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The interiors of giant planets remain poorly understood. Even for the planets in the Solar System, difficulties in observation lead to large uncertainties in the properties of planetary cores. Exoplanets that have undergone rare evolutionary processes provide a route to understanding planetary interiors. Planets found in and near the typically barren hot-Neptune 'desert'1,2 (a region in mass-radius space that contains few planets) have proved to be particularly valuable in this regard. These planets include HD149026b3, which is thought to have an unusually massive core, and recent discoveries such as LTT9779b4 and NGTS-4b5, on which photoevaporation has removed a substantial part of their outer atmospheres. Here we report observations of the planet TOI-849b, which has a radius smaller than Neptune's but an anomalously large mass of [Formula: see text] Earth masses and a density of [Formula: see text] grams per cubic centimetre, similar to Earth's. Interior-structure models suggest that any gaseous envelope of pure hydrogen and helium consists of no more than [Formula: see text] per cent of the total planetary mass. The planet could have been a gas giant before undergoing extreme mass loss via thermal self-disruption or giant planet collisions, or it could have avoided substantial gas accretion, perhaps through gap opening or late formation6. Although photoevaporation rates cannot account for the mass loss required to reduce a Jupiter-like gas giant, they can remove a small (a few Earth masses) hydrogen and helium envelope on timescales of several billion years, implying that any remaining atmosphere on TOI-849b is likely to be enriched by water or other volatiles from the planetary interior. We conclude that TOI-849b is the remnant core of a giant planet.
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BACKGROUND: Unconscious racial bias in anesthesia care has been shown to exist. We hypothesized that black children may undergo inhalation induction less often, receive less support from child life, have fewer opportunities to have a family member present for induction, and receive premedication with oral midazolam less often. METHODS: We retrospectively collected data on those <18 years of age from January 1, 2012 to January 1, 2018 including age, sex, race, height, weight, American Society of Anesthesiologists (ASA) physical status, surgical service, and deidentified anesthesiology attending physician. Outcome data included mask versus intravenous induction, midazolam premedication, child life consultation, and family member presence. Racial differences between all outcomes were assessed in the cohort using a multivariable logistic regression model. RESULTS: A total of 33,717 Caucasian and 3901 black children were eligible for the study. For the primary outcome, black children 10-14 years were 1.3 times more likely than Caucasian children to receive mask induction (adjusted odds ratio [AOR], 1.3; 95% confidence interval [CI], 1.1-1.6; P = .001). Child life consultation was poorly documented (<0.5%) and not analyzed. Black children <15 years of age were at least 31% less likely than Caucasians to have a family member present for induction (AOR range, 0.4-0.6; 95% CI range, 0.31-0.84; P < .010). Black children <5 years of age were 13% less likely than Caucasians to have midazolam given preoperatively (AOR, 0.9; 95% CI, 0.8-0.9; P = .012). CONCLUSIONS: This study suggests that disparities in strategies for mitigating anxiety in the peri-induction period exist and adultification may be 1 cause for this bias. Black children 10 to 14 years of age are 1.3 times as likely as their Caucasian peers to be offered inhalation induction to reduce anxiety. However, black children are less likely to receive premedication with midazolam in the perioperative period or to have family members present at induction. The cause of this difference is unclear, and further prospective studies are needed to fully understand this difference.
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Anestesia Geral , Ansiedade/prevenção & controle , Negro ou Afro-Americano , Disparidades em Assistência à Saúde/etnologia , Procedimentos Cirúrgicos Operatórios , População Branca , Administração Oral , Adolescente , Comportamento do Adolescente/etnologia , Fatores Etários , Anestesia Geral/efeitos adversos , Anestesia Geral/psicologia , Ansiolíticos/administração & dosagem , Ansiedade/etnologia , Ansiedade/psicologia , Criança , Comportamento Infantil/etnologia , Feminino , Humanos , Masculino , Midazolam/administração & dosagem , Pré-Medicação , Estudos Retrospectivos , Fatores de Risco , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Procedimentos Cirúrgicos Operatórios/psicologiaRESUMO
This case report offers rare insights into crossmodal responses to psychedelic drug use in a congenitally blind (CB) individual as a form of synthetic synesthesia. BP's personal experience provides us with a unique report on the psychological and sensory alterations induced by hallucinogenic drugs, including an account of the absence of visual hallucinations, and a compelling look at the relationship between LSD induced synesthesia and crossmodal correspondences. The hallucinatory experiences reported by BP are of particular interest in light of the observation that rates of psychosis within the CB population are extremely low. The phenomenology of the induced hallucinations suggests that experiences acquired through other means, might not give rise to "visual" experiences in the phenomenological sense, but instead gives rise to novel experiences in the other functioning senses.
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Percepção Auditiva/fisiologia , Cegueira/congênito , Alucinações/induzido quimicamente , Alucinógenos/farmacologia , Dietilamida do Ácido Lisérgico/farmacologia , Música , Transtornos da Percepção/induzido quimicamente , Percepção do Tato/fisiologia , Adulto , Humanos , Masculino , SinestesiaRESUMO
Perceptual learning can be specific to a trained stimulus or optimally generalized to novel stimuli with the breadth of generalization being imperative for how we structure perceptual training programs. Adapting an established auditory interval discrimination paradigm to utilise complex signals, we trained human adults on a standard interval for either 2, 4, or 10 days. We then tested the standard, alternate frequency, interval, and stereo input conditions to evaluate the rapidity of specific learning and breadth of generalization over the time course. In comparison with previous research using simple stimuli, the speed of perceptual learning and breadth of generalization were more rapid and greater in magnitude, including novel generalization to an alternate temporal interval within stimulus type. We also investigated the long term maintenance of learning and found that specific and generalized learning was maintained over 3 and 6 months. We discuss these findings regarding stimulus complexity in perceptual learning and how they can inform the development of effective training protocols.
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Estimulação Acústica/métodos , Percepção Auditiva/fisiologia , Generalização Psicológica/fisiologia , Aprendizagem/fisiologia , Adulto , Limiar Auditivo/fisiologia , Feminino , Humanos , Masculino , Memória de Longo Prazo/fisiologia , Plasticidade Neuronal/fisiologia , Localização de Som , Adulto JovemRESUMO
PURPOSE: This study aimed to determine the spectrum of temporal bone computed tomography (CT) abnormalities in children with conductive hearing loss (CHL) with and without microtia. PATIENTS AND METHODS: From 1993 to 2008, a total of 3396 pediatric records including CHL were reviewed at our institution and revealed 180 cases of persistent CHL, 46 of whom had diagnostic temporal bone CT examinations. All of these examinations were systematically reviewed by two pediatric neuroradiologists, working in consensus, who had 5 and 18 years, respectively, of dedicated pediatric neuroradiology experience. RESULTS: Of the 46 children, 16 were boys and 30 were girls (age: 0.2-16 years; mean: 5 years). Also, 21 (46%) children had microtia and 25 (54%) children did not, as determined by clinical evaluation. External auditory canal atresia/stenosis (EAC-A/S) was the most common anomaly in both microtia and non-microtia groups. Two or more anomalies were observed in 18/21 children with microtia. The frequency of EAC-A/S was greater in children with microtia versus those without it (86% versus 32%, respectively; P = 0.0003). Syndromic diagnoses were also significantly more frequently made in children with microtia versus those without microtia (76% versus 20%, respectively; P = 0.0001). Temporal bone CT scans were normal in 10 children (22%) with persistent CHL. CONCLUSION: Microtia is an important finding in children with CHL. EAC and middle ear/ossicle anomalies were significantly more frequently seen in children with microtia, and multiple anomalies and bilateral microtia were more common in children with syndromic associations. These findings highlight the importance of understanding the embryological development of the temporal bone. The presence of one anomaly should raise suspicion of the possibility of other anomalies, especially in the setting of microtia. Bilateral microtia and multiple anomalies should also raise suspicion of genetic syndromes.
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Anormalidades Congênitas/diagnóstico por imagem , Orelha/anormalidades , Perda Auditiva Condutiva/diagnóstico por imagem , Osso Temporal/anormalidades , Adolescente , Criança , Pré-Escolar , Anormalidades Congênitas/fisiopatologia , Microtia Congênita , Orelha/diagnóstico por imagem , Orelha/fisiopatologia , Feminino , Perda Auditiva Condutiva/fisiopatologia , Humanos , Lactente , Masculino , Radiografia , Estudos Retrospectivos , Osso Temporal/diagnóstico por imagem , Osso Temporal/fisiopatologiaRESUMO
PURPOSE: To investigate impacts of multiple daily insulin injections (MDII) and continuous subcutaneous insulin infusion (CSII) on disease management and patient lifestyle by patients and significant others (SOs). HYPOTHESES: Older patients (>50 years) and their SOs will perceive differences in satisfaction between CSII and MDII impact on diabetes management and lifestyle. METHODS: Patient and paired SO completed parallel instruments framed by sociotechnical systems theory and the life patterns model. Alpha = .901-.940. RESULTS: Whites reported greater satisfaction with CSII and non-Whites with MDII. Both reported increased independence. CSII scored significantly higher than MDII. Age did not reduce positive impacts. CSII enhanced independence of SOs but 38.6% of SOs did not know how to suspend CSII for hypoglycemia; 47.3% of patients believed SOs would not know. CONCLUSIONS: Neither age nor diabetes type contraindicate using CSII in older patients. CSII is perceived more impactful on disease management and lifestyle. Education of SOs needs emphasis.
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Diabetes Mellitus Tipo 2/terapia , Idoso , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Recruiting a diverse group of medical students, house officers, and faculty in medicine is challenging-particularly for predominantly white, midwest institutions that may not be racially or ethnically diverse. PURPOSE: To evaluate a novel clinical simulation program, SiMfest, for recruiting house officers from historically marginalized populations to our institution to demonstrate our leadership's commitment to high-quality education and recruitment of these students to enhance diversity in academic medicine. METHODS: The Office for Health Equity and Inclusion, institutional leadership, and clinical department chairs developed a novel and engaging series of clinical simulations, SiMfest, to engage the pipeline of historically marginalized trainees and demonstrate our leadership's commitment to high-quality education. SiMfest is a two-hour simulation session presented annually (2017-2019) by our institution at the Student National Medical Association Annual Medical Education Conference. RESULTS: Over 800 students participated in SiMfest sessions over three years. Of the 461 participants who completed a survey after participation, 301 identified as female, and 382 indicated a racial category considered as historically marginalized in medicine-91% of whom identified as African American or Black. Thirty percent (nâ¯=â¯125) of respondents identified as pre-medical (e.g., undergraduate, post-baccalaureate) students and 69% (nâ¯=â¯289) identified as current medical students. Over 80% of students would recommend SiMfest to others. Additionally, 73% (nâ¯=â¯87) of pre-medical and 54% (nâ¯=â¯143) of medical students reported exposure to a previously unknown specialty. Thirty-three department representatives reported their SiMfest experience revealed new information about historically marginalized applicants that they may not have engaged with through the traditional application process but would be more likely to engage with in future diversity, equity, and inclusion initiatives. CONCLUSION: SiMfest harnessed our institution's high-quality training, personnel resources, and diversity, equity, and inclusion values to bring historically marginalized students in medicine and department leadership together to learn about one another and offer experiential learning. SiMfest may serve as a model for other institutions to draw on their strengths to develop innovative recruitment programs that promote the education and engagement of undergraduate and medical students from historically marginalized populations while simultaneously promoting diversity, equity, and inclusion culture change.
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Educação Médica , Estudantes de Medicina , Humanos , Feminino , Estudos Prospectivos , Pessoal de Saúde , DocentesRESUMO
Introduction: Effective cross-cultural care is foundational for mitigating health inequities and providing high-quality care to diverse populations. However, medical school teaching practices vary widely, and learners have limited opportunities to develop these critical skills. To understand the current state of cross-cultural education and to identify potential opportunities for improvement, we disseminated a validated survey instrument among medical students at a single institution. Methods: Learners across 4 years of medical school participated in the cross-cultural care assessment, using a tool previously validated with resident physicians and modified for medical students. The survey assessed medical student perspectives on (1) preparedness, (2) skillfulness, and (3) educational curriculum and learning environment. Cross-sectional data were analyzed by class year, comparing trends between school years. Results: Of 700 possible survey responses, we received 260 (37% response rate). Fourth-year students had significantly higher scores than first-year students (p<0.05) for 7 of 12 preparedness items and 4 of 9 skillfulness items. Less than 50% of students indicated readiness to deliver cross-cultural care by their fourth year in 9 of 12 preparedness items and 6 of 9 skillfulness items. Respondents identified inadequate cross-cultural education as the primary barrier. Discussion: Medical students reported a lack of readiness to provide cross-cultural care, with self-assessed deficiencies persisting through the fourth year of medical school. Medical educators can use data from the cross-cultural care survey to longitudinally assess students and enhance curricular exposures where deficiencies exist. Optimizing cross-cultural education has the potential to improve the learning environment and overall patient care.
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Virtual reality exposure therapy (VRET) is a novel intervention technique that allows individuals to experience anxiety-evoking stimuli in a safe environment, recognise specific triggers and gradually increase their exposure to perceived threats. Public-speaking anxiety (PSA) is a prevalent form of social anxiety, characterised by stressful arousal and anxiety generated when presenting to an audience. In self-guided VRET, participants can gradually increase their tolerance to exposure and reduce anxiety-induced arousal and PSA over time. However, creating such a VR environment and determining physiological indices of anxiety-induced arousal or distress is an open challenge. Environment modelling, character creation and animation, psychological state determination and the use of machine learning (ML) models for anxiety or stress detection are equally important, and multi-disciplinary expertise is required. In this work, we have explored a series of ML models with publicly available data sets (using electroencephalogram and heart rate variability) to predict arousal states. If we can detect anxiety-induced arousal, we can trigger calming activities to allow individuals to cope with and overcome distress. Here, we discuss the means of effective selection of ML models and parameters in arousal detection. We propose a pipeline to overcome the model selection problem with different parameter settings in the context of virtual reality exposure therapy. This pipeline can be extended to other domains of interest where arousal detection is crucial. Finally, we have implemented a biofeedback framework for VRET where we successfully provided feedback as a form of heart rate and brain laterality index from our acquired multimodal data for psychological intervention to overcome anxiety.
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Diversity impacts performance of our teams, fosters innovation, and improves outcomes of our patients in otolaryngology head and neck surgery. In addition to the moral imperative, increasing the otolaryngology diversity workforce will decrease health care disparities while equity and justice can increase the culture humility to take care of an increasingly diverse patient population. To move toward justice, otolaryngology departments need to end biases in faculty hiring, development, research evaluations, and publication practices. The more intentional our efforts, the more benefit to our patients, providers, staff, learners, and society.
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Otolaringologia , Humanos , Recursos HumanosRESUMO
Translational research describes the process of applying observations and scientific discoveries made in the laboratory to clinical applications that can improve the health of individual patients, most often through clinical trials. To apply the findings of translational research studies to the broader population, the study population must accurately reflect the group of patients afflicted by a particular disease. Yet, it is well known that significant disparities exist for underrepresented groups and lower socioeconomic populations in clinical trials. In fact, only 20% of randomized controlled studies published in high-impact oncology journals include subgroup analyses to assess differences in outcomes based on race or ethnicity.1 If effective interventions to decrease health disparities in research are to be implemented, it is critical to understand the multifactorial influences that create such differences. These are complex and include individual patient factors, family and social support, provider and organizational factors, as well as policy and community factors. Patient access to tertiary or quaternary care academic centers or designated cancer centers with the funding and resources to carry out translational research and knowledge of ongoing available research endeavors is often critical. Active community engagement and outreach and deep understanding of a particular health system's catchment area are necessary to increase both awareness and participation in clinical trials. Without significant progress in biomedical research patient recruitment, existing racial and ethnic health disparities will be challenging to overcome.
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Pesquisa Biomédica , Acessibilidade aos Serviços de Saúde , Etnicidade , Humanos , Seleção de Pacientes , Pesquisa Translacional Biomédica , Estados UnidosRESUMO
OBJECTIVE: To evaluate strategies to increase racial and ethnic diversity in the surgical workforce among trainees and faculty across surgical specialties. DATA SOURCES: Embase, OVID/Medline, and Web of Science Core Collection. REVIEW METHODS: A review of US-based, peer-reviewed articles examining the effect of targeted strategies on racial and ethnic diversity in the surgical workforce was conducted from 2000 to 2020 with the PRISMA checklist and STROBE tool. Studies without an outlined strategy and associated outcomes were excluded. Eleven studies met inclusion criteria and were completed in general surgery, orthopaedic surgery, and otolaryngology-head and neck surgery. CONCLUSIONS: Efforts to increase exposure to surgery through internship programs and required clerkships with efforts to improve mentorship were common (6 of 11 [54.5%] and 3 of 11 [27.3%] studies, respectively). Three (27.3%) studies aimed to diversify the recruitment and selection process for the residency match and faculty hiring, and 2 (18.2%) aimed to increase representation among trainees, faculty, and leadership through holistic review processes paired with departmental commitment. Outcome metrics included surgical residency applications for individuals underrepresented in medicine, interview and match rates, faculty hiring, measures of a successful academic surgical career, and leadership representation. All strategies were successful in increasing diversity in the surgical workforce. IMPLICATIONS FOR PRACTICE: A convincing yet limited body of literature exists to describe strategies and outcomes that address racial and ethnic diversity in the surgical workforce. While future inquiry is needed to move this field of interest forward, the evidence presented provides a framework for surgical residency programs/departments to develop approaches to increase racial and ethnic diversity.
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Internato e Residência , Especialidades Cirúrgicas , Diversidade Cultural , Etnicidade , Humanos , Grupos Raciais , Recursos HumanosRESUMO
The importance of diversity is well established and holds important implications for workplace and physician-patient relationships. Evaluation of diversity statistics within otolaryngology-head and neck surgery reveals areas of deficiency that may be improved with targeted proactive approaches. This article provides a general overview of diversity within otolaryngology, highlights key components of diversity initiatives, and provides strategies for implementation.
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Otolaringologia , Humanos , Relações Médico-PacienteRESUMO
Public health crises palpably demonstrate how social determinants of health have led to disparate health outcomes. The staggering mortality rates among African Americans, Native Americans, and Latinx Americans during the COVID-19 pandemic have revealed how recalcitrant structural inequities can exacerbate disparities and render not just individuals but whole communities acutely vulnerable. While medical curricula that educate students about disparities are vital in rousing awareness, it is experience that is most likely to instill passion for change. The authors first consider the roots of health care disparities in relation to the current pandemic. Then, they examine the importance of salient learning experiences that may inspire a commitment to championing social justice. Experiences in diverse communities can imbue medical students with a desire for lifelong learning and advocacy. The authors introduce a 3-pillar framework that consists of trust building, structural competency, and cultural humility. They discuss how these pillars should underpin educational efforts to improve social determinants of health. Effecting systemic change requires passion and resolve; therefore, perseverance in such efforts is predicated on learners caring about the structural inequities in housing, education, economic stability, and neighborhoods-all of which influence the health of individuals and communities.
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COVID-19/psicologia , Educação Médica/ética , Etnicidade/estatística & dados numéricos , Racismo/etnologia , Negro ou Afro-Americano , Conscientização , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/virologia , Educação Médica/estatística & dados numéricos , Feminino , Disparidades em Assistência à Saúde/etnologia , Humanos , Masculino , Grupos Minoritários , Aprendizagem Baseada em Problemas/estatística & dados numéricos , Saúde Pública/ética , Saúde Pública/estatística & dados numéricos , SARS-CoV-2/genética , Determinantes Sociais da Saúde/etnologia , Determinantes Sociais da Saúde/estatística & dados numéricos , Justiça Social/ética , Participação dos Interessados , Estudantes de Medicina/estatística & dados numéricos , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: Create and validate an objective structured assessment of technical skills (OSATS) for otolaryngology residents learning how to perform a tonsillectomy. STUDY DESIGN: Multicenter prospective longitudinal validation study. METHODS: A multi-institutional study at six tertiary academic otolaryngology residency programs from July 2009 to May 2012. Using the modified Delphi technique, a panel of pediatric otolaryngologists created a tonsillectomy task-based checklist (TBC) for a tonsil OSATS using a 5-point Likert-type scale. Residents were assessed by pediatric otolaryngology staff at the time of surgery with the TBC and a global rating scale. Procedure time, patient age, number of previously performed tonsillectomies, and surgical technique were also collected. RESULTS: One hundred sixty-seven tonsil OSATS were completed for 38 residents, and competency was recorded for 99 (59.2%). Residents scored as competent had performed significantly more previous tonsillectomies than those deemed noncompetent, 44.4 ± 35.6 and 13.5 ± 11.6, respectively (P < .001). The mean overall score on the tonsil TBC was 4.0 ± 0.8 and 2.6 ± 1.0 for competent and noncompetent, respectively (P < .001). Higher number of tonsillectomies performed and mean tonsil TBC score significantly increased the likelihood of competency (P < .001). Each additional tonsillectomy performed increased the likelihood of achieving competency by 6.3% (P = .006, 95% confidence interval (CI): 1.330-1.110), and each 1.0 point increase in mean tonsil TBC score increased the likelihood of competency by a factor of 2.71 (P = .006, 95% CI:1.330-5.513). There is a 95% likelihood of competency at 48 tonsillectomies or a tonsil TBC score of 4.91. CONCLUSION: The tonsil OSATS is a valid and feasible instrument to assess resident competency with tonsillectomy and provides timely objective feedback. LEVEL OF EVIDENCE: 4. Laryngoscope, 131:E359-E366, 2021.
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Competência Clínica , Avaliação Educacional/métodos , Internato e Residência , Otolaringologia/educação , Tonsilectomia/educação , Centros Médicos Acadêmicos , Adolescente , Lista de Checagem/métodos , Criança , Pré-Escolar , Técnica Delphi , Estudos de Viabilidade , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Estudos Prospectivos , Reprodutibilidade dos Testes , Centros de Atenção TerciáriaRESUMO
The COVID-19 pandemic is exacerbating longstanding challenges facing children with tracheostomies and their families. Myriad ethical concerns arising in the long-term care of children with tracheostomies during the COVID-19 pandemic revolve around inadequate access to care, healthcare resources, and rehabilitation services. Marginalized communities such as those from Black and Hispanic origins face disproportionate chronic illness because of racial and other underlying disparities. In this paper, we describe how these disparities also present challenges to children who are technology-dependent, such as those with tracheostomies and discuss the emerging ethical discourse regarding healthcare and resource access for this population during the pandemic.
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COVID-19/epidemiologia , Disparidades nos Níveis de Saúde , Assistência de Longa Duração/métodos , Pandemias , SARS-CoV-2 , Traqueostomia/ética , COVID-19/terapia , Criança , HumanosRESUMO
Visual-to-auditory sensory substitution devices (SSDs) provide improved access to the visual environment for the visually impaired by converting images into auditory information. Research is lacking on the mechanisms involved in processing data that is perceived through one sensory modality, but directly associated with a source in a different sensory modality. This is important because SSDs that use auditory displays could involve binaural presentation requiring both ear canals, or monaural presentation requiring only one - but which ear would be ideal? SSDs may be similar to reading, as an image (printed word) is converted into sound (when read aloud). Reading, and language more generally, are typically lateralised to the left cerebral hemisphere. Yet, unlike symbolic written language, SSDs convert images to sound based on visuospatial properties, with the right cerebral hemisphere potentially having a role in processing such visuospatial data. Here we investigated whether there is a hemispheric bias in the processing of visual-to-auditory sensory substitution information and whether that varies as a function of experience and visual ability. We assessed the lateralization of auditory processing with two tests: a standard dichotic listening test and a novel dichotic listening test created using the auditory information produced by an SSD, The vOICe. Participants were tested either in the lab or online with the same stimuli. We did not find a hemispheric bias in the processing of visual-to-auditory information in visually impaired, experienced vOICe users. Further, we did not find any difference between visually impaired, experienced vOICe users and sighted novices in the hemispheric lateralization of visual-to-auditory information processing. Although standard dichotic listening is lateralised to the left hemisphere, the auditory processing of images in SSDs is bilateral, possibly due to the increased influence of right hemisphere processing. Auditory SSDs might therefore be equally effective with presentation to either ear if a monaural, rather than binaural, presentation were necessary.
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Percepção Auditiva/fisiologia , Auxiliares Sensoriais , Transtornos da Visão/fisiopatologia , Visão Ocular/fisiologia , Percepção Visual/fisiologia , Estimulação Acústica , Adulto , Testes com Listas de Dissílabos , Feminino , Lateralidade Funcional , Humanos , Idioma , Aprendizagem , MasculinoRESUMO
Nitric oxide-donating non-steroidal anti-inflammatory drugs are safer than traditional NSAIDs and inhibit the growth of prostate cancer cells with greater potency than NSAIDs. In vivo, prostate cancer deposits are found in a hypoxic environment which induces resistance to chemotherapy. The aim of this study was to assess the effects and mechanism of action of a NO-NSAID called NO-sulindac on the PC-3 prostate cancer cell line under hypoxic conditions. NO-sulindac was found to have pro-apoptotic, cytotoxic, and anti-invasive effect on PC-3 cells under normoxia and hypoxia. NO-sulindac was significantly more cytotoxic than sulindac at all oxygen levels. The sulindac/linker and NO-releasing subunits both contributed to the cytotoxic effects of NO-sulindac. Resistance of PC-3 cells to NO-sulindac was induced as the oxygen concentration declined. Hypoxia-induced chemoresistance was reversed by knocking-down hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA using RNAi. Nuclear HIF-1alpha levels were upregulated at 0.2% oxygen but reduced by treatment with NO-sulindac, as was Akt phosphorylation. NO-sulindac treatment of hypoxic PC-3 cells transfected with a reporter construct, downregulated activation of the hypoxia response element (HRE) promoter. Co-transfection of PC-3 cells with the HRE promoter reporter construct and myr-Akt (constitutively active Akt) plasmids reversed the NO-sulindac induced reduction in HRE activation. Real-time polymerase chain reaction analysis of hypoxic, NO-sulindac treated PC-3 cells showed downregulation of lysyl oxidase and carbonic anhydrase IX mRNA expression. Collectively, these novel findings demonstrate that NO-sulindac directly inhibits the hypoxia response of PC-3 prostate cancer cells by inhibiting HIF-1alpha translation via the Akt signalling pathway. The ability of NO-sulindac to inhibit tumour adaption to hypoxia has considerable relevance to the future management of prostate cancer with the same cellular properties as PC-3.
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Regulação Neoplásica da Expressão Gênica , Hipóxia , Neoplasias da Próstata/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sulindaco/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Interferência de RNA , Elementos de Resposta , Transdução de SinaisRESUMO
An 8-year-old female with pancreatic-insufficiency cystic fibrosis presented with recurrent pharyngitis, and reduction in body mass index and height velocity during the previous 2 years. Her symptoms (eg, snoring and restless sleep) suggested obstructive sleep apnea, and physical examination revealed tonsillar hypertrophy. While her respiratory disturbance index on nocturnal polysomnography was normal, there was evidence of prolonged periods of snoring, associated with hypercapnia. Adenotonsillectomy decreased the snoring, improved her sleep, and in the 18-month follow-up period she had substantial weight-gain and growth improvement. This case demonstrates that adenotonsillar hypertrophy associated with recurrent pharyngitis and primary snoring might hinder growth in a patient with cystic fibrosis.