RESUMEN
BACKGROUND & AIMS: A disturbing increase in early-onset colorectal cancer (EOCRC) has prompted recent guidelines to recommend lowering the colorectal cancer (CRC) screening starting age from 50 to 45 years old for average-risk individuals. Little is known about the prevalence of colorectal neoplasia in individuals between 45 and 49 years old, or even younger, in the United States. We analyzed a large, nationally representative data set of almost 3 million outpatient colonoscopies to determine the prevalence of, and risk factors for, colorectal neoplasia among patients aged 18 to 54. METHODS: Findings from high-quality colonoscopies were analyzed from AMSURG ambulatory endoscopy centers (ASCs) that report their results in the GI Quality Improvement Consortium (GIQuIC) Registry. Logistic regression was used to identify risk factors for EOCRC. RESULTS: Increasing age, male sex, White race, family history of CRC, and examinations for bleeding or screening were all associated with higher odds of advanced premalignant lesions (APLs) and CRC. Among patients aged 45 to 49, 32% had any neoplasia, 7.5% had APLs, and 0.58% had CRC. Rates were almost as high in those aged 40 to 44. Family history of CRC portended neoplasia rates 5 years earlier. Rates of APLs were higher in American Indian/Alaskan Natives, but lower among Blacks, Asians, and Hispanics, compared with White counterparts. The prevalence of any neoplasia and APL gradually increased between 2014 and 2019, in all age groups. CONCLUSIONS: These data provide support for lowering the screening age to 45 for all average-risk individuals. Early messaging to patients and providers in the years leading up to age 45 is warranted, especially in those with a family history of CRC.
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Colonoscopía , Neoplasias Colorrectales , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Detección Precoz del Cáncer , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Sistema de Registros , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: The prevalence of obesity has grown over the past several decades. It exerts a negative effect on multiple body systems, including the integumentary system, and it increases the risk for development of chronic diseases. Caring for hospitalized patients with severe obesity presents unique challenges, especially when wounds are present. CASES: This article reviews 3 patients with severe obesity hospitalized with extensive full-thickness lower extremity wounds. In all 3 cases, the wounds were comparable to the presentation and evolution of a typical deep tissue pressure injury. In addition, none of the wounds were classified as pressure injuries. These extensive wounds seen in patients with severe obesity lack a clear etiology and pathophysiology, but present wound care nurses and other care providers with unique challenges well beyond evidence-based principles for selection of appropriate topical care. CONCLUSION: These cases illustrate lessons learned when caring for 3 patients during several months of hospitalization at a large academic medical center. Additional research is needed to enhance our knowledge of the etiology of these wounds, especially since the population of patients with severe obesity has become more prevalent.
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Obesidad Mórbida , Humanos , Obesidad Mórbida/complicaciones , Obesidad/complicaciones , Obesidad/epidemiología , Pacientes , Enfermedad CrónicaRESUMEN
The p53-regulated long noncoding RNA lincRNA-p21 has been proposed to act in trans via several mechanisms ranging from repressing genes in the p53 transcriptional network to regulating mRNA translation and protein stability. To further examine lincRNA-p21 function, we generated a conditional knockout mouse model. We find that lincRNA-p21 predominantly functions in cis to activate expression of its neighboring gene, p21. Mechanistically, we show that lincRNA-p21 acts in concert with hnRNP-K as a coactivator for p53-dependent p21 transcription. Additional phenotypes of lincRNA-p21 deficiency could be attributed to diminished p21 levels, including deregulated expression and altered chromatin state of some Polycomb target genes, a defective G1/S checkpoint, increased proliferation rates, and enhanced reprogramming efficiency. These findings indicate that lincRNA-p21 affects global gene expression and influences the p53 tumor suppressor pathway by acting in cis as a locus-restricted coactivator for p53-mediated p21 expression.
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Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular , Proteínas del Grupo Polycomb/fisiología , ARN Largo no Codificante/genética , Animales , Proliferación Celular , Células Cultivadas , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Epigénesis Genética , Ratones , Ratones Noqueados , Activación Transcripcional , TranscriptomaRESUMEN
To enter a cell and establish infection, HIV must first fuse its lipid envelope with the host cell plasma membrane. Whereas the process of HIV membrane fusion can be tracked by fluorescence microscopy, the 3D configuration of proteins and lipids at intermediate steps can only be resolved with cryo-electron tomography (cryoET). However, cryoET of whole cells is technically difficult. To overcome this problem, we have adapted giant plasma membrane vesicles (or blebs) from native cell membranes expressing appropriate receptors as targets for fusion with HIV envelope glycoprotein-expressing pseudovirus particles with and without Serinc host restriction factors. The fusion behavior of these particles was probed by TIRF microscopy on bleb-derived supported membranes. Timed snapshots of fusion of the same particles with blebs were examined by cryo-ET. The combination of these methods allowed us to characterize the structures of various intermediates on the fusion pathway and showed that when Serinc3 or Serinc5 (but not Serinc2) were present, later fusion products were more prevalent, suggesting that Serinc3/5 act at multiple steps to prevent progression to full fusion. In addition, the antifungal amphotericin B reversed Serinc restriction, presumably by intercalation into the fusing membranes. Our results provide a highly detailed view of Serinc restriction of HIV-cell membrane fusion and thus extend current structural and functional information on Serinc as a lipid-binding protein.
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Membrana Celular/metabolismo , Microscopía por Crioelectrón , VIH-1/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de la Membrana/metabolismo , Línea Celular , Células HEK293 , Células HeLa , Interacciones Huésped-Patógeno , Humanos , Fusión de Membrana , Microscopía Fluorescente , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismoRESUMEN
Myotonic dystrophy (dystrophia myotonica, DM) is a multi-systemic disease caused by expanded CTG or CCTG microsatellite repeats. Characterized by symptoms in muscle, heart and central nervous system, among others, it is one of the most variable diseases known. A major pathogenic event in DM is the sequestration of muscleblind-like proteins by CUG or CCUG repeat-containing RNAs transcribed from expanded repeats, and differences in the extent of MBNL sequestration dependent on repeat length and expression level may account for some portion of the variability. However, many other cellular pathways are reported to be perturbed in DM, and the severity of specific disease symptoms varies among individuals. To help understand this variability and facilitate research into DM, we generated 120 RNASeq transcriptomes from skeletal and heart muscle derived from healthy and DM1 biopsies and autopsies. A limited number of DM2 and Duchenne muscular dystrophy samples were also sequenced. We analyzed splicing and gene expression, identified tissue-specific changes in RNA processing and uncovered transcriptome changes strongly correlating with muscle strength. We created a web resource at http://DMseq.org that hosts raw and processed transcriptome data and provides a lightweight, responsive interface that enables browsing of processed data across the genome.
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Músculo Esquelético/metabolismo , Miocardio/metabolismo , Distrofia Miotónica/genética , Adulto , Empalme Alternativo/genética , Secuencia de Bases , Femenino , Perfilación de la Expresión Génica/métodos , Corazón/fisiología , Humanos , Masculino , Repeticiones de Microsatélite/genética , Músculo Esquelético/fisiología , Distrofia Miotónica/metabolismo , Análisis de Componente Principal , ARN/genética , Empalme del ARN/genética , Proteínas de Unión al ARN/metabolismo , Transcriptoma/genéticaRESUMEN
Angelman syndrome is a single-gene disorder characterized by intellectual disability, developmental delay, behavioural uniqueness, speech impairment, seizures and ataxia. It is caused by maternal deficiency of the imprinted gene UBE3A, encoding an E3 ubiquitin ligase. All patients carry at least one copy of paternal UBE3A, which is intact but silenced by a nuclear-localized long non-coding RNA, UBE3A antisense transcript (UBE3A-ATS). Murine Ube3a-ATS reduction by either transcription termination or topoisomerase I inhibition has been shown to increase paternal Ube3a expression. Despite a clear understanding of the disease-causing event in Angelman syndrome and the potential to harness the intact paternal allele to correct the disease, no gene-specific treatment exists for patients. Here we developed a potential therapeutic intervention for Angelman syndrome by reducing Ube3a-ATS with antisense oligonucleotides (ASOs). ASO treatment achieved specific reduction of Ube3a-ATS and sustained unsilencing of paternal Ube3a in neurons in vitro and in vivo. Partial restoration of UBE3A protein in an Angelman syndrome mouse model ameliorated some cognitive deficits associated with the disease. Although additional studies of phenotypic correction are needed, we have developed a sequence-specific and clinically feasible method to activate expression of the paternal Ube3a allele.
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Síndrome de Angelman/genética , Síndrome de Angelman/terapia , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/uso terapéutico , ARN Largo no Codificante/antagonistas & inhibidores , ARN Largo no Codificante/genética , Alelos , Síndrome de Angelman/complicaciones , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Padre , Femenino , Silenciador del Gen/efectos de los fármacos , Impresión Genómica/genética , Masculino , Trastornos de la Memoria/complicaciones , Trastornos de la Memoria/genética , Trastornos de la Memoria/terapia , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Obesidad/complicaciones , Obesidad/genética , Obesidad/terapia , Oligonucleótidos Antisentido/farmacología , Fenotipo , ARN sin Sentido/antagonistas & inhibidores , ARN sin Sentido/deficiencia , ARN sin Sentido/genética , Factores de Tiempo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
While slow processing speed (PS) is well documented in youth with ADHD, growing evidence suggests that this difficulty affects children with other neuropsychiatric conditions. Clarifying the relationship between slow PS and different forms of psychopathology is important clinically, given the potential impact of PS on academic functioning, and conceptually. In 751 youth, ages 6-21, consecutively referred for neuropsychiatric evaluation, we examined the association between slow PS (i.e., Wechsler PS Index < 85) and seven neuropsychiatric diagnostic groups. In 492 of these youth, we also related slow PS to eight psychopathology symptom dimensions. Finally, we modeled the relationship between PS, other cognitive functions and academic achievement. Data are from the Longitudinal Study of Genetic Influences on Cognition. Analyses included one-sample t tests, ANOVA, logistic regression, mixed modeling, and structural equation modeling (SEM), controlling for age, sex, and medication. Compared to normative data, all clinical groups showed PS decrements. Compared to referred youth without full diagnoses and accounting for other psychopathology, risk for slow PS was elevated in youth with autism spectrum disorder (OR = 1.8), psychotic disorders (OR = 3.4) and ADHD-inattentive type (OR = 1.6). Having multiple comorbidities also increased risk for slow PS. Among dimensions, inattention (OR = 1.5) associated with slow PS but did not fully explain the association with autism or psychosis. In SEM, PS had direct effects on academic achievement and indirect effects through working memory. Findings extend evidence that PS relates to multiple aspects of child psychopathology and associates with academic achievement in child psychiatric outpatients.
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Cognición/fisiología , Psicopatología/métodos , Trastornos Psicóticos/psicología , Éxito Académico , Adolescente , Adulto , Niño , Femenino , Humanos , Estudios Longitudinales , Masculino , Pacientes Ambulatorios , Adulto JovenRESUMEN
BACKGROUND: Since the 1960s, the federal government has been providing or funding a selection of community-based primary healthcare (PHC) programs on First Nations reserves. A key question is whether local access to PHC can help address health inequities in First Nations on-reserve communities in British Columbia (BC). OBJECTIVES: This paper examines whether hospitalization for Ambulatory Care Sensitive Conditions (1) can be used as a proxy measure for the organization of PHC in First Nations reserve areas; and (2) is associated with premature mortality rates. METHODS: In this descriptive correlational study, we used administrative data available through Population Data BC, including demographic and ecological information (i.e. geo-codes indicating location of residence). We used two different measures of hospitalization: rates of episodic hospital care and rates of length of stay. We correlated hospitalization rates with premature mortality rates and the level of care available in First Nations communities, which depends on a federal funding formula based upon community size and, more specifically, the level of isolation from a provincial point of care. RESULTS: First Nations communities in BC that have local 24/7 access to PHC services have similar rates of hospitalization for ACSC to those living in urban centres. This is demonstrated by the similarities in the strengths of the correlation between premature mortality rates and rates of avoidable hospitalization for conditions treatable in a PHC setting. This is not the case for communities served by a Health Centre (weaker correlation) and for communities serviced by a Health Station or with no on-reserve point of care (no correlation). CONCLUSIONS: Improving access to PHC services in First Nations communities can be associated with a significant reduction in avoidable hospitalization and premature mortality rates. The method we tested is an important tool that could serve health care planning decisions in small communities.
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Atención Ambulatoria , Hospitalización , Inuk , Atención Primaria de Salud , Adolescente , Adulto , Anciano , Colombia Británica , Niño , Preescolar , Servicios de Salud Comunitaria , Bases de Datos Factuales , Femenino , Hospitalización/tendencias , Humanos , Lactante , Masculino , Persona de Mediana Edad , Grupos de Población , Adulto JovenRESUMEN
The effect of load carriage on pulmonary function was investigated during a treadmill march of increasing intensity. 24 male infantry soldiers marched on six occasions wearing either: no load, 15 kg, 30 kg, 40 kg or 50 kg. Each loaded configuration included body armour which was worn as battle-fit or loose-fit (40 kg only). FVC and FEV1 were reduced by 6 to 15% with load. Maximal mouth pressures were reduced post load carriage by up to 11% (inspiratory) and 17% (expiratory). Increased ventilatory demands associated with carrying increased mass were met by increases in breathing frequency (from 3 to 26 breaths·min-1) with minimal changes to tidal volume. 72% of participants experienced expiratory flow limitation whilst wearing the heaviest load. Loosening the armour had minimal effects on pulmonary function. It was concluded that as mass and exercise intensity are increased, the degree of expiratory flow limitation also increases. Practitioner Summary: This study investigated the effect of soldier load carriage on pulmonary function, to inform the trade-off between protection and burden. Load carriage caused an inefficient breathing pattern, respiratory muscle fatigue and expiratory flow limitation during marching. These effects were exacerbated by increases in mass carried and march intensity.
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Ropa de Protección/efectos adversos , Equipo Deportivo/efectos adversos , Caminata/fisiología , Soporte de Peso/fisiología , Adulto , Humanos , Masculino , Personal Militar , Fatiga Muscular , Ventilación Pulmonar , Músculos Respiratorios , Adulto JovenRESUMEN
RNA binding proteins of the conserved CUGBP1, Elav-like factor (CELF) family contribute to heart and skeletal muscle development and are implicated in myotonic dystrophy (DM). To understand their genome-wide functions, we analyzed the transcriptome dynamics following induction of CELF1 or CELF2 in adult mouse heart and of CELF1 in muscle by RNA-seq, complemented by crosslinking/immunoprecipitation-sequencing (CLIP-seq) analysis of mouse cells and tissues to distinguish direct from indirect regulatory targets. We identified hundreds of mRNAs bound in their 3' UTRs by both CELF1 and the developmentally induced MBNL1 protein, a threefold greater overlap in target messages than expected, including messages involved in development and cell differentiation. The extent of 3' UTR binding by CELF1 and MBNL1 predicted the degree of mRNA repression or stabilization, respectively, following CELF1 induction. However, CELF1's RNA binding specificity in vitro was not detectably altered by coincubation with recombinant MBNL1. These findings support a model in which CELF and MBNL proteins bind independently to mRNAs but functionally compete to specify down-regulation or localization/stabilization, respectively, of hundreds of mRNA targets. Expression of many alternative 3' UTR isoforms was altered following CELF1 induction, with 3' UTR binding associated with down-regulation of isoforms and genes. The splicing of hundreds of alternative exons was oppositely regulated by these proteins, confirming an additional layer of regulatory antagonism previously observed in a handful of cases. The regulatory relationships between CELFs and MBNLs in control of both mRNA abundance and splicing appear to have evolved to enhance developmental transitions in major classes of heart and muscle genes.
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Proteínas CELF/genética , Regulación de la Expresión Génica , Proteínas del Tejido Nervioso/genética , Empalme del ARN , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Animales , Proteínas CELF/metabolismo , Proteínas CELF1/genética , Proteínas CELF1/metabolismo , Regulación hacia Abajo , Exones , Regulación del Desarrollo de la Expresión Génica , Corazón/fisiología , Humanos , Ratones , Ratones Transgénicos , Músculo Esquelético/metabolismo , Distrofia Miotónica/genética , Distrofia Miotónica/terapia , Proteínas del Tejido Nervioso/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas de Unión al ARN/metabolismo , Análisis de Secuencia de ARN , TranscriptomaRESUMEN
BACKGROUND: Indigenous peoples globally experience a disproportionate burden of mental illness due to forced policies and practices of colonization and cultural disruption. The objective of this study was to provide a baseline profile of hospitalization rates for mental health-related Ambulatory Care Sensitive Conditions among First-Nations living both on and off reserve in British Columbia, Canada, and explore the relationship between local access to health services and mental health-related hospitalization rates. METHODS: A population-based time trend analysis of mental health-related Ambulatory Care Sensitive Conditions hospitalizations was conducted using de-identified administrative health data. The study population included all residents eligible under the universal British Columbia Medical Services Plan and living on and off First Nations reserves between 1994/95 and 2009/10. The definition of mental health-related Ambulatory Care Sensitive Conditions included mood disorders and schizophrenia, and three different change measures were used to operationalize avoidable hospitalizations: 1) rates of episodes of hospital care, 2) rates of length of stay, and 3) readmission rates. Data were analyzed using generalized estimating equations approach, controlling for age, sex, and socio-economic status, to account for change over time. RESULTS: Our findings show that First Nations living on reserve have higher hospitalization rates for mental disorders compared to other British Columbia residents up until 2008. Those living off reserve had significantly higher hospitalization rates throughout the study period. On-reserve communities served by nursing stations had the lowest rates of hospitalization whereas communities with limited local services had the highest rates. Compared to other British Columbia residents, all First Nations have a shorter length of stay and lower readmission rates. CONCLUSIONS: This study suggests that despite reduced rates of hospitalization for mental-health related Ambulatory Care Sensitive Conditions over time for First Nations, gaps in mental health care still exist. We argue greater investments in primary mental health care are needed to support First Nations health. However, these efforts should place equal importance on prevention and the social determinants of health.
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Atención Ambulatoria/estadística & datos numéricos , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Indígenas Norteamericanos/estadística & datos numéricos , Grupos Minoritarios/estadística & datos numéricos , Adulto , Colombia Británica/epidemiología , Femenino , Humanos , Masculino , Salud Mental/estadística & datos numéricos , Persona de Mediana Edad , Grupos de PoblaciónRESUMEN
AIMS AND OBJECTIVES: To elucidate the terminology associated with preceptorships, articulate an operational description of preceptorship that may be useful in formalising the precepting process and provide guidance for constructing a clinical environment where precepting can thrive. BACKGROUND: Precepting facilitates the transition of nurses into new roles. Precepting may improve patient outcomes and safety, as well as enhance nursing satisfaction. Most research focuses on preceptor preparation and perceptions. A comprehensive operational description of what is required to formalise the precepting process is missing from the literature. DESIGN: This concept analysis was completed using a combination of Walker and Avant's and Rodger's methods. METHODS: Existing literature relating to preceptorship was reviewed. Critical attributes, antecedents, consequences and empirical referents were identified. Model, contrary, related and borderline cases were developed. RESULTS: Preceptorships have the specific attributes of being (i) one-on-one relationships, (ii) embedded within formalised programmes, (iii) that evolve over set amounts of time, (iv) to systematically facilitate practical experiences. Antecedents include how precepting is triggered and organisational supporting activities that may facilitate effective precepting. Consequences include new hire preparedness, confidence and increased retention. Empirical referents are provided for assessing hands-on clinical expertise, individualisation of precepting programmes and the preceptor-preceptee relationship. CONCLUSIONS: This concept analysis provides a holistic view of the precepting process that shifts the focus from the people or checklist to formalised preceptorships. RELEVANCE TO CLINICAL PRACTICE: Continuity throughout an organisation's system streamlines the process of hiring new employees and transitioning nursing students to practice. Organisational policies, dedicated resources and engagement in systematically improving the precepting process are critical. Nurse managers must promote and support formalised preceptorships by providing preceptors and preceptees the time and space needed and fostering a culture that supports preceptorships.
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Educación en Enfermería/métodos , Rol de la Enfermera , Preceptoría/organización & administración , Estudiantes de Enfermería/psicología , Humanos , Tutoría/organización & administración , PercepciónRESUMEN
The priming of macrophages with IFN-γ prior to TLR stimulation results in enhanced and prolonged inflammatory cytokine production. In this study, we demonstrate that, following TLR stimulation, macrophages upregulate the adenosine 2b receptor (A2bR) to enhance their sensitivity to immunosuppressive extracellular adenosine. This upregulation of A2bR leads to the induction of macrophages with an immunoregulatory phenotype and the downregulation of inflammation. IFN-γ priming of macrophages selectively prevents the induction of the A2bR in macrophages to mitigate sensitivity to adenosine and to prevent this regulatory transition. IFN-γ-mediated A2bR blockade leads to a prolonged production of TNF-α and IL-12 in response to TLR ligation. The pharmacologic inhibition or the genetic deletion of the A2bR results in a hyperinflammatory response to TLR ligation, similar to IFN-γ treatment of macrophages. Conversely, the overexpression of A2bR on macrophages blunts the IFN-γ effects and promotes the development of immunoregulatory macrophages. Thus, we propose a novel mechanism whereby IFN-γ contributes to host defense by desensitizing macrophages to the immunoregulatory effects of adenosine. This mechanism overcomes the transient nature of TLR activation, and prolongs the antimicrobial state of the classically activated macrophage. This study may offer promising new targets to improve the clinical outcome of inflammatory diseases in which macrophage activation is dysregulated.
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Interferón gamma/inmunología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Receptor de Adenosina A2B/inmunología , Regulación hacia Arriba/inmunología , Animales , Femenino , Interferón gamma/genética , Interleucina-12/genética , Interleucina-12/inmunología , Activación de Macrófagos/genética , Ratones , Ratones Noqueados , Receptor de Adenosina A2B/genética , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Regulación hacia Arriba/genéticaRESUMEN
OBJECTIVE: Urban minority girls are at risk for summertime weight gain, and may also experience insufficient summertime sleep. Few studies have objectively measured sleep in this population or examined correlates, including physical activity (PA). This study is the first to objectively describe summertime sleep among urban minority girls. METHODS: Data were collected at a community-based summer program that promoted PA (n = 60 girls, ages 10-14 years), at two time points: before beginning programming (T1; unstructured context) and during the final week of programming (T2; structured context). RESULTS: At both time points, participants experienced shorter nighttime sleep than the recommended amount for girls their age. African American girls recorded significantly less sleep than Latina girls in the unstructured context. Findings also suggest that sleep schedules have an influential role in youths' abilities to obtain adequate sleep. CONCLUSION: Overall, summertime sleep is an understudied health behavior that may be important to consider among minority youth.
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Negro o Afroamericano/psicología , Ejercicio Físico/psicología , Conductas Relacionadas con la Salud/etnología , Hispánicos o Latinos/psicología , Grupos Minoritarios/psicología , Estaciones del Año , Sueño , Adolescente , Chicago , Niño , Femenino , Estudios de Seguimiento , Humanos , Salud Urbana/etnologíaRESUMEN
Antisense oligonucleotides (ASOs) are synthetic oligonucleotides that alter expression of disease-associated transcripts via Watson-Crick hybridization. ASOs that function through RNase H or the RNA-induced silencing complex (RISC) result in enzymatic degradation of target RNA. ASOs designed to sterically block access of proteins to the RNA modulate mRNA metabolism but do not typically cause degradation. Here, we rationally design steric blocking ASOs to promote mRNA reduction and characterize the terminating mechanism. Transfection of ASOs complementary to constitutive exons in STAT3 and Sod1 results in greater than 70% reduction of mRNA and protein. The ASOs promote aberrant exon skipping and generation of premature termination codon (PTC)-containing mRNAs. We inhibit the nonsense-mediated mRNA decay (NMD) pathway and show that the PTC-containing mRNAs are recognized by the UPF1 ATPase, cleaved by the SMG6 endonuclease and degraded by the XRN1 cytoplasmic exonuclease. NMD surveillance, however, does not entirely explain the mechanism of decreased STAT3 expression. In addition to exon skipping, ASO treatment causes intron retention and reduction of chromatin-associated STAT3 mRNA. The application of steric blocking ASOs to promote RNA degradation allows one to explore more nucleotide modifications than tolerated by RNase H or RISC-dependent ASOs, with the goal of improving ASO drug properties.
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Técnicas de Silenciamiento del Gen , Oligonucleótidos Antisentido/genética , Estabilidad del ARN , Animales , Secuencia de Bases , Cromatina/metabolismo , Exones , Femenino , Células HeLa , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Oligorribonucleótidos/genética , Interferencia de ARN , Procesamiento Postranscripcional del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1RESUMEN
BACKGROUND/AIMS: Primary chordomas, rare cancers arising from the notochord remnants, are extremely rare in the pediatric population. This study examined a large cohort of primary chordoma patients to determine factors impacting prognosis and survival. METHODS: Demographic and clinical data on 1,358 primary chordoma patients (86 pediatric patients ≤19 years of age and 1,272 adult patients ≥20 years of age) were abstracted from the Surveillance, Epidemiology, and End Result (SEER) database (1973-2011). RESULTS: Pediatric primary chordomas present most often as small tumors <4 cm in the cranium of male Caucasians. Despite the majority of primary chordomas presenting with locoregional involvement (90.4%), pediatric patients had more distant disease (14.8 vs. 9.2%, p < 0.05). Survival among pediatric patients having surgery only was significantly longer than for adults (22.5 vs. 14.3 years, p < 0.001). Overall survival was longer (17.2 vs. 12.6 years) and overall mortality was lower in pediatric patients (38.4 vs. 49.8%), but cancer-specific mortality was higher (37.2 vs. 28.6%, p < 0.005). CONCLUSIONS: Pediatric primary chordomas present most often as small tumors <4 cm in the cranium of male Caucasians. Despite having a higher rate of metastasis, they have prolonged survival compared to adults. Surgical resection significantly improves survival in pediatric primary chordoma patients, and should be considered as first-line therapy in all eligible children.
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Cordoma/mortalidad , Bases de Datos Factuales/tendencias , Vigilancia de la Población , Neoplasias de la Columna Vertebral/mortalidad , Adolescente , Adulto , Anciano , Niño , Cordoma/diagnóstico , Cordoma/epidemiología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vigilancia de la Población/métodos , Neoplasias de la Columna Vertebral/diagnóstico , Neoplasias de la Columna Vertebral/epidemiología , Tasa de Supervivencia/tendencias , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: Men diagnosed with prostate cancer (PCa) can receive supportive care from an array of sources including female partners and prostate cancer support groups (PCSGs). However, little is known about how heterosexual gender relations and supportive care play out among couples who attend PCSGs. Distilling such gender relation patterns is a key to understanding and advancing supportive care for men who experience PCa and their families. PURPOSE: This study describes connections between heterosexual gender relations and PCa supportive care among couples who attend PCSGs. METHOD: In-depth, individual interviews with 30 participants (15 men treated for PCa and their female partners) were analyzed using interpretive descriptive methods. Couples were asked about their relationships, supportive care needs, and attendance at PCSGs. A heterosexual gender relations framework was used to theorize the findings. RESULTS: Findings showed that traditional heterosexual gender relations guided most couples' PCa-related support both in and out of PCSGs. Three themes were inductively derived: "Not pushing too hard"-balancing women's support with men's autonomy, "Confreres"-men supporting men at PCSGs, and "Women are better at reassuring"-support from and for women. CONCLUSIONS: Couples both aligned to and resisted traditional gender roles to accommodate, explain, and rationalize how, as a couple, they approached PCa supportive care needs.
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Heterosexualidad/psicología , Neoplasias de la Próstata/psicología , Grupos de Autoayuda , Apoyo Social , Esposos/psicología , Adaptación Psicológica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/terapia , Parejas Sexuales/psicologíaRESUMEN
Low-income minority females are disproportionately affected by obesity. The relevance of summer months to weight gain is often overlooked. Some evidence suggests that summer programming, such as day camps, may offer increased opportunities for structured physical activities resulting in less weight gain. This study examined the effectiveness of Girls in the Game, a six-hour four-week sports and fitness summer camp program, in increasing physical activity (PA) and reducing body mass index and media use. Statistically significant increases were observed in four physical activity measures including total PA, MVPA, average number of ten-minute bouts of MVPA, and minutes participants spent in bouts of at least ten minutes of MVPA. This chapter highlights the importance of investigating the potential relationships among weight, physical activity, sedentary time, media use, and participation in summer camp programming.
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Negro o Afroamericano , Índice de Masa Corporal , Ejercicio Físico , Hispánicos o Latinos , Obesidad/prevención & control , Evaluación de Programas y Proyectos de Salud , Adolescente , Niño , Femenino , Humanos , Pobreza , Población UrbanaRESUMEN
INTRODUCTION: With rapidly growing members of the Islamic faith, health care providers should expect to care for Muslim patients regardless of their chosen specialty. The quality of care provided hinges on their knowledge and understanding of Islam. This study aimed to analyze the influence of an educational animation on undergraduate nursing students' cultural comfort and knowledge concerning the health care needs of Muslims. METHODS: An educational animation was created addressing the unique health care needs of Muslim patients. Surveys (pre, post, 6 weeks) (n = 658) assessed cultural comfort and knowledge on covered topics. RESULTS: Student knowledge (pre: 12.4 ± 0.1; post: 14.4 ± 0.2; p < .01) and cultural comfort (pre: 4.0 ± 0.03; post: 4.1 ± 0.03; p < .05) increased after viewing the online educational animation. The increase in knowledge was sustained at 6 weeks. Students recommended additional topics for the future. DISCUSSION: This study highlights how an innovative educational animation can enhance students' understanding of providing care for Muslim patients, positively impacting patient outcomes.
Asunto(s)
Bachillerato en Enfermería , Islamismo , Estudiantes de Enfermería , Humanos , Islamismo/psicología , Estudiantes de Enfermería/psicología , Estudiantes de Enfermería/estadística & datos numéricos , Bachillerato en Enfermería/métodos , Bachillerato en Enfermería/normas , Femenino , Masculino , Adulto , Encuestas y Cuestionarios , Educación a Distancia/métodos , Educación a Distancia/normas , Competencia Cultural/educación , Competencia Cultural/psicología , Conocimientos, Actitudes y Práctica en SaludRESUMEN
There are at least 21 families of enveloped viruses that infect mammals, and many contain members of high concern for global human health. All enveloped viruses have a dedicated fusion protein or fusion complex that enacts the critical genome-releasing membrane fusion event that is essential before viral replication within the host cell interior can begin. Because all enveloped viruses enter cells by fusion, it behooves us to know how viral fusion proteins function. Viral fusion proteins are also major targets of neutralizing antibodies, and hence they serve as key vaccine immunogens. Here we review current concepts about viral membrane fusion proteins focusing on how they are triggered, structural intermediates between pre- and postfusion forms, and their interplay with the lipid bilayers they engage. We also discuss cellular and therapeutic interventions that thwart virus-cell membrane fusion.