RESUMEN
Relapse rates in high-risk neuroblastoma remain exceedingly high. The malignant cells that are responsible for relapse have not been identified, and mechanisms of therapy resistance remain poorly understood. Here, we used single nucleus RNA sequencing and bulk whole genome sequencing to identify and characterize the residual malignant persister cells that survive chemotherapy from a cohort of 20 matched diagnosis and definitive surgery tumor samples from patients treated with high-risk neuroblastoma induction chemotherapy. We show that persister cells share common mechanisms of chemotherapy escape including suppression of MYCN activity and activation of NF-κB signaling, the latter is further enhanced by cell-cell communication between the malignant cells and the tumor microenvironment. Overall, our work dissects the transcriptional landscape of cellular persistence in high-risk neuroblastoma and paves the way to the development of new therapeutic strategies to prevent disease relapse.
RESUMEN
Professional organizations point to the underutilization of genetic testing in cardiology as a lack of genetic literacy. Yet, few studies have examined the interpretive work required from clinicians to make results clinically actionable. Based on interviews with twenty-nine cardiologists, we find that although genetic testing may provide epistemic closure by substantiating a suspected diagnosis at the molecular level, genetic testing often disrupted cardiologists' diagnostic inferential processes. These epistemic disruptions were not intrinsic to a particular genetic result type (positive, negative, or VUS), but arose from reconciling genetic results with the patient's symptoms and medical and family history. Drawing from the sociology of diagnosis and professional expertise, we examine how cardiologists resolved epistemic disruptions by either sidelining or repairing genetic test results. However, such attempts at making genetic test results actionable for diagnosis may not resolve epistemic disruptions. We argue that rather than clinicians lacking individual literacy, the limited uptake of genetic test results reflects a collective problem of gaps in the genetic knowledge base that leads to medical agnosis, or an inability to make sense of a patient's symptoms uncertainty, rather than diagnosis.
RESUMEN
PURPOSE: The importance of cellular context to the synergy of DNA damage response (DDR)-targeted agents is important for tumors with mutations in DDR pathways, but less well-established for tumors driven by oncogenic transcription factors. In this study, we exploit the widespread transcriptional dysregulation of the EWS-FLI1 transcription factor to identify an effective DDR-targeted combination therapy for Ewing sarcoma. EXPERIMENTAL DESIGN: We used matrix drug screening to evaluate synergy between a DNA-PK inhibitor (M9831) or an ATR inhibitor (berzosertib) and chemotherapy. The combination of berzosertib and cisplatin was selected for broad synergy, mechanistically evaluated for Ewing sarcoma selectivity, and optimized for in vivo schedule. RESULTS: Berzosertib combined with cisplatin demonstrates profound synergy in multiple Ewing sarcoma cell lines at clinically achievable concentrations. The synergy is due to loss of expression of the ATR downstream target CHEK1, loss of cell-cycle check-points, and mitotic catastrophe. Consistent with the goals of the project, EWS-FLI1 drives the expression of CHEK1 and five other ATR pathway members. The loss of CHEK1 expression is not due to transcriptional repression and instead caused by degradation coupled with suppression of protein translation. The profound synergy is realized in vivo with a novel optimized schedule of this combination in subsets of Ewing sarcoma models, leading to durable complete responses in 50% of animals bearing two different Ewing sarcoma xenografts. CONCLUSIONS: These data exploit EWS-FLI1 driven alterations in cell context to broaden the therapeutic window of berzosertib and cisplatin to establish a promising combination therapy and a novel in vivo schedule. See related commentary by Ohmura and Grünewald, p. 3358.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada , Cisplatino , Sinergismo Farmacológico , Proteína Proto-Oncogénica c-fli-1 , Proteína EWS de Unión a ARN , Sarcoma de Ewing , Ensayos Antitumor por Modelo de Xenoinjerto , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/patología , Sarcoma de Ewing/genética , Humanos , Cisplatino/farmacología , Animales , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Ratones , Proteína EWS de Unión a ARN/genética , Proteína EWS de Unión a ARN/antagonistas & inhibidores , Línea Celular Tumoral , Proteína Proto-Oncogénica c-fli-1/genética , Proteína Proto-Oncogénica c-fli-1/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Daño del ADN/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Isoxazoles , PirazinasRESUMEN
SUMMARY: With the increasing rates of exome and whole genome sequencing, the ability to classify large sets of germline sequencing variants using up-to-date American College of Medical Genetics-Association for Molecular Pathology (ACMG-AMP) criteria is crucial. Here, we present Automated Germline Variant Pathogenicity (AutoGVP), a tool that integrates germline variant pathogenicity annotations from ClinVar and sequence variant classifications from a modified version of InterVar (PVS1 strength adjustments, removal of PP5/BP6). This tool facilitates large-scale, clinically focused classification of germline sequence variants in a research setting. AVAILABILITY AND IMPLEMENTATION: AutoGVP is an open source dockerized workflow implemented in R and freely available on GitHub at https://github.com/diskin-lab-chop/AutoGVP.
Asunto(s)
Variación Genética , Genómica , Humanos , Flujo de Trabajo , Virulencia , Programas Informáticos , Células Germinativas , Pruebas GenéticasRESUMEN
BACKGROUND: Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic germline variants in patients without a family history remains unclear. METHODS: Germline DNA sequencing was performed on 786 neuroblastoma patients. The frequency of rare cancer predisposition gene pathogenic or likely pathogenic variants in patients was compared with 2 cancer-free control cohorts. Matched tumor DNA sequencing was evaluated for second hits, and germline DNA array data from 5585 neuroblastoma patients and 23â505 cancer-free control children were analyzed to identify rare germline copy number variants. Patients with germline pathogenic or likely pathogenic variants were compared with those without to test for association with clinical characteristics, tumor features, and survival. RESULTS: We observed 116 pathogenic or likely pathogenic variants involving 13.9% (109 of 786) of neuroblastoma patients, representing a statistically significant excess burden compared with cancer-free participants (odds ratio [OR] = 1.60, 95% confidence interval [CI] = 1.27 to 2.00). BARD1 harbored the most statistically significant enrichment of pathogenic or likely pathogenic variants (OR = 32.30, 95% CI = 6.44 to 310.35). Rare germline copy number variants disrupting BARD1 were identified in patients but absent in cancer-free participants (OR = 29.47, 95% CI = 1.52 to 570.70). Patients harboring a germline pathogenic or likely pathogenic variant had a worse overall survival compared with those without (P = 8.6 x 10-3). CONCLUSIONS: BARD1 is an important neuroblastoma predisposition gene harboring both common and rare germline pathogenic or likely pathogenic variations. The presence of any germline pathogenic or likely pathogenic variant in a cancer predisposition gene was independently predictive of worse overall survival. As centers move toward paired tumor-normal sequencing at diagnosis, efforts should be made to centralize data and provide an infrastructure to support cooperative longitudinal prospective studies of germline pathogenic variation.
Asunto(s)
Predisposición Genética a la Enfermedad , Neuroblastoma , Niño , Humanos , Estudios Prospectivos , Proteína BRCA1/genética , Mutación de Línea Germinal , Neuroblastoma/genética , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
With the increasing rates of exome and whole genome sequencing, the ability to classify large sets of germline sequencing variants using up-to-date American College of Medical Genetics - Association for Molecular Pathology (ACMG-AMP) criteria is crucial. Here, we present Automated Germline Variant Pathogenicity (AutoGVP), a tool that integrates germline variant pathogenicity annotations from ClinVar and sequence variant classifications from a modified version of InterVar (PVS1 strength adjustments, removal of PP5/BP6). This tool facilitates large-scale, clinically-focused classification of germline sequence variants in a research setting.
RESUMEN
Botulinum neurotoxin subtype A4 (BoNT/A4) is ~1000-fold less potent than BoNT/A1. This study addresses the basis for low BoNT/A4 potency. Utilizing BoNT/A1-A4 and BoNT/A4-A1 Light Chain-Heavy Chain (LC-HC) chimeras, HC-A4 was responsible for low BoNT/A4 potency. Earlier studies showed BoNT/A1-receptor binding domain (Hcc) bound a ß-strand peptide (556-564) and glycan-N559 within Luminal Domain 4 (LD4) of SV2C, the BoNT/A protein receptor. Relative to BoNT/A1, the Hcc of BoNT/A4 possesses two amino acid variants (D1141 and N1142) within the ß-peptide binding interface and one amino acid variant (R1292) located near the SV2C glycan-N559. Introduction of BoNT/A4 ß-strand peptide variant (D1141 and N1142) into BoNT/A1 reduced toxin potency 30-fold, and additional introduction of the BoNT/A4 glycan-N559 variant (D1141, N1142, and R1292) further reduced toxin potency to approach BoNT/A4. While introduction of BoNT/A1 glycan-N559 variant (G1292) into BoNT/A4 did not alter toxin potency, additional introduction of BoNT/A1 ß-strand peptide variants (G1141, S1142, and G1292) resulted in potency approaching BoNT/A1 potency. Thus, outcomes from these functional and modeling studies indicate that in rodent models, disruption of Hcc -SV2C ß-peptide and -glycan-N559 interactions mediate low BoNT/A4 potency, while in human motor neurons, disruption of Hcc-SV2C ß-peptide alone mediates low BoNT/A4 potency, which link to a species-specific variation at SV2C563.
Asunto(s)
Aminoácidos , Humanos , Unión Proteica , Dominios ProteicosRESUMEN
Importance: Neuroblastoma accounts for 12% of childhood cancer deaths. The genetic contribution of rare pathogenic germline variation in patients without a family history remains unclear. Objective: To define the prevalence, spectrum, and clinical significance of pathogenic germline variation in cancer predisposition genes (CPGs) in neuroblastoma patients. Design Setting and Participants: Germline DNA sequencing was performed on the peripheral blood from 786 neuroblastoma patients unselected for family history. Rare variants mapping to CPGs were evaluated for pathogenicity and the percentage of cases harboring pathogenic (P) or likely pathogenic (LP) variants was quantified. The frequency of CPG P-LP variants in neuroblastoma cases was compared to two distinct cancer-free control cohorts to assess enrichment. Matched tumor DNA sequencing was evaluated for "second hits" at CPGs and germline DNA array data from 5,585 neuroblastoma cases and 23,505 cancer-free control children was analyzed to identify rare germline copy number variants (CNVs) affecting genes with an excess burden of P-LP variants in neuroblastoma. Neuroblastoma patients with germline P-LP variants were compared to those without P-LP variants to test for association with clinical characteristics, tumor features, and patient survival. Main Outcomes and Measures: Rare variant prevalence, pathogenicity, enrichment, and association with clinical characteristics, tumor features, and patient survival. Results: We observed 116 P-LP variants in CPGs involving 13.9% (109/786) of patients, representing a significant excess burden of P-LP variants compared to controls (9.1%; P = 5.14 × 10-5, Odds Ratio: 1.60, 95% confidence interval: 1.27-2.00). BARD1 harbored the most significant burden of P-LP variants compared to controls (1.0% vs. 0.03%; P = 8.18 × 10-7; Odds Ratio: 32.30, 95% confidence interval: 6.44-310.35). Rare germline CNVs disrupting BARD1 were also identified in neuroblastoma patients (0.05%) but absent in controls (P = 7.08 × 10-3; Odds Ratio: 29.47, 95% confidence interval: 1.52 - 570.70). Overall, P-LP variants in DNA repair genes in this study were enriched in cases compared to controls (8.1% vs. 5.7%; P = 0.01; Odds Ratio: 1.45, 95% confidence interval: 1.08-1.92). Neuroblastoma patients harboring a germline P-LP variant had a worse overall survival when compared to patients without P-LP variants (P = 8.6 × 10-3), and this remained significant in a multivariate Cox proportional-hazards model (P = 0.01). Conclusions and Relevance: Neuroblastoma patients harboring germline P-LP variants in CPGs have worse overall survival and BARD1 is an important predisposition gene affected by both common and rare pathogenic variation. Germline sequencing should be performed for all neuroblastoma patients at diagnosis to inform genetic counseling and support future longitudinal and mechanistic studies. Patients with a germline P-LP variant should be closely monitored, regardless of risk group assignment.
RESUMEN
Genomic tests regularly produce Variants of Uncertain Significance (VUS), mutations of which currently little is known but may turn out to be disease-causing. The communication of such variants in the United States is typically delegated to genetic counsellors. Based on in-depth interviews, we examined this communication as an indicator of the genetic counsellor's professional status: did they take a subordinate position by reporting out the results as provided by laboratories or did they assert professional authority by interpreting and possibly reducing the uncertainty of VUS results? We found that genetic counsellors put their professional spin on VUS results and they prepared patients for the full range of possible interpretations by normalising the existence of VUS results; intervened in the ecology of testing laboratories to stack the deck in favour of the expected results; and conducted their own research to reclassify a VUS. They marshalled organisational, technical, scientific and communication expertise to ease the sting of uncertainty but were ultimately limited by their role in the counselling encounter rather than in the basic research or laboratory community. We concluded that genetic counsellors use uncertainty to assert professional authority that interpreted genetic test results in light of the patient's symptoms and risk profile and uncertainty tolerance.
Asunto(s)
Consejeros , Humanos , Incertidumbre , Pruebas Genéticas , Mutación , GenómicaRESUMEN
BACKGROUND: To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available. METHODS: We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n = 40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade gliomas (pHGGs) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations. RESULTS: ALT is common in pHGGs (n = 24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGGs and in 30% of ALT- pHGGs. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT. CONCLUSIONS: We demonstrate that ATRX is mutated in only a subset of ALT+ pHGGs, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with the development of ALT in patients with pHGG.
Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Niño , Reparación de la Incompatibilidad de ADN , Homeostasis del Telómero/genética , Proteína Nuclear Ligada al Cromosoma X/genética , Glioma/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Mutación , Telómero/genética , Telómero/patologíaRESUMEN
Desmoplastic small round cell tumor (DSRCT) is a rare pediatric sarcoma with poor overall survival. This tumor is absolutely dependent on the continued expression and activity of its defining molecular lesion, the EWS-WT1 transcription factor. Unfortunately, the therapeutic targeting of transcription factors is challenging, and there is a critical need to identify compounds that inhibit EWS-WT1. Here we show that the compound lurbinectedin inhibits EWS-WT1 by redistributing the protein within the nucleus to the nucleolus. This nucleolar redistribution interferes with the activity of EWS-WT1 to reverse the expression of over 70% of the transcriptome. In addition, the compound blocks the expression of the EWS-WT1 fusion protein to inhibit cell proliferation at the lowest GI50 ever reported for this compound in any cell type. The effects occur at concentrations that are easily achievable in the clinic and translate to the in vivo setting to cause tumor regressions in multiple mice in a xenograft and PDX model of DSRCT. Importantly, this mechanism of nucleolar redistribution is also seen with wild-type EWSR1 and the related fusion protein EWS-FLI1. This provides evidence for a "class effect" for the more than 18 tumors driven by EWSR1 fusion proteins. More importantly, the data establish lurbinectedin as a promising clinical candidate for DSRCT.
Asunto(s)
Carbolinas , Tumor Desmoplásico de Células Pequeñas Redondas , Compuestos Heterocíclicos de 4 o más Anillos , Proteínas de Fusión Oncogénica , Sarcoma , Animales , Carbolinas/farmacología , Tumor Desmoplásico de Células Pequeñas Redondas/tratamiento farmacológico , Tumor Desmoplásico de Células Pequeñas Redondas/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Ratones , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteína EWS de Unión a ARN/genética , Proteína EWS de Unión a ARN/metabolismoRESUMEN
Gene duplication is a fundamental process that has the potential to drive phenotypic differences between populations and species. While evolutionarily neutral changes have the potential to affect phenotypes, detecting selection acting on gene duplicates can uncover cases of adaptive diversification. Existing methods to detect selection on duplicates work mostly inter-specifically and are based upon selection on coding sequence changes, here we present a method to detect selection directly on a copy number variant segregating in a population. The method relies upon expected relationships between allele (new duplication) age and frequency in the population dependent upon the effective population size. Using both a haploid and a diploid population with a Moran Model under several population sizes, the neutral baseline for copy number variants is established. The ability of the method to reject neutrality for duplicates with known age (measured in pairwise dS value) and frequency in the population is established through mathematical analysis and through simulations. Power is particularly good in the diploid case and with larger effective population sizes, as expected. With extension of this method to larger population sizes, this is a tool to analyze selection on copy number variants in any natural or experimentally evolving population. We have made an R package available at https://github.com/peterbchi/CNVSelectR/ which implements the method introduced here.
Asunto(s)
Diploidia , Duplicación de Gen , Alelos , Fenotipo , Selección GenéticaRESUMEN
Fathers are more than social accidents. Research has demonstrated that fathers matter to children's development. Despite noted progress, challenges remain on how best to conceptualize and assess fathering and father-child relationships. The current monograph is the result of an SRCD-sponsored meeting of fatherhood scholars brought together to discuss these challenges and make recommendations for best practices for incorporating fathers in studies on parenting and children's development. The first aim of this monograph was to provide a brief update on the current state of research on fathering and to lay out a developmental ecological systems perspective as a conceptual framework for understanding the different spaces fathers inhabit in their children's lives. Because there is wide variability in fathers' roles, the ecological systems perspective situates fathers, mothers, children, and other caregivers within an evolving network of interrelated social relationships in which children and their parents change over time and space (e.g., residence). The second aim was to present examples of empirical studies conducted by members of the international working group that highlighted different methods, data collection, and statistical analyses used to capture the variability in father-child relationships. The monograph ends with a commentary that elaborates on the ecological systems framework with a discussion of the broader macrosystem and social-contextual influences that impinge on fathers and their children. The collection of articles contributes to research on father-child relationships by advancing theory and presenting varied methods and analysis strategies that assist in understanding the father-child relationship and its impact on child development.
Asunto(s)
Desarrollo Infantil , Relaciones Padre-Hijo , Padre/psicología , Responsabilidad Parental/psicología , Niño , Humanos , InvestigaciónRESUMEN
Genome-wide heterozygosity has long been hypothesized to play a role in buffering organisms against developmental perturbations, potentially resulting in increased symmetry. If true, this could in part explain the maintenance of standing genetic variation in wild populations. Marine threespine sticklebacks (Gasterosteus aculeatus) were sampled across their eastern Pacific coastal distribution from Alaska to California and variations in asymmetry for both structural and nonstructural armor traits (lateral plates) were assessed. Structural plates consistently showed less asymmetry than nonstructural plates, but standardized measures of heterozygosity were not correlated with the extent of asymmetry expressed by a fish. Fish that were heterozygous for the major-effect gene controlling lateral plate variation (Ectodysplasin) had higher occurrences of asymmetry, even when the individuals were phenotypically fully plated. Collectively, this suggests that heterozygosity at a major-effect locus can have a greater impact on asymmetry than heterozygosity sampled across the genome.
Asunto(s)
Adaptación Fisiológica/genética , Ectodisplasinas/genética , Selección Genética , Smegmamorpha/genética , Animales , Organismos Acuáticos , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , Heterocigoto , Mutación , Océano PacíficoRESUMEN
This study reports on the development and validation of the Fatherhood Research and Practice Network coparenting perceptions scale for nonresident fathers. Although other measures of coparenting have been developed, this is the first measure developed specifically for low-income, nonresident fathers. Focus groups were conducted to determine various aspects of coparenting. Based on this, a scale was created and administered to 542 nonresident fathers. Participants also responded to items used to examine convergent and predictive validity (i.e., parental responsibility, contact with the mother, father self-efficacy and satisfaction, child behavior problems, and contact and engagement with the child). Factor analyses and reliability tests revealed three distinct and reliable perceived coparenting factors: undermining, alliance, and gatekeeping. Validity tests suggest substantial overlap between the undermining and alliance factors, though undermining was uniquely related to child behavior problems. The alliance and gatekeeping factors showed strong convergent validity and evidence for predictive validity. Taken together, results suggest this relatively short measure (11 items) taps into three coparenting dimensions significantly predictive of aspects of individual and family life.
Asunto(s)
Escala de Evaluación de la Conducta/normas , Relaciones Padre-Hijo , Padre/psicología , Responsabilidad Parental/psicología , Autoimagen , Adulto , Niño , Femenino , Humanos , Masculino , Edad Paterna , Pobreza/psicología , Reproducibilidad de los Resultados , Características de la Residencia , Autoeficacia , Conducta SocialRESUMEN
A child's relationship with his or her nonresident father has been found to be related to that child's development in important ways. However, validated measures of the relationship between nonresident fathers and their children are rare, particularly for low-income nonresident fathers. To provide guidance for researchers and practitioners evaluating nonresident fatherhood programs, this study uses a sample of 420 primarily low-income nonresident fathers to examine the reliability, convergent validity, and predictive validity of measures of father-child closeness and conflict contained in the Child-Parent Relationship Scale-Short Form (CPRS-SF). Validity was examined across 3 child age groups: preschool, middle childhood, and adolescence. The CPRS-SF closeness scale demonstrated measurement equivalence across time (conflict did not) and had excellent reliability and validity. Compared to the closeness scale, the CPRS-SF conflict scale was related to fewer validity items but still showed both convergent and predictive validity, including predicting child behavior problems (which the closeness scale did not). Both the closeness and conflict scales are recommended for use with low-income nonresident fathers. Age differences in validity findings are discussed. (PsycINFO Database Record
Asunto(s)
Conflicto Psicológico , Relaciones Padre-Hijo , Pobreza/psicología , Psicometría/instrumentación , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Psicometría/normas , Reproducibilidad de los ResultadosRESUMEN
Low-income, nonresident fathers are often involved in complex coparenting networks that may involve multiple mothers, relatives, and other adults. However, the coparenting literature has often obscured this complexity through limiting attention to father-mother relationships. The current study used family systems theory to examine the effects of fathers' coparenting with mothers and relatives on fathers' parenting self-efficacy, father-child closeness, and father-child conflict. Predictors included the number of fathers' coparenting mothers and relatives, the quality of those coparenting relationships, and coparenting alliances specifically between fathers and the biological mother of a target child. Approximately 19% of a community sample of fathers (N = 401) reported more than 1 mother in their coparenting network, and 63% reported at least 1 relative. Overall, fathers who reported having more-cooperative coparenting relatives in their networks reported higher parenting self-efficacy and father-child closeness. We further noted a race or ethnicity interaction effect for closeness and conflict, such that having more-cooperative coparenting relatives was associated with increased closeness for non-Hispanic Black fathers but not for non-Hispanic White fathers. Amount of cooperation with coparenting relatives was associated with increased conflict for non-Hispanic Black fathers but not for Hispanic fathers. Implications for future research and practice are discussed. (PsycINFO Database Record
Asunto(s)
Conducta Cooperativa , Relaciones Familiares/psicología , Relaciones Padre-Hijo , Responsabilidad Parental/psicología , Pobreza/psicología , Autoeficacia , Adulto , Niño , Relaciones Familiares/etnología , Relaciones Padre-Hijo/etnología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Responsabilidad Parental/etnología , Pobreza/etnología , Estados Unidos/etnologíaRESUMEN
In this paper, we examine non-lesbian, gay, bisexual and transgender-affirming religiosity among behaviourally-bisexual Latino men as it relates to sexual attitudes, experiences and behaviours. We asked how does religiosity correspond to masculine identities, sex roles and condom efficacy? And how might religiosity influence contexts of health risks? Data were analysed from a mixed-methods study of 142 behaviourally-bisexual Latino men, aged 18-60 years. Major findings include positive correlations between religiosity and (1) masculine ideologies, (2) internalised homonegativity, (3) less comfort with receptive sex, (4) low condom efficacy and (5) higher levels of loneliness and incidents of discriminatory events. Results are paired with illustrative, descriptive case studies from life history interviews. It is suggested that non-lesbian, gay, bisexual and transgender-affirming religiosity plays a paradoxical role in the lives of behaviourally-bisexual Latino men - on one hand, increasing internalised homonegativity and attendant health risks and, on the other, providing social support to members of a marginalised population.
Asunto(s)
Bisexualidad , Hispánicos o Latinos , Homofobia , Hombres , Religión y Sexo , Sexo Seguro , Autoeficacia , Adolescente , Adulto , Condones/estadística & datos numéricos , Identidad de Género , Infecciones por VIH/prevención & control , Humanos , Modelos Lineales , Masculino , Masculinidad , Persona de Mediana Edad , Análisis Multivariante , Adulto JovenRESUMEN
In the late 1860s and early 1870s, Darwin had corresponded with the French physician and physiologist, G. B. A. Duchenne, regarding Duchenne's experimental manipulation of human facial expression of emotion, by applying Galvanic electrical stimulation directly to facial muscles. Duchenne had produced a set of over 60 photographic plates to illustrate his view that there are different muscles in the human face that are separately responsible for each individual emotion. Darwin studied this material very carefully and he received permission from Duchenne in 1871 to reproduce several of these images in The Expression of the Emotions in Man and Animals (1872). Darwin had doubted Duchenne's view that there were individual muscle groups that mediate the expression of dozens of separable emotions, and he wondered whether there might instead be a fewer set of core emotions that are expressed with great stability worldwide and across cultures. Prompted by his doubts regarding the veracity of Duchenne's model, Darwin conducted what may have been the first-ever single-blind study of the recognition of human facial expression of emotion. This single experiment was a little-known forerunner for an entire modern field of study with contemporary clinical relevance. Moreover, his specific question about cross-cultural recognition of the cardinal emotions in faces is a topic that is being actively studied (in the twenty-first century) with the hope of developing novel biomarkers to aid the discovery of new therapies for the treatment of schizophrenia, autism, and other neuropsychiatric diseases.
Asunto(s)
Emociones , Expresión Facial , Neurofarmacología/historia , Músculos Faciales/fisiología , Historia del Siglo XIX , Humanos , Cinésica , Neuropsicología/historia , Teoría PsicológicaRESUMEN
OBJECTIVE: To estimate comprehensive cost of rheumatoid arthritis (RA) patients to society and individual stakeholders, including patients/employees, employers, family members/caregivers, and government. RESEARCH DESIGN AND METHODS: Administrative claims databases covering privately insured and Medicare and Medicaid beneficiaries in the US were used to compute the excess payer and beneficiary-paid costs per patient with RA compared with matched controls. Similarly, per-person excess costs for caregivers and uninsured patients with RA were estimated. Costs were estimated for other burdens, including costs of work-loss to employers, adaptations to home and work environments, lost on-the-job productivity, informal and hired care/household help, and job turnover costs. Intangible costs associated with quality-of-life deterioration were estimated based on legal system jury awards, whereas costs for premature mortality were based on lifetime earnings data. Per-capita cost estimates were weighted by the relevant population to estimate societal costs. Because data were incomplete, several assumptions were required; these assumptions could lead to an over- or under-estimation of cost burdens. RESULTS: Annual excess health care costs of RA patients were $8.4 billion, and costs of other RA consequences were $10.9 billion. These costs translate to a total annual cost of $19.3 billion. From a stakeholder perspective, 33% of the total cost was allocated to employers, 28% to patients, 20% to the government, and 19% to caregivers. Adding intangible costs of quality-of-life deterioration ($10.3 billion) and premature mortality ($9.6 billion), total annual societal costs of RA (direct, indirect, and intangible) increased to $39.2 billion. CONCLUSIONS: Societal costs of RA in the US are $19.3 billion and $39.2 billion (in 2005 dollars) without and with intangible costs, respectively. This study was one of the first to attempt to quantify the comprehensive burdens of RA. Despite several assumptions made in areas in which few data exist, the findings generate useful insights into the full burden of RA.