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BACKGROUND: Managing disease risk among first-degree relatives of probands diagnosed with a heritable disease is central to precision medicine. A critical component is often clinical screening, which is particularly important for conditions like dilated cardiomyopathy (DCM) that remain asymptomatic until severe disease develops. Nonetheless, probands are frequently ill-equipped to disseminate genetic risk information that motivates at-risk relatives to complete recommended clinical screening. An easily implemented remedy for this key issue has been elusive. METHODS: The DCM Precision Medicine Study developed Family Heart Talk, a booklet designed to help probands with DCM communicate genetic risk and the need for cardiovascular screening to their relatives. The effectiveness of the Family Heart Talk booklet in increasing cardiovascular clinical screening uptake among first-degree relatives was assessed in a multicenter, open-label, cluster-randomized, controlled trial. The primary outcome measured in eligible first-degree relatives was completion of screening initiated within 12 months after proband enrollment. Because probands randomized to the intervention received the booklet at the enrollment visit, eligible first-degree relatives were limited to those who were alive the day after proband enrollment and not enrolled on the same day as the proband. RESULTS: Between June 2016 and March 2020, 1241 probands were randomized (1:1) to receive Family Heart Talk (n=621) or not (n=620) within strata defined by site and self-identified race/ethnicity (non-Hispanic Black, non-Hispanic White, or Hispanic). Final analyses included 550 families (n=2230 eligible first-degree relatives) in the Family Heart Talk arm and 561 (n=2416) in the control arm. A higher percentage of eligible first-degree relatives completed screening in the Family Heart Talk arm (19.5% versus 16.0%), and the odds of screening completion among these first-degree relatives were higher in the Family Heart Talk arm after adjustment for proband randomization stratum, sex, and age quartile (odds ratio, 1.30 [1-sided 95% CI, 1.08-∞]). A prespecified subgroup analysis did not find evidence of heterogeneity in the adjusted intervention odds ratio across race/ethnicity strata (P=0.90). CONCLUSIONS: Family Heart Talk, a booklet that can be provided to patients with DCM by clinicians with minimal additional time investment, was effective in increasing cardiovascular clinical screening among first-degree relatives of these patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03037632.
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Cardiomiopatía Dilatada , Humanos , Cardiomiopatía Dilatada/diagnóstico , Etnicidad , Familia , Salud de la Familia , Medición de RiesgoRESUMEN
BACKGROUND: Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied. METHODS: We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link. RESULTS: Patients' mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD. CONCLUSIONS: Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03037632.
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Cardiomiopatía Dilatada , Medicina de Precisión , Femenino , Humanos , Masculino , Persona de Mediana Edad , Población Negra , Cardiomiopatía Dilatada/epidemiología , Cardiomiopatía Dilatada/etnología , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/terapia , Desfibriladores Implantables , Evaluación de Medicamentos , Adulto , Anciano , Blanco , Negro o Afroamericano , Estados Unidos/epidemiologíaRESUMEN
Core to the goal of scientific exploration is the opportunity to guide future decision-making. Yet, elected officials often miss opportunities to use science in their policymaking. This work reports on an experiment with the US Congress-evaluating the effects of a randomized, dual-population (i.e., researchers and congressional offices) outreach model for supporting legislative use of research evidence regarding child and family policy issues. In this experiment, we found that congressional offices randomized to the intervention reported greater value of research for understanding issues than the control group following implementation. More research use was also observed in legislation introduced by the intervention group. Further, we found that researchers randomized to the intervention advanced their own policy knowledge and engagement as well as reported benefits for their research following implementation.
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Formulación de Políticas , Ciencia/legislación & jurisprudencia , Toma de Decisiones , Medicina Basada en la Evidencia/legislación & jurisprudencia , Política de Salud/legislación & jurisprudencia , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/legislación & jurisprudenciaRESUMEN
Our insight into the diverse and complex nature of dilated cardiomyopathy (DCM) genetic architecture continues to evolve rapidly. The foundations of DCM genetics rest on marked locus and allelic heterogeneity. While DCM exhibits a Mendelian, monogenic architecture in some families, preliminary data from our studies and others suggests that at least 20% to 30% of DCM may have an oligogenic basis, meaning that multiple rare variants from different, unlinked loci, determine the DCM phenotype. It is also likely that low-frequency and common genetic variation contribute to DCM complexity, but neither has been examined within a rare variant context. Other types of genetic variation are also likely relevant for DCM, along with gene-by-environment interaction, now established for alcohol- and chemotherapy-related DCM. Collectively, this suggests that the genetic architecture of DCM is broader in scope and more complex than previously understood. All of this elevates the impact of DCM genetics research, as greater insight into the causes of DCM can lead to interventions to mitigate or even prevent it and thus avoid the morbid and mortal scourge of human heart failure.
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Alelos , Cardiomiopatía Dilatada/genética , Sitios Genéticos , Variación Genética , Cardiomiopatía Dilatada/prevención & control , Estudios de Cohortes , Conectina/química , Estudios Transversales , Interacción Gen-Ambiente , Humanos , Modelos Estadísticos , Fenotipo , Sarcómeros/químicaRESUMEN
Importance: Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients. Objective: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM. Design: Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance. Exposure: Presence of DCM. Main Outcomes and Measures: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic). Results: A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001). Conclusion and Relevance: Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.
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Indio Americano o Nativo de Alaska , Población Negra , Cardiomiopatía Dilatada , Hispánicos o Latinos , Población Blanca , Humanos , Indio Americano o Nativo de Alaska/genética , Población Negra/genética , Cardiomiopatía Dilatada/etnología , Cardiomiopatía Dilatada/genética , Estudios Transversales , Genómica , Hispánicos o Latinos/genética , Población Blanca/genéticaRESUMEN
BACKGROUND: Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. METHODS: An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated. RESULTS: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. CONCLUSIONS: In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.
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Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/genética , Medicina Basada en la Evidencia/métodos , Testimonio de Experto/métodos , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/métodos , Medicina Basada en la Evidencia/normas , Testimonio de Experto/normas , Pruebas Genéticas/normas , HumanosRESUMEN
PURPOSE: The cardiac phenotype of hereditary transthyretin amyloidosis (hTTR) usually presents as a restrictive or hypertrophic cardiomyopathy, and, although rarely observed as dilated cardiomyopathy (DCM), TTR is routinely included in DCM genetic testing panels. However, the prevalence and phenotypes of TTR variants in patients with DCM have not been reported. METHODS: Exome sequences of 729 probands with idiopathic DCM were analyzed for TTR and 35 DCM genes. RESULTS: Rare TTR variants were identified in 2 (0.5%; 95% CI = 0.1%-1.8%) of 404 non-Hispanic White DCM probands; neither of them had features of hTTR. In 1 proband, a TTR His110Asn variant and a variant of uncertain significance in DSP were identified, and in the other proband, a TTR Val50Met variant known to cause hTTR and a likely pathogenic variant in FLNC were identified. The TTR Val142Ile variant was identified in 8 (3.0%) non-Hispanic Black probands, comparable with African/African American Genome Aggregation Database controls (OR = 1.01; 95% CI = 0.46-1.99). CONCLUSION: Among the 729 DCM probands, 2 had rare TTR variants identified without the features of hTTR, and both had other plausible genetic causes of DCM. Moreover, the frequency of TTR Val142Ile was comparable to a control sample. These findings suggest that hTTR variants may have a limited role in patients with DCM without TTR-specific findings.
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Neuropatías Amiloides Familiares , Cardiomiopatía Dilatada , Neuropatías Amiloides Familiares/genética , Cardiomiopatía Dilatada/genética , Exoma , Pruebas Genéticas , Humanos , Medicina de PrecisiónRESUMEN
Importance: Idiopathic dilated cardiomyopathy (DCM) aggregates in families, and early detection in at-risk family members can provide opportunity to initiate treatment prior to late-phase disease. Most studies have included only White patients, yet Black patients with DCM have higher risk of heart failure-related hospitalization and death. Objective: To estimate the prevalence of familial DCM among DCM probands and the age-specific cumulative risk of DCM in first-degree relatives across race and ethnicity groups. Design, Setting, and Participants: A family-based, cross-sectional study conducted by a multisite consortium of 25 US heart failure programs. Participants included patients with DCM (probands), defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes, and their first-degree relatives. Enrollment commenced June 7, 2016; proband and family member enrollment concluded March 15, 2020, and April 1, 2021, respectively. Exposures: The presence of DCM in a proband. Main Outcomes and Measures: Familial DCM defined by DCM in at least 1 first-degree relative; expanded familial DCM defined by the presence of DCM or either left ventricular enlargement or left ventricular systolic dysfunction without known cause in at least 1 first-degree relative. Results: The study enrolled 1220 probands (median age, 52.8 years [IQR, 42.4-61.8]; 43.8% female; 43.1% Black and 8.3% Hispanic) and screened 1693 first-degree relatives for DCM. A median of 28% (IQR, 0%-60%) of living first-degree relatives were screened per family. The crude prevalence of familial DCM among probands was 11.6% overall. The model-based estimate of the prevalence of familial DCM among probands at a typical US advanced heart failure program if all living first-degree relatives were screened was 29.7% (95% CI, 23.5% to 36.0%) overall. The estimated prevalence of familial DCM was higher in Black probands than in White probands (difference, 11.3% [95% CI, 1.9% to 20.8%]) but did not differ significantly between Hispanic probands and non-Hispanic probands (difference, -1.4% [95% CI, -15.9% to 13.1%]). The estimated prevalence of expanded familial DCM was 56.9% (95% CI, 50.8% to 63.0%) overall. Based on age-specific disease status at enrollment, estimated cumulative risks in first-degree relatives at a typical US advanced heart failure program reached 19% (95% CI, 13% to 24%) by age 80 years for DCM and 33% (95% CI, 27% to 40%) for expanded DCM inclusive of partial phenotypes. The DCM hazard was higher in first-degree relatives of non-Hispanic Black probands than non-Hispanic White probands (hazard ratio, 1.89 [95% CI, 1.26 to 2.83]). Conclusions and Relevance: In a US cross-sectional study, there was substantial estimated prevalence of familial DCM among probands and modeled cumulative risk of DCM among their first-degree relatives. Trial Registration: ClinicalTrials.gov Identifier: NCT03037632.
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Cardiomiopatía Dilatada/epidemiología , Salud de la Familia/estadística & datos numéricos , Grupos Raciales/estadística & datos numéricos , Adulto , Factores de Edad , Población Negra/estadística & datos numéricos , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/etnología , Intervalos de Confianza , Estudios Transversales , Diagnóstico Precoz , Salud de la Familia/etnología , Femenino , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/epidemiología , Hipertrofia Ventricular Izquierda/etnología , Masculino , Persona de Mediana Edad , Prevalencia , Grupos Raciales/etnología , Riesgo , Estados Unidos/epidemiología , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/epidemiología , Disfunción Ventricular Izquierda/etnología , Población Blanca/estadística & datos numéricosRESUMEN
BACKGROUND: Managing nutrition in critically ill patients is an important intervention to promote healing. It is unknown whether the implementation of a protocol that guides enteral nutrition (EN) support is effective in improving the outcomes of critically ill patients. Furthermore, it is unknown whether a nurse-driven protocol is more or less effective than a protocol not managed by nurses. AIMS AND OBJECTIVES: The purpose of this literature review is to determine the current state of the science regarding evidence-based protocols for the administration and management of EN in critically ill patients. SEARCH STRATEGY, INCLUSION, AND EXCLUSION CRITERIA: Studies were identified by searching the Cumulative Index to Nursing and Allied Health Literature Plus database for the terms "enteral nutrition AND nursing." Studies with EN protocols for adult, critically ill patients published since 2011 were included. Studies without a protocol and those pertaining to paediatric, disease-specific, medical-surgical, or community-based populations were excluded. A total of 10 studies meeting the inclusion criteria were identified. CONCLUSIONS: Defining and implementing both early initiation of EN and adequate titration to goal are important for achieving the maximum nutritional advantage. The highest benefit is also derived from identifying and delivering an individualized caloric and/or protein goal. A protocol increases standardization of practice in relation to these themes as well as the management of gastric residual volume, complications, and potentially for managing feeding interruptions. Because of the significant effects of nursing care on nearly all aspects of the management and delivery of EN, a nurse-driven protocol may yield higher compliance and greater effectiveness than a protocol that is not nurse driven. RELEVANCE TO CLINICAL PRACTICE: Nurses are at the forefront of EN administration, although interprofessional collaboration remains paramount. Current practice must align with the best practice in the development and implementation of an EN protocol.
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Protocolos Clínicos/normas , Enfermedad Crítica , Nutrición Enteral , Práctica Clínica Basada en la Evidencia , Enfermería de Cuidados Críticos , Nutrición Enteral/enfermería , Nutrición Enteral/normas , Humanos , Unidades de Cuidados Intensivos , Factores de TiempoRESUMEN
Studies have shown that patients with hypertrophic cardiomyopathy (HCM) may misinterpret the meaning of uninformative genetic testing results to mean that a genetic etiology and family members' risk is ruled out. We hypothesized that poor comprehension of the laboratory genetic test report may contribute to this misunderstanding. We conducted a qualitative study to examine patient understanding of uninformative laboratory results and reports and elicit suggestions for an improved report. Fifteen participants with HCM were interviewed after undergoing genetic testing and receiving their report. While all patients read the report, most participants reported only partially reading it. Most reported not understanding the report at all or only partially understanding it because a provider explained it to them. Some participants said that the report was helpful for understanding their result, but there was evidence of misunderstanding; most participants stated that specific aspects of the report were unhelpful. While most of our participants communicated risk with relatives, none said that the report helped with the communication. Most participants did not recall or find the accompanying physician-directed result letter useful for their understanding or familial communication. Many participants expressed need for a supplemental report that illustrates a personalized clinical 'action plan' that could summarize clinical and familial implications of the result for the patient and their family. We conclude that laboratory reports and physician-directed result letters did not help participants understand their results or their familial implications. Our results suggest opportunities for research to explore the utility of a patient-directed result supplement to improve patient comprehension of genetic test results and outline clinical recommendations via a patient action plan.
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Cardiomiopatía Hipertrófica/genética , Comprensión , Pruebas Genéticas , Relaciones Profesional-Paciente , Familia , Femenino , Asesoramiento Genético/métodos , Humanos , Masculino , Persona de Mediana Edad , Investigación CualitativaRESUMEN
BACKGROUND: Metastatic breast cancer carries a poor prognosis despite the success of newly targeted therapies. Treatment options remain especially limited for the subtype of triple negative breast cancer (TNBC). Several signaling pathways, including NF-κB, are altered in TNBC, and the complexity of this disease implies multi-faceted pathway interactions. Given that IKKε behaves as an oncogene in breast cancer, we hypothesized that IKKε regulates NF-κB signaling to control diverse oncogenic functions in TNBC. METHODS: Vector expression and RNA interference were used to investigate the functional role of IKKε in triple-negative breast cancer cells. Viability, protein expression, NF-κB binding activity, invasion, anoikis, and spheroid formation were examined in cells expressing high or low levels of IKKε, in conjunction with p52 RNA interference or MEK inhibition. RESULTS: This study found that non-canonical NF-κB p52 levels are inversely proportional to ΙΚΚε, and growth of TNBC cells in anchorage supportive, high-attachment conditions requires IKKε and activated MEK. Growth of these cells in anchorage resistant conditions requires IKKε and activated MEK or p52. In this model, IKKε and MEK cooperate to support overall viability whereas the p52 transcription factor is only required for viability in low attachment conditions, underscoring the contrasting roles of these proteins. CONCLUSIONS: This study illustrates the diverse functions of IKKε in TNBC and highlights the adaptability of NF-κB signaling in maintaining cancer cell survival under different growth conditions. A better understanding of the diversity of NF-κB signaling may ultimately improve the development of novel therapeutic regimens for TNBC.
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Regulación Neoplásica de la Expresión Génica , Quinasa I-kappa B/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Subunidad p52 de NF-kappa B/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Supervivencia Celular/genética , Femenino , Humanos , Quinasa I-kappa B/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Subunidad p52 de NF-kappa B/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
This paper explains the healing benefits, the "sweet unexpected" of the title, which results from using poetry to engage trauma, including traumatic grief. The benefits of poetry are presented alongside a discussion of a 22-year-old nonprofit called The Pongo Poetry Project. The sweet unexpected includes the ease with which trauma survivors engage their trauma narrative, the critical insights that emerge in poetry, the beneficial social context of sharing poetry, and the healing benefits of poetry for writers, care providers, and readers alike. The paper concludes by providing resources that can help people use poetry in their own work.
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Adaptación Psicológica , Pesar , Sobrevivientes/psicología , Humanos , NarraciónRESUMEN
BACKGROUND: Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. It was hypothesized that blocking IAPs with birinapant would increase tumor cell death and result in objective responses for women with platinum-refractory and -resistant ovarian cancer. METHODS: In this phase 2, Cancer Therapy Evaluation Program-sponsored study, patients received birinapant at 47 mg/m(2) on days 1, 8, and 15 of 28-day cycles. Pharmacokinetics were obtained during cycle 1. Plasma, peripheral blood mononuclear cells (PBMCs), and percutaneous tumor biopsy samples were collected before cycle 1 and after 6 weeks. The primary endpoint was an objective response or progression-free survival lasting greater than 6 months in a mini-max design. RESULTS: Eleven patients received birinapant; after this, accrual was terminated for lack of a clinical benefit. Birinapant was well tolerated, with predominantly grade 2 adverse events and 1 case of grade 3 lymphopenia. Pretreatment biopsy samples and PBMCs were collected; paired posttreatment biopsy samples and PBMCs were collected from 7 and 10 patients, respectively. There was consistent downregulation of cellular inhibitor of apoptosis protein 1 in tumors (P = .016) and PBMCs (P < .01). Procaspase 3 also decreased in tumors (P = .031) and PBMCs (P < .01); cleaved caspase 3 colocalized with H2A histone family member X (γ-H2AX) in tumors after birinapant exposure. Peripheral T and B cells decreased significantly after treatment, but natural killer cells did not (P = .04, P = .05, and P = .43, respectively). CONCLUSIONS: Birinapant shows consistent target suppression in vivo without single-agent antitumor activity in this small population. Single-agent pharmacodynamics are necessary to understand the drug's mechanism of action and set the stage for rational combination therapy. Preclinical studies are ongoing to identify optimal synergistic combinations for future clinical trials.
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Adenocarcinoma de Células Claras/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Carcinoma Endometrioide/tratamiento farmacológico , Dipéptidos/uso terapéutico , Resistencia a Antineoplásicos , Indoles/uso terapéutico , Neoplasias Quísticas, Mucinosas y Serosas/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adenocarcinoma de Células Claras/metabolismo , Anciano , Antineoplásicos/farmacocinética , Proteínas Reguladoras de la Apoptosis , Linfocitos B , Carcinoma Endometrioide/metabolismo , Carcinoma Epitelial de Ovario , Caspasa 3/metabolismo , Dipéptidos/farmacocinética , Supervivencia sin Enfermedad , Femenino , Humanos , Indoles/farmacocinética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Células Asesinas Naturales , Leucocitos Mononucleares/metabolismo , Recuento de Linfocitos , Linfopenia/inducido químicamente , Persona de Mediana Edad , Proteínas Mitocondriales , Neoplasias Quísticas, Mucinosas y Serosas/metabolismo , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Ováricas/metabolismo , Compuestos de Platino/uso terapéutico , Linfocitos T , Insuficiencia del Tratamiento , Resultado del Tratamiento , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
BACKGROUND: shRNA-mediated lethality screening is a useful tool to identify essential targets in cancer biology. Ovarian cancer (OC) is extremely heterogeneous and most cases are advanced stages at diagnosis. OC has a high response rate initially, but becomes resistant to standard chemotherapy. We previously employed high throughput global shRNA sensitization screens to identify NF-kB related pathways. Here, we re-analyzed our previous shRNA screens in an unbiased manner to identify clinically applicable molecular targets. METHODS: We proceeded with siRNA lethality screening using the top 55 genes in an expanded set of 6 OC cell lines. We investigated clinical relevance of candidate targets in The Cancer Genome Atlas OC dataset. To move these findings towards the clinic, we chose four pharmacological inhibitors to recapitulate the top siRNA effects: Oxozeaenol (for MAP3K7/TAK1), BI6727 (PLK1), MK1775 (WEE1), and Lapatinib (ERBB2). Cytotoxic effects were measured by cellular viability assay, as single agents and in 2-way combinations. Co-treatments were evaluated in either sequential or simultaneous exposure to drug for short term and extended periods to simulate different treatment strategies. RESULTS: Loss-of-function shRNA screens followed by short-term siRNA validation screens identified therapeutic targets in OC cells. Candidate genes were dysregulated in a subset of TCGA OCs although the alterations of these genes showed no statistical significance to overall survival. Pharmacological inhibitors such as Oxozeaenol, BI6727, and MK1775 showed cytotoxic effects in OC cells regardless of cisplatin responsiveness, while all OC cells tested were cytostatic to Lapatinib. Co-treatment with BI6727 and MK1775 at sub-lethal concentrations was equally potent to BI6727 alone at lethal concentrations without cellular re-growth after the drugs were washed off, suggesting the co-inhibition at reduced dosages may be more efficacious than maximal single-agent cytotoxic concentrations. CONCLUSIONS: Loss-of-function screen followed by in vitro target validation using chemical inhibitors identified clinically relevant targets. This approach has the potential to systematically refine therapeutic strategies in OC. These molecular target-driven strategies may provide additional therapeutic options for women whose tumors have become refractory to standard chemotherapy.
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Neoplasias Ováricas/genética , Transcriptoma , Western Blotting , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , FN-kappa B/metabolismo , Neoplasias Ováricas/metabolismo , ARN Interferente Pequeño/genéticaRESUMEN
Concerns over health care in US Immigration and Customs Enforcement (ICE) facilities have grown over the past decade, including reports of medical mismanagement, inadequate mental health care, and inappropriate use of solitary confinement. Despite being a federally funded agency, reporting and accountability of health outcomes in ICE facilities is limited. This manuscript outlines current standards for health in ICE detention, how compliance is evaluated, why this process fails, and how current processes can be improved to achieve transparency and accountability. Ultimately, health metrics must be: 1) frequent; 2) timely; 3) granular; 4) collected by an independent body; and 5) publicly reported. Financial compensation for health service providers must be contingent on meeting these required metrics, with contract termination for persistent violations. Transparent and accountable monitoring systems, as are required in other federally funded healthcare facilities, are essential to accurately measure health outcomes and harms of individuals held in detention.
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INTRODUCTION: The aim of this review is to identify common mood concerns in ICD patients and suggest brief psychological screeners essential for early detection and monitoring in patient care. AREAS COVERED: Reliable and valid psychological assessment tools are reviewed, including those specifically designed for ICD patient populations. EXPERT OPINION: Psychological assessment, in combination with cardiologic standard of care, can help overcome many barriers associated with poor implantable cardioverter-defibrillator (ICD) management and related cardiovascular outcomes. Earlier identification and treatment of mood concerns in ICD patients has been shown to improve quality of life (QOL) and patient outcomes. At this time, however, logistical challenges and time restraints, in addition to knowledge of appropriate treatment plans or referral options, remain central barriers to providing integrated, patient-centered care. Ultimately, all cardiology clinics would benefit from a collaborative care team that includes a mental health consultant or in-house psychologists who can provide consultations or referral services. Additionally, all patients that come to the clinics should complete proactive screening measures as routine component of care to assess the presence of mood concerns to improve patient outcomes and aid in treatment planning.
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Study objective: To develop a digital platform to conduct family-based, dilated cardiomyopathy (DCM) genetic research. Design: The DCM Project Portal, a direct-to-participant electronic recruitment, consent, and communication tool, was designed using prior experience with traditional enrollment methods and characteristics and feedback of current participants. Participants: DCM patients (probands) and their family members enrolled from June 7, 2016 to March 15, 2020 at 25 US advanced heart failure programs. Results: The portal was designed as a self-guided, three module (registration, eligibility, and consent) process with supporting informational and messaging resources integrated throughout. The experience is tailored to user type and the format adaptable with programmatic growth. Characteristics of participants of the recently completed DCM Precision Medicine Study were assessed as an exemplary user population. A majority of the diverse (34 % non-Hispanic Black (NHE-B), 9.1 % Hispanic; 53.6 % female) proband (n = 1223) and family member (n = 1781) participants aged ≥18 years reported not at all or rarely having problems learning about their health from written information (81 %) and a high confidence in completing medical forms (77.2 % very much or often confident), supporting a self-guided model. A majority of participants across age and race-ethnicity groups reported internet access, with highest rates of no reported access in those ≥77 years (31.9 %), NHE-B (25.2 %), and Hispanic (22.9 %), a similar pattern to those reported by the US Census Bureau as of 2021. Conclusions: The portal is an example of a digital approach to family-based genetic research that offers opportunity to improve access and efficiency of research operations.
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BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ~1 in 500 and exhibits marked genetic heterogeneity. Previously published in 2019, 57 HCM-associated genes were curated providing the first systematic evaluation of gene-disease validity. Here we report work by the ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel (HCVD-GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes. METHODS: The ClinGen systematic gene curation framework was used to re-classify the gene-disease relationships for HCM and related syndromic entities involving left ventricular hypertrophy. Genes previously curated were included if their classification was not definitive, and if the time since curation was >2-3 years. New genes with literature assertions for HCM were included for initial evaluation. Existing genes were curated for new inheritance patterns where evidence existed. Curations were presented on twice monthly calls, with the HCVD-GCEP composed of 29 individuals from 21 institutions across 6 countries. RESULTS: Thirty-one genes were re-curated and an additional 5 new potential HCM-associated genes were curated. Among the re-curated genes, 17 (55%) genes changed classification: 1 limited and 4 disputed (from no known disease relationship), 9 disputed (from limited), and 3 definitive (from moderate). Among these, 3 (10%) genes had a clinically relevant upgrade, including TNNC1, a 9th sarcomere gene with definitive HCM association. With new evidence, two genes were curated for multiple inheritance patterns (TRIM63, disputed for autosomal dominant but moderate for autosomal recessive; ALPK3, strong for autosomal dominant and definitive for recessive). CSRP3 was curated for a semi-dominant mode of inheritance (definitive). Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes. Five genes recently reported to cause HCM were curated: RPS6KB1 and RBM20 (limited), KLHL24 and MT-TI (moderate), and FHOD3 (definitive). CONCLUSIONS: We report 29 genes with definitive, strong or moderate evidence of causation for HCM or isolated LVH, including sarcomere, sarcomere-associated and syndromic conditions.
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In this article, I review the literature on burnout and resilience among clergy. The existing research shows that the factors related to clergy burnout include the quality of interpersonal skills, relationships outside the congregation, establishment of peer/mentor relationships, the existence of high role expectations, personal spirituality and the ability to set healthy emotional boundaries. Recent studies using positive psychology as a framework identify a number of personal and situational qualities that promote resilience in clergy. Based on these findings, I suggest interventions that should be made by faith groups to better support clergy and make recommendations for further research.
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Agotamiento Profesional/psicología , Clero/psicología , Cuidado Pastoral/métodos , Resiliencia Psicológica , Autoimagen , Espiritualidad , Adaptación Psicológica , Humanos , Relaciones Interpersonales , ReligiónRESUMEN
Aims: Among genetically at-risk first-degree relatives (FDRs) of probands with dilated cardiomyopathy (DCM), the ability to detect changes in left ventricular (LV) mechanics with normal LV size and ejection fraction (LVEF) remains incompletely explored. We sought to define a pre-DCM phenotype among at-risk FDRs, including those with variants of uncertain significance (VUSs), using echocardiographic measures of cardiac mechanics. Methods and Results: LV structure and function, including speckle-tracking analysis for LV global longitudinal strain (GLS), were evaluated in 124 FDRs (65% female; median age 44.9 [IQR: 30.6-60.3] years) of 66 DCM probands of European ancestry sequenced for rare variants in 35 DCM genes. FDRs had normal LV size and LVEF. Negative FDRs of probands with pathogenic or likely pathogenic (P/LP) variants (n=28) were a reference group to which negative FDRs of probands without P/LP variants (n=30), FDRs with only VUSs (n=27), and FDRs with P/LP variants (n=39) were compared. In an analysis accounting for age-dependent penetrance, FDRs below the median age showed minimal differences in LV GLS across groups while those above it with P/LP variants or VUSs had lower absolute values than the reference group (-3.9 [95% CI: -5.7, -2.1] or -3.1 [-4.8, -1.4] %-units) and negative FDRs of probands without P/LP variants (-2.6 [-4.0, -1.2] or -1.8 [-3.1, -0.6]). Conclusions: Older FDRs with normal LV size and LVEF who harbored P/LP variants or VUSs had lower absolute LV GLS values, indicating that some DCM-related VUSs are clinically relevant. LV GLS may have utility for defining a pre-DCM phenotype. Clinical Trial Registration: clinicaltrials.gov, NCT03037632.