. This study explores these factors and their relationship with emotional regulation and meditative practice as a self-regulation technique. Purpose: To investigate the difference in vocal characteristics and heart rate variability in experienced (EM) and novice (NM) meditators before and after a meditation practice and in non-meditators - control group (CG), before and after a control test. Methods: 3 x 2 quasi-factorial study. Three groups were evaluated (experienced meditators EM; novice meditators NM; and control group CG, non-meditators) at two points in the experimental manipulation - before and after a meditation session for meditators, and before and after a word search task for the control group. The fundamental frequency, jitter, shimmer, harmonic-to-noise ratio and the first (F1), second (F2) and third (F3) formants of the vowel [a]; heart rate variation (SDNN, RMSSD, LF/HF, SD1 and SD2); anxiety state and vocal self-perception, were investigated, before and after the intervention. Results: The EM group achieved optimal vocal tract relaxation. The NM and CG groups showed changes in F1. Long-term meditative practice was associated with a large difference in F3, SDNN and SD2 in heart rate variation. Conclusion: The results suggest that meditation practice influences vocal expression and emotional reaction, and that experience in meditation practice favors this relationship. (AU)
Introducción: La voz es un indicador de los estados emocionales, influida por factores como el tono vagal, la respiración y la variabilidad de la frecuencia cardiaca. Este estudio explora estos factores y su relación con la regulación emocional y la práctica de la meditación. Objetivo: Investigar la diferencia en las características vocales y variabilidad de la frecuencia cardiaca en meditadores experimentados (EM) y novatos (NM) antes y después de una práctica de meditación y en no meditadores - grupo control (GC), antes y después de una prueba control. Métodos: Estudio cuasi-factorial 3 x 2. Se evaluaron tres grupos (meditadores experimentados EM; meditadores novatos NM; y grupo control CG, no meditadores) en dos momentos - antes y después de una sesión de meditación para los meditadores, y antes y después de una tarea de búsqueda de palabras para el grupo control. Se investigaron la frecuencia fundamental, jitter, shimmer, relación armónico-ruido y los formantes primero (F1), segundo (F2) y tercero (F3) de la vocal [a]; la variación de la frecuencia cardiaca (SDNN, RMSSD, LF/HF, SD1 y SD2); el estado de ansiedad y autopercepción vocal, antes y después de la intervención. Resultados: El grupo EM consiguió una relajación óptima del tracto vocal. Los grupos NM y CG mostraron cambios en F1. La práctica de meditación a largo plazo se asocia con una gran diferencia en F3, SDNN y SD2 en la variación de la frecuencia cardiaca. Conclusión: Los resultados sugieren que la práctica de meditación influye en la expresión vocal y reacción emocional. (AU)
Assuntos
Humanos , Masculino , Feminino , Adulto , Voz , Meditação , Regulação Emocional , Estudos Controlados Antes e Depois , Reconhecimento de Voz/fisiologiaRESUMO
A key challenge in animal behavior is disentangling the social stimuli that drive conspecific behaviors. For some species, like teleost fish, putative sexual signaling cues are inextricably linked to others, making it difficult to parse the precise roles distinct signals play in driving conspecific behaviors. In the African cichlid Astatotilapia burtoni, males are either dominant or subordinate, wherein bright coloration, territoriality, and courtship behavior inextricably correlate positively with rank. Here, we leveraged androgen receptor (AR) mutant male A. burtoni that lack dominance-typical coloration but not behavior to isolate the role of male coloration in driving female mating behaviors in this species. We found in independent behavioral assays that females behave aggressively towards AR mutant but not WT males, yet still mated with both types of males. Females showed enhanced activation of esr2b + cells in the hypothalamus when housed with either mutant or WT males and this activation scaled with spawning activities. Therefore, there is not a simple relationship between male coloration and female mating behaviors in A. burtoni, suggesting independent sensory mechanisms converge on hypothalamic esr2b cells to coordinate behavioral output.
Assuntos
Ciclídeos , Receptores Androgênicos , Comportamento Sexual Animal , Animais , Ciclídeos/fisiologia , Ciclídeos/genética , Feminino , Masculino , Receptores Androgênicos/genética , Comportamento Sexual Animal/fisiologia , Mutação , Hipotálamo/fisiologia , Hipotálamo/metabolismo , Pigmentação/genética , Pigmentação/fisiologia , Agressão/fisiologiaRESUMO
Hepatocellular carcinoma (HCC) progression is associated with dysfunctional mitochondria and bioenergetics impairment. However, no data about the relationship between mitochondrial supercomplexes (hmwSC) formation and ATP production rates in HCC are available. Our group has developed an adenosine derivative, IFC-305, which improves mitochondrial function, and it has been proposed as a therapeutic candidate for HCC. We aimed to determine the role of IFC-305 on both mitochondrial structure and bioenergetics in a sequential cirrhosis-HCC model in rats. Our results showed that IFC-305 administration decreased the number and size of liver tumors, reduced the expression of tumoral markers, and reestablished the typical architecture of the hepatic parenchyma. The livers of treated rats showed a reduction of mitochondria number, recovery of the mtDNA/nDNA ratio, and mitochondrial length. Also, IFC-305 increased cardiolipin and phosphatidylcholine levels and promoted hmwSC reorganization with changes in the expression levels of hmwSC assembly-related genes. IFC-305 in HCC modified the expression of several genes encoding elements of electron transport chain complexes and increased the ATP levels by recovering the complex I, III, and V activity. We propose that IFC-305 restores the mitochondrial bioenergetics in HCC by normalizing the quantity, morphology, and function of mitochondria, possibly as part of its hepatic restorative effect.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratos , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Dietilnitrosamina/toxicidade , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Mitocôndrias/metabolismo , Adenosina/metabolismo , Metabolismo Energético , Trifosfato de Adenosina/metabolismoRESUMO
Social behaviors are regulated by sex steroid hormones, such as androgens and estrogens. However, the specific molecular and neural processes modulated by steroid hormones to generate social behaviors remain to be elucidated. We investigated whether some actions of androgen signaling in the control of social behavior may occur through the regulation of estradiol synthesis in the highly social cichlid fish, Astatotilapia burtoni. Specifically, we examined the expression of cyp19a1, a brain-specific aromatase, in the brains of male A. burtoni lacking a functional ARα gene (ar1), which was recently found to be necessary for aggression in this species. We found that cyp19a1 expression is higher in wild-type males compared to ar1 mutant males in the anterior tuberal nucleus (ATn), the putative fish homolog of the mammalian ventromedial hypothalamus, a brain region that is critical for aggression across taxa. Using in situ hybridization chain reaction, we determined that cyp19a1+ cells coexpress ar1 throughout the brain, including in the ATn. We speculate that ARα may modulate cyp19a1 expression in the ATn to govern aggression in A. burtoni. These studies provide novel insights into the hormonal mechanisms of social behavior in teleosts and lay a foundation for future functional studies.
Assuntos
Síndrome de Resistência a Andrógenos , Ciclídeos , Humanos , Animais , Masculino , Aromatase/genética , Aromatase/metabolismo , Ciclídeos/genética , Ciclídeos/metabolismo , Hipotálamo , Estradiol/metabolismo , Mamíferos/metabolismoRESUMO
BACKGROUND/OBJECTIVE: The prokinetic levosulpiride elevates vasoinhibin levels in the vitreous of patients with proliferative diabetic retinopathy (PDR) suggesting clinical benefits due to the anti-vasopermeability and anti-angiogenic properties of vasoinhibin. We investigated the biological activity of levosulpiride in centre-involving diabetic macular oedema (DME). PATIENTS/METHODS: Prospective, randomized, double-blinded, dual-centre, phase 2 trial in patients with centre-involving DME orally treated with placebo (n = 17) or levosulpiride (n = 17) for 8 weeks or in patients with PDR undergoing elective pars plana vitrectomy and receiving placebo (n = 18) or levosulpiride (n = 18) orally for the 1 week before vitrectomy. RESULTS: Levosulpiride improved changes from baseline in best-corrected visual acuity (p ≤ 0.037), central foveal thickness (CFT, p ≤ 0.013), and mean macular volume (MMV, p ≤ 0.002) at weeks 4, 6, and 8 compared to placebo. At 8 weeks, the proportion of eyes gaining ≥5 ETDRS letters at 4 m (41% vs. 28%), losing ≥21 µm in CFT (55% vs. 28%), and dropping ≥0.06 mm3 in MMV (65% vs. 29%) was higher after levosulpiride than placebo. The overall grading of visual and structural parameters improved with levosulpiride (p = 0.029). Levosulpiride reduced VEGF (p = 0.025) and PlGF (p = 0.008) levels in the vitreous of PDR patients. No significant adverse side-effects were detected. CONCLUSIONS: Oral levosulpiride for 8 weeks improved visual and structural outcomes in patients with centre-involving DME by mechanisms that may include intraocular upregulation of vasoinhibin and downregulation of VEGF and PlGF. Larger clinical trials evaluating long-term efficacy and safety are warranted.
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Diabetes Mellitus , Retinopatia Diabética , Edema Macular , Sulpirida/análogos & derivados , Humanos , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/cirurgia , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Estudos Prospectivos , Injeções Intravítreas , Inibidores da AngiogêneseRESUMO
Multidrug-resistant(MDR) tuberculosis in Southern Africa is of great concern, exacerbated by the spread of a clone harboring a mutation missed by Xpert Ultra. In Southern Mozambique, the presence of such mutation and rising cases of non-MDR isoniazid resistance highlights the need to ensure accurate detection of antimicrobial-resistance in the country.
Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Rifampina/farmacologia , Rifampina/uso terapêutico , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Farmacorresistência Bacteriana/genética , Moçambique , Mutação , Sensibilidade e EspecificidadeRESUMO
El espectro acretismo placentario es una patología que cursa con una alta morbimortalidad, viéndose en los últimos años un incremento en su incidencia y cobrando relevancia por la tasa de cesáreas en aumento, siendo su principal factor de riesgo. Se describe el caso de una paciente de 32 años, portadora de acretismo placentario, diagnosticado mediante ecografía a las 31 semanas de edad gestacional, donde se logró planificar paso a paso la cirugía con equipo, colocando previo a la cirugía balones en arterias hipogástricas y catéter doble Jota, haciendo una estadificación intraoperatoria detallada. A propósito del caso clínico se realiza una revisión y actualización de la patología, enfatizando en la planificación detallada de la cirugía y el abordaje con equipos de referencia.
Placenta Accreta Spectrum is a condition associated with high morbidity and mortality. In recent years, there has been an increase in its incidence, highlighting its importance due to the rising rate of cesarean sections which is its main risk factor. A case is described of a 32-year-old patient with placenta accreta, diagnosed via ultrasound at 31 weeks of gestation. The surgery was meticulously planned with the team, including the placement of balloons in the hypogastric arteries and a double-J catheter, allowing for detailed intraoperative staging. In relation to the clinical case, a review and update of the pathology is carried out, emphasizing the detailed planning of the surgery and the approach in specialized teams.
O Espectro do Acretismo Placentário é uma patologia de alta morbimortalidade, com incidência crescente nos últimos anos e ganhando relevância devido ao aumento da taxa de cesarianas, sendo este o seu principal fator de risco. Descrevemos o caso de uma paciente de 32 anos com acretismo placentário, diagnosticado por ultrassonografia com 31 semanas de idade gestacional, na qual a cirurgia foi planejada passo a passo com a equipe multidisciplinar, com a colocação de balões nas artérias hipogástricas e um cateter duplo jack antes da cirurgia e realizando um estadiamento intraoperatório detalhado. Uma revisão e atualização da bibliografia, enfatizando o planejamento detalhado da cirurgia e a abordagem em equipes composta por profissionais de várias especialidades médicas.
RESUMO
A key challenge in animal behavior is disentangling the social stimuli that drive conspecific behaviors. For behaviors like birdsong, insights can be made through the experimental isolation of relevant cues that affect behavior. However, for some species like teleost fish, putative sexual signaling cues are inextricably linked to others, making it difficult to parse the precise roles distinct signals play in driving conspecific behaviors. In the African cichlid Astatotilapia burtoni, males are dominant or subordinate, wherein bright coloration and territorial and courtship behavior inextricably correlate positively with rank. Here, we leveraged androgen receptor (AR) mutant male A. burtoni that lack dominance-typical coloration but not behavior to isolate the role of male coloration in driving female mating behaviors in this species. We found in independent behavioral assays that females behave aggressively towards AR mutant but not WT males but still mated with both types of males. Females showed enhanced activation of esr2b+ cells in the hypothalamus when housed with either mutant or WT males and this activation scaled with spawning activities. Therefore, there is not a simple relationship between male coloration and female mating behaviors in A. burtoni, suggesting independent sensory mechanisms converge on hypothalamic esr2b+ cells to coordinate behavioral output.
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Metabolic syndrome is a multifactorial disease with high prevalence worldwide. It is related to cardiovascular disease, diabetes, and obesity. Approximately 80% of patients with metabolic syndrome have some degree of fatty liver disease. An adenosine derivative (IFC-305) has been shown to exert protective effects in models of liver damage as well as on elements involved in central metabolism; therefore, here, we evaluated the effect of IFC-305 in an experimental model of metabolic syndrome in rats induced by a high-fat diet and 10% sucrose in drinking water for 18 weeks. We also determined changes in fatty acid uptake in the Huh-7 cell line. In the experimental model, increases in body mass, serum triglycerides and proinflammatory cytokines were induced in rats, and the adenosine derivative significantly prevented these changes. Interestingly, IFC-305 prevented alterations in glucose and insulin tolerance, enabling the regulation of glucose levels in the same way as in the control group. Histologically, the alterations, including mitochondrial morphological changes, observed in response to the high-fat diet were prevented by administration of the adenosine derivative. This compound exerted protective effects against metabolic syndrome, likely due to its action in metabolic regulation, such as in the regulation of glucose blood levels and hepatocyte fatty acid uptake.
Assuntos
Síndrome Metabólica , Humanos , Ratos , Animais , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/prevenção & controle , Síndrome Metabólica/induzido quimicamente , Sacarose/metabolismo , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Adenosina/metabolismo , Glucose/metabolismo , Ácidos Graxos/metabolismo , Fígado/metabolismoRESUMO
BACKGROUND: Liver fibrosis is a global health problem, and studying its development provides important information to address its treatment. Here, we characterized the effects of an adenosine compound (IFC-305) on preventing fibrosis and liver inflammation. METHODS: We studied the impact of IFC-305 on a carbon tetrachloride-induced liver fibrosis model in Wistar male rats at 4, 6, and 8 weeks. The effects were characterized by liver tissue histology, macrophages identification by flow cytometry with CD163+/CD11b/c+ antibodies, hepatic and plasmatic cytokine levels employing MILLIPLEX MAP and ELISA, Col1a1 and Il6 gene expression by RTqPCR, lipoperoxidation by TBARS reaction, and reactive oxygen species using 2'-7'dichlorofluorescin diacetate. RESULTS: CCl4-induced liver fibrosis and inflammation were significantly reduced in rats treated with IFC-305 at 6 and 8 weeks. In addition, we observed diminished expression of Col1a1; a decrease in the inflammatory cytokines IL-1ß, IL-6, MCP-1, TNF-α, and IL-4 a; reduction in inflammatory macrophages; inhibition of lipoperoxidation; and ROS production in Kupffer cells. CONCLUSION: This study showed that IFC-305 can inhibit liver fibrosis establishment by regulating the immune response during CCl4-induced damage. The immunomodulatory action of IFC-305 supports its use as a potential therapeutic strategy for preventing liver fibrosis.
Assuntos
Inflamação , Fígado , Ratos , Masculino , Animais , Ratos Wistar , Fibrose , Inflamação/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/prevenção & controle , Citocinas/metabolismo , Tetracloreto de Carbono/toxicidade , AdenosinaRESUMO
Conditions, accidents, and aging processes have brought with them the need to develop implants with higher technology that allow not only the replacement of missing tissue but also the formation of tissue and the recovery of its function. The development of implants is due to advances in different areas such as molecular-biochemistry (which allows the understanding of the molecular/cellular processes during tissue repair), materials engineering, tissue regeneration (which has contributed advances in the knowledge of the properties of the materials used for their manufacture), and the so-called intelligent biomaterials (which promote tissue regeneration through inductive effects of cell signaling in response to stimuli from the microenvironment to generate adhesion, migration, and cell differentiation processes). The implants currently used are combinations of biopolymers with properties that allow the formation of scaffolds with the capacity to mimic the characteristics of the tissue to be repaired. This review describes the advances of intelligent biomaterials in implants applied in different dental and orthopedic problems; by means of these advances, it is expected to overcome limitations such as additional surgeries, rejections and infections in implants, implant duration, pain mitigation, and mainly, tissue regeneration.
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Materiais Biocompatíveis , Engenharia Tecidual , Materiais Biocompatíveis/uso terapêutico , Materiais Biocompatíveis/química , Próteses e Implantes/efeitos adversos , Cicatrização , Diferenciação CelularRESUMO
In 1929, August Krogh wrote that for every question in biology, there is a species or collection of species in which pursuing such questions is the most appropriate for achieving the deepest insights. Referred to as "Krogh's Principle," these words are a guiding force for many biologists. In practice, Krogh's principle might guide a biologist interested in studying bi-parental care to choose not to use lab mice, in which the female does most of the parenting, but instead study species in which bi-parental care is present and clearly observable, such as in certain poison dart frogs. This approach to pursuing biological questions has been fruitful, with more in-depth insights achievable with new technologies. However, up until recently, an important limitation of Krogh's principle for biologists interested in the functions of certain genes, was certain techniques were only available for a few traditional model organisms such as lab mice, fruit flies (Drosophila melanogaster), zebrafish (Danio rerio) and C. elegans (Caenorhabditis elegans), in which testing the functions of molecular systems on biological processes can be achieved using genetic knockout (KO) and transgenic technology. These methods are typically more precise than other approaches (e.g., pharmacology) commonly used in nontraditional model organisms to address similar questions. Therefore, some of the most in-depth insights into our understanding of the molecular control of these mechanisms have come from a small number of genetically tractable species. Recent advances in gene editing technology such as CRISPR (Clustered Regularly Interspersed Short Palindromic Repeats)/Cas9 gene editing as a laboratory tool has changed the insights achievable for biologists applying Krogh's principle. In this review, we will provide a brief summary on how some researchers of nontraditional model organisms have been able to achieve different levels of experimental precision with limited genetic tractability in their non-traditional model organism in the field of behavioral neuroendocrinology, a field in which understanding tissue and brain-region specific actions of molecules of interest has been a major goal. Then, we will highlight the exciting potential of Krogh's principle using discoveries made in a popular model species of social behavior, the African cichlid fish Astatotilapia burtoni. Specifically, we will focus on insights gained from studies of the control of social status by sex steroid hormones (androgens and estrogens) in A. burtoni that originated during field observations during the 1970s, and have recently culminated in novel insights from CRISPR/Cas9 gene editing in laboratory studies. Our review highlighting discoveries in A. burtoni may function as a roadmap for others using Krogh's principle aiming to incorporate gene editing into their research program. Gene editing is thus a powerful complimentary laboratory tool researchers can use to yield novel insights into understanding the molecular mechanisms of physiology and behavior in non-traditional model organisms.
Assuntos
Caenorhabditis elegans , Edição de Genes , Animais , Feminino , Camundongos , Edição de Genes/métodos , Drosophila melanogaster , Neuroendocrinologia , Peixe-ZebraRESUMO
BACKGROUND: From the start of the SARS-CoV-2 outbreak, global sequencing efforts have generated an unprecedented amount of genomic data. Nonetheless, unequal sampling between high-income and low-income countries hinders the implementation of genomic surveillance systems at the global and local level. Filling the knowledge gaps of genomic information and understanding pandemic dynamics in low-income countries is essential for public health decision making and to prepare for future pandemics. In this context, we aimed to discover the timing and origin of SARS-CoV-2 variant introductions in Mozambique, taking advantage of pandemic-scale phylogenies. METHODS: We did a retrospective, observational study in southern Mozambique. Patients from Manhiça presenting with respiratory symptoms were recruited, and those enrolled in clinical trials were excluded. Data were included from three sources: (1) a prospective hospital-based surveillance study (MozCOVID), recruiting patients living in Manhiça, attending the Manhiça district hospital, and fulfilling the criteria of suspected COVID-19 case according to WHO; (2) symptomatic and asymptomatic individuals with SARS-CoV-2 infection recruited by the National Surveillance system; and (3) sequences from SARS-CoV-2-infected Mozambican cases deposited on the Global Initiative on Sharing Avian Influenza Data database. Positive samples amenable for sequencing were analysed. We used Ultrafast Sample placement on Existing tRees to understand the dynamics of beta and delta waves, using available genomic data. This tool can reconstruct a phylogeny with millions of sequences by efficient sample placement in a tree. We reconstructed a phylogeny (~7·6 million sequences) adding new and publicly available beta and delta sequences. FINDINGS: A total of 5793 patients were recruited between Nov 1, 2020, and Aug 31, 2021. During this time, 133â328 COVID-19 cases were reported in Mozambique. 280 good quality new SARS-CoV-2 sequences were obtained after the inclusion criteria were applied and an additional 652 beta (B.1.351) and delta (B.1.617.2) public sequences were included from Mozambique. We evaluated 373 beta and 559 delta sequences. We identified 187 beta introductions (including 295 sequences), divided in 42 transmission groups and 145 unique introductions, mostly from South Africa, between August, 2020 and July, 2021. For delta, we identified 220 introductions (including 494 sequences), with 49 transmission groups and 171 unique introductions, mostly from the UK, India, and South Africa, between April and November, 2021. INTERPRETATION: The timing and origin of introductions suggests that movement restrictions effectively avoided introductions from non-African countries, but not from surrounding countries. Our results raise questions about the imbalance between the consequences of restrictions and health benefits. This new understanding of pandemic dynamics in Mozambique can be used to inform public health interventions to control the spread of new variants. FUNDING: European and Developing Countries Clinical Trials, European Research Council, Bill & Melinda Gates Foundation, and Agència de Gestió d'Ajuts Universitaris i de Recerca.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias/prevenção & controle , Filogenia , Moçambique/epidemiologia , Estudos Retrospectivos , Estudos ProspectivosRESUMO
BACKGROUND: Sexual dysfunction is a known side effect of pelvic radiotherapy, resulting from a complex intersection of physiologic and psychosocial factors. Maintaining sexual function is relevant to long-term quality of life and is an important aspect of survivorship. Many female patients report being insufficiently informed before treatment about the potential sexual side effects of radiation therapy. AIM: To elucidate how radiation oncologists communicate sexual function side effects with their female patients and how discussing sexual side effects of cancer treatment can positively affect patient-physician rapport. METHODS: Semistructured interviews in English and Spanish were conducted with 20 female participants who received pelvic radiation as part of their cancer treatment. Patients responded to advertisements or were referred by physicians. All interviews were conducted virtually between June and October 2021. Thematic analysis was conducted with NVivo. Patients also completed an online demographics survey in REDCap. OUTCOMES: We found 4 primary themes addressing patient perspectives on patient-physician communication of sexual dysfunction and how it affected the cancer care experience. RESULTS: Theme 1: This may be expected, but I didn't expect it! The participants who were not properly informed about sexual side effects felt blindsided and embarrassed about their symptoms. Theme 2: I do not feel like a woman anymore . . . The psychological impact included lower self-esteem and no longer feeling sexy nor like a woman. Theme 3: Fine, I'll deal with this myself! Patients turned to the internet rather than their doctors for answers once they began experiencing symptoms, and they found information, normalization, and community online. Theme 4: Ask me about my sex life and find out if sex is a priority for me. Participants emphasized that their radiation oncologist should take a sexual history early to monitor sexual dysfunction and to identify individual patient priorities surrounding sex posttreatment. CLINICAL IMPLICATIONS: This evidence provides a guide to patient-physician communication that may help to mitigate the impacts of radiotherapy on female sexual function as well as the negative impact that the absence of communication about sexual dysfunction may have on patient-physician trust. STRENGTHS AND LIMITATIONS: While this project did have a small sample size, there is considerable diversity in race, education level, and age, with interviews conducted in Spanish and English. CONCLUSION: Overall these findings provide physicians with important information about the unmet information needs of patients and their preferences for how to help them feel more prepared and less distressed when sexual dysfunction occurs.
Assuntos
Médicos , Disfunções Sexuais Fisiológicas , Humanos , Feminino , Qualidade de Vida , Disfunções Sexuais Fisiológicas/psicologia , Comunicação , Relações Médico-PacienteRESUMO
In the management of infectious disease outbreaks, grouping cases into clusters and understanding their underlying epidemiology are fundamental tasks. In genomic epidemiology, clusters are typically identified either using pathogen sequences alone or with sequences in combination with epidemiological data such as location and time of collection. However, it may not be feasible to culture and sequence all pathogen isolates, so sequence data may not be available for all cases. This presents challenges for identifying clusters and understanding epidemiology, because these cases may be important for transmission. Demographic, clinical and location data are likely to be available for unsequenced cases, and comprise partial information about their clustering. Here, we use statistical modelling to assign unsequenced cases to clusters already identified by genomic methods, assuming that a more direct method of linking individuals, such as contact tracing, is not available. We build our model on pairwise similarity between cases to predict whether cases cluster together, in contrast to using individual case data to predict the cases' clusters. We then develop methods that allow us to determine whether a pair of unsequenced cases are likely to cluster together, to group them into their most probable clusters, to identify which are most likely to be members of a specific (known) cluster, and to estimate the true size of a known cluster given a set of unsequenced cases. We apply our method to tuberculosis data from Valencia, Spain. Among other applications, we find that clustering can be predicted successfully using spatial distance between cases and whether nationality is the same. We can identify the correct cluster for an unsequenced case, among 38 possible clusters, with an accuracy of approximately 35â%, higher than both direct multinomial regression (17â%) and random selection (< 5â%).
Assuntos
Surtos de Doenças , Genômica , Humanos , Análise por Conglomerados , Modelos LogísticosRESUMO
Outbreak strains of Mycobacterium tuberculosis are promising candidates as targets in the search for intrinsic determinants of transmissibility, as they are responsible for many cases with sustained transmission; however, the use of low-resolution typing methods and restricted geographical investigations represent flaws in assessing the success of long-lived outbreak strains. We can now address the nature of outbreak strains by combining large genomic data sets and phylodynamic approaches. We retrospectively sequenced the whole genome of representative samples assigned to an outbreak circulating in the Canary Islands (the GC strain) since 1993, which accounts for ~20% of local tuberculosis cases. We selected a panel of specific single nucleotide polymorphism (SNP) markers for an in-silico search for additional outbreak-related sequences within publicly available tuberculosis genomic data. Using this information, we inferred the origin, spread, and epidemiological parameters of the GC strain. Our approach allowed us to accurately trace the historical and more recent dispersion of the GC strain. We provide evidence of a highly successful nature within the Canarian archipelago but limited expansion abroad. Estimation of epidemiological parameters from genomic data disagree with a distinctive biology of the GC strain. With the increasing availability of genomic data allowing for the accurate inference of strain spread and critical epidemiological parameters, we can now revisit the link between Mycobacterium tuberculosis genotypes and transmission, as is routinely carried out for SARS-CoV-2 variants of concern. We demonstrate that social determinants rather than intrinsically higher bacterial transmissibility better explain the success of the GC strain. Importantly, our approach can be used to trace and characterize strains of interest worldwide. IMPORTANCE Infectious disease outbreaks represent a significant problem for public health. Tracing outbreak expansion and understanding the main factors behind emergence and persistence remain critical to effective disease control. Our study allows researchers and public health authorities to use Whole-Genome Sequencing-based methods to trace outbreaks, and shows how available epidemiological information helps to evaluate the factors underpinning outbreak persistence. Taking advantage of all the freely available information placed in public repositories, researchers can accurately establish the expansion of an outbreak beyond original boundaries, and determine the potential risk of a strain to inform health authorities which, in turn, can define target strategies to mitigate expansion and persistence. Finally, we show the need to evaluate strain transmissibility in different geographic contexts to unequivocally associate spread to local or pathogenic factors, an important lesson taken from genomic surveillance of SARS-CoV-2.
RESUMO
Research across species has led to important discoveries on the functions of steroid hormones in the regulation of behavior. However, like in many fields, advancements in transgenic and mutagenic technology allowed mice to become the premier genetic model for conducting many experiments to understand how steroids control social behavior. Since there has been a general lack of parallel methodological developments in other species, many of the findings cannot be generalized. This is especially the case for teleost fish, in which a whole-genome duplication produced novel paralogs for key steroid hormone signaling genes. In this review, we summarize technical advancements over the history of the field of neuroendocrinology that have led to important insights in our understanding of the control of social behavior by steroids. We demonstrate that early mouse genetic models to understand these mechanisms suffered from several issues that were remedied by more precise transgenic technological advancements. We then highlight the importance of CRISPR/Cas9 gene editing tools that will in time bridge the gap between mice and non-traditional model species for understanding principles of steroid hormone action in the modulation of social behavior. We specifically highlight the role of teleost fish in bridging this gap because they are 1) highly genetically tractable and 2) provide a novel advantage in achieving precise genetic control. The field of neuroendocrinology is entering a new "gene editing revolution" that will lead to novel discoveries about the roles of steroid hormones in the regulation and evolutionary trajectories of social behavior.
Assuntos
Peixes , Edição de Genes , Animais , Camundongos , Animais Geneticamente Modificados , Peixes/fisiologia , Comportamento Social , Esteroides , HormôniosRESUMO
Participation in sexual medicine research may depend on a patient's willingness to speak openly about sex, sexual function, or other sensitive topics. These topics may be difficult or uncomfortable to talk about, and this discomfort may be further amplified when a patient comes from a cultural background that stigmatizes open conversation about sex and sexuality. We used qualitative analysis to better understand the intersection between cultural identity, the experience of sexual dysfunction as a side-effect of pelvic radiotherapy, and willingness to communicate about sexual dysfunction with healthcare providers, in Cuban American women in Miami, Florida. Doing so, we found four unique themes among Cuban American participants regarding the intersection of national identity, Hispanic identity, Catholic religion, and their experience of radiotherapy-related sexual dysfunction: Marianismo, Machismo, Familismo, and Espiritismo. These themes, a reflection of the cohort's shared identity, were found to have an effect on participant views of sexual health, romantic relationships, coping strategies, and relative comfort discussing problems with intercourse. These cultural values served as barriers to openly discussing sexual dysfunction with not just medical providers and research teams but also their partners, families, and friends. In order to encourage Cuban American participation in sexual medicine studies, future research should evaluate strategies to overcome these barriers.