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OBJECTIVE: Higher uncertainty is associated with poorer quality of life and may be impacted by clinician communication about the future. We determined how patients undergoing lung transplant evaluation experience uncertainty and communication about the future from clinicians. METHODS: We performed a convergent parallel mixed-methods study using a cross-sectional survey and semistructured interviews. Patients undergoing lung transplant evaluation at the University of Colorado and the University of Washington answered questions about future communication and completed the Mishel Uncertainty in Illness Scale-Adult (MUIS-A; range 33-165, higher scores indicate more uncertainty). Interviews were analyzed using content analysis. Integration of survey and interview results occurred during data interpretation. RESULTS: A total of 101 patients completed the survey (response rate: 47%). Twelve survey participants completed interviews. In the survey, most patients identified changing family roles as important (76%), which was infrequently discussed with clinicians (31%). Most patients (86%) worried about the quality of their life in the future, and 74% said that not knowing what to expect in the future prevented them from making plans. The mean MUIS-A score was 85.5 (standard deviation 15.3). Interviews revealed three themes: (1) uncertainty of the future distresses participants; (2) participants want practical information from clinicians; and (3) communication preferences vary among participants. CONCLUSION: Participants experienced distressing uncertainty and wanted information about the future. Communication topics that were important to participants were not always addressed by physicians. Clinicians should address how chronic lung disease and lung transplant can directly impact patients' lives and support patients to cope with uncertainty.
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Comunicación , Trasplante de Pulmón , Relaciones Médico-Paciente , Calidad de Vida , Humanos , Trasplante de Pulmón/psicología , Masculino , Femenino , Estudios Transversales , Incertidumbre , Persona de Mediana Edad , Encuestas y Cuestionarios , Estudios de Seguimiento , Adulto , Prioridad del Paciente/psicología , Pronóstico , AncianoRESUMEN
BACKGROUND: Decision making for adult tracheostomy and prolonged mechanical ventilation is emotionally complex. Expectations of surrogate decision makers and physicians rarely align. Little is known about what surrogates need to make goal-concordant decisions. Currently, little is known about the decisional needs of surrogates and providers, impeding efforts to improve the decision-making process. METHODS: Using a thematic analysis approach, we performed a qualitative study with semistructured interviews with surrogates of adult patients receiving mechanical ventilation (MV) being considered for tracheostomy and physicians routinely caring for patients receiving MV. Recruitment was stopped when thematic saturation was reached. We describe the decision-making process, identify core decisional needs, and map the process and needs for possible elements of a future shared decision-making tool. RESULTS: Forty-three participants (23 surrogates and 20 physicians) completed interviews. Hope, Lack of Knowledge Data, and Uncertainty emerged as the 3 main themes that described the decision-making process and were interconnected with one another and, at times, opposed each other. Core decisional needs included information about patient wishes, past activity/medical history, short- and long-term outcomes, and meaningful recovery. The themes were the lens through which the decisional needs were weighed. Decision making existed as a balance between surrogate emotions and understanding and physician recommendations. CONCLUSIONS: Tracheostomy and prolonged MV decision making is complex. Hope and Uncertainty were conceptual themes that often battled with one another. Lack of Knowledge & Data plagued both surrogates and physicians. Multiple tangible factors were identified that affected surrogate decision making and physician recommendations. IMPLICATIONS: Understanding this complex decision-making process has the potential to improve the information provided to surrogates and, potentially, increase the goal-concordant care and alignment of surrogate and physician expectations. HIGHLIGHTS: Decision making for tracheostomy and prolonged mechanical ventilation is a complex interactive process between surrogate decision makers and providers.Qualitative themes of Hope, Uncertainty, and Lack of Knowledge & Data shared by both providers and surrogates were identified and described the decision-making process.Concrete decisional needs of patient wishes, past activity/medical history, short- and long-term outcomes, and meaningful recovery affected each of the larger themes and represented key information from which surrogates and providers based decisions and recommendations.The qualitative themes and decisional needs identified provide a roadmap to design a shared decision-making intervention to improve adult tracheostomy and prolonged mechanical ventilation decision making.
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BACKGROUND: Outcomes for individuals with cystic fibrosis (CF) have improved due to highly effective modulator therapy (HEMT). However, lung transplant (LTx) remains an important treatment for people with advanced lung disease. This study assessed attitudes and knowledge about LTx in the HEMT era. METHODS: All patients from the University of Washington CF clinic were surveyed March 25-May 30, 2020. Questions addressed self-rated LTx preparedness and knowledge, as well as barriers and facilitators to discussing LTx. Demographic and clinical data were extracted from the electronic health record. RESULTS: There were 159/224 (71%) responses. Respondents had a median forced expiratory volume in one second (FEV1) of 70%, and 142 (89%) were on modulatory therapy. One hundred thirteen (71%) respondents felt that it was moderately or very important to be prepared to make decisions about LTx, though only 56 (35%) felt moderately or very prepared. Only 83 (30%) and 47 (52%) participants correctly answered questions about life expectancy and improved quality of life after LTx, respectively. Respondents with Medicaid insurance less frequently answered questions correctly. The most common barriers to discussing LTx were fear of being a burden on loved ones for 58 respondents (36%) and cost of LTx for 46 (29%). Most participants (94%) trusted their CF doctor, and 75% of participants selected trust as a facilitator for LTx discussions. CONCLUSIONS: Many individuals with CF, especially those with lower socioeconomic status, lacked knowledge and did not feel very prepared for decisions about LTx. Earlier education and discussions about LTx represent an area for improvement in CF care.
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Fibrosis Quística , Conocimientos, Actitudes y Práctica en Salud , Trasplante de Pulmón , Humanos , Fibrosis Quística/cirugía , Fibrosis Quística/psicología , Masculino , Femenino , Adulto , Encuestas y Cuestionarios , Calidad de Vida , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Documenting goals of care in the electronic health record is meant to relay patient preferences to other clinicians. Evaluating the content and documentation of nurse and social worker led goals of care conversations can inform future goals of care initiative efforts. METHODS: As part of the ADvancing symptom Alleviation with Palliative Treatment trial, this study analyzed goals of care conversations led by nurses and social workers and documented in the electronic health record. Informed by a goals of care communication guide, we identified five goals of care components: illness understanding, goals and values, end of life planning, surrogate, and advance directives. Forty conversation transcripts underwent content analysis. Through an iterative team process, we defined documentation accuracy as four categories: (1) Complete-comprehensive accurate documentation of the conversation, (2) Incomplete-partial documentation of the conversation, (3) Missing-discussed and not documented, and (4) Incorrect-misrepresented in documentation. We also defined-Not Discussed-for communication guide questions that were not discussed nor documented. A constant comparative approach was used to determine the presence or absence of conversation content in the documentation. RESULTS: All five goals of care components were discussed in 67% (27/40) of conversation transcripts. Compared to the transcripts, surrogate (37/40, 93%) and advance directives (36/40, 90%) were often documented completely. Almost 40% of goals and values (15/40, 38%) and half of end of life planning (19/40, 48%) were incomplete. Illness understanding was missing (13/40, 33%), not discussed (13/40, 33%), or incorrect (2/40, 5%). CONCLUSION: Nurse and social worker led goals of care conversations discussed and documented most components of the goals of care communication guide. Further research may guide how best to determine the relative importance of accuracy, especially in the broad setting of incomplete, missing, and incorrect EHR documentation.
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Comunicación , Documentación , Registros Electrónicos de Salud , Planificación de Atención al Paciente , Humanos , Documentación/normas , Documentación/métodos , Femenino , Masculino , Anciano , Directivas Anticipadas , Cuidados Paliativos , Trabajadores Sociales , Cuidado Terminal/normasRESUMEN
Importance: Many patients with chronic obstructive pulmonary disease (COPD), heart failure (HF), and interstitial lung disease (ILD) endure poor quality of life despite conventional therapy. Palliative care approaches may benefit this population prior to end of life. Objective: Determine the effect of a nurse and social worker palliative telecare team on quality of life in outpatients with COPD, HF, or ILD compared with usual care. Design, Setting, and Participants: Single-blind, 2-group, multisite randomized clinical trial with accrual between October 27, 2016, and April 2, 2020, in 2 Veterans Administration health care systems (Colorado and Washington), and including community-based outpatient clinics. Outpatients with COPD, HF, or ILD at high risk of hospitalization or death who reported poor quality of life participated. Intervention: The intervention involved 6 phone calls with a nurse to help with symptom management and 6 phone calls with a social worker to provide psychosocial care. The nurse and social worker met weekly with a study primary care and palliative care physician and as needed, a pulmonologist, and cardiologist. Usual care included an educational handout developed for the study that outlined self-care for COPD, ILD, or HF. Patients in both groups received care at the discretion of their clinicians, which could include care from nurses and social workers, and specialists in cardiology, pulmonology, palliative care, and mental health. Main Outcomes and Measures: The primary outcome was difference in change in quality of life from baseline to 6 months between the intervention and usual care groups (FACT-G score range, 0-100, with higher scores indicating better quality of life, clinically meaningful change ≥4 points). Secondary quality-of-life outcomes at 6 months included disease-specific health status (Clinical COPD Questionnaire; Kansas City Cardiomyopathy Questionnaire-12), depression (Patient Health Questionnaire-8) and anxiety (Generalized Anxiety Disorder-7) symptoms. Results: Among 306 randomized patients (mean [SD] age, 68.9 [7.7] years; 276 male [90.2%], 30 female [9.8%]; 245 White [80.1%]), 177 (57.8%) had COPD, 67 (21.9%) HF, 49 (16%) both COPD and HF, and 13 (4.2%) ILD. Baseline FACT-G scores were similar (intervention, 52.9; usual care, 52.7). FACT-G completion was 76% (intervention, 117 of 154; usual care, 116 of 152) at 6 months for both groups. Mean (SD) length of intervention was 115.1 (33.4) days and included a mean of 10.4 (3.3) intervention calls per patient. In the intervention group, 112 of 154 (73%) patients received the intervention as randomized. At 6 months, mean FACT-G score improved 6.0 points in the intervention group and 1.4 points in the usual care group (difference, 4.6 points [95% CI, 1.8-7.4]; P = .001; standardized mean difference, 0.41). The intervention also improved COPD health status (standardized mean difference, 0.44; P = .04), HF health status (standardized mean difference, 0.41; P = .01), depression (standardized mean difference, -0.50; P < .001), and anxiety (standardized mean difference, -0.51; P < .001) at 6 months. Conclusions and Relevance: For adults with COPD, HF, or ILD who were at high risk of death and had poor quality of life, a nurse and social worker palliative telecare team produced clinically meaningful improvements in quality of life at 6 months compared with usual care. Trial Registration: ClinicalTrials.gov Identifier: NCT02713347.
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Insuficiencia Cardíaca , Enfermedades Pulmonares , Cuidados Paliativos , Grupo de Atención al Paciente , Telemedicina , Adulto , Anciano , Femenino , Humanos , Masculino , Insuficiencia Cardíaca/enfermería , Insuficiencia Cardíaca/terapia , Enfermedades Pulmonares Intersticiales/enfermería , Enfermedades Pulmonares Intersticiales/terapia , Calidad de Vida , Método Simple Ciego , Trabajadores Sociales , Telemedicina/métodos , Rol de la Enfermera , Cuidados Paliativos/métodos , Enfermedad Pulmonar Obstructiva Crónica/enfermería , Enfermedad Pulmonar Obstructiva Crónica/terapia , Grupo de Atención al Paciente/organización & administración , Cuidado Terminal/métodos , Atención Ambulatoria/métodos , Servicios de Salud para Veteranos , Enfermedades Pulmonares/enfermería , Enfermedades Pulmonares/terapia , Enfermeras y EnfermerosRESUMEN
Background: Decision-making about tracheostomy and prolonged mechanical ventilation (PMV) is emotionally complex. Expectations of surrogate decision-makers and physicians rarely align. Little is known about what surrogates need to make goal-concordant decisions. We sought to identify drivers of tracheostomy and PMV decision-making. Methods: Using Grounded Theory, we performed a qualitative study with semi-structured interviews with surrogates of patients receiving mechanical ventilation (MV) being considered for tracheostomy and physicians routinely caring for patients receiving MV. Recruitment was stopped when thematic saturation was reached. Separate codebooks were created for surrogate and physician interviews. Themes and factors affecting decision-making were identified and a theoretical model tracheostomy decision-making was developed. Results: 43 participants (23 surrogates and 20 physicians) completed interviews. A theoretical model of themes and factors driving decision-making emerged for the data. Hope, Lack of Knowledge & Data, and Uncertainty emerged as the three main themes all which were interconnected with one another and, at times, opposed each other. Patient Wishes, Past Activity/Medical History, Short and Long-Term Outcomes, and Meaningful Recovery were key factors upon which surrogates and physicians based decision-making. The themes were the lens through which the factors were viewed and decision-making existed as a balance between surrogate emotions and understanding and physician recommendations. Conclusions: Tracheostomy and prolonged MV decision-making is complex. Hope and Uncertainty were conceptual themes that often battled with one another. Lack of Knowledge & Data plagued both surrogates and physicians. Multiple tangible factors were identified that affected surrogate decision-making and physician recommendations. Implications: Understanding this complex decision-making process has the potential to improve the information provided to surrogates and, potentially, increase the goal concordant care and alignment of surrogate and physician expectations. Highlights: Decision-making for tracheostomy and prolonged mechanical ventilation is a complex interactive process between surrogate decision-makers and providers.Using a Grounded Theory framework, a theoretical model emerged from the data with core themes of Hope, Uncertainty, and Lack of Knowledge & Data that was shared by both providers and surrogates.The core themes were the lenses through which the key decision-making factors of Patient Wishes, Past Activity/Medical History, Short and Long-Term Outcomes, and Meaningful Recovery were viewed.The theoretical model provides a roadmap to design a shared decision-making intervention to improve tracheostomy and prolonged mechanical ventilation decision-making.
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CONTEXT: Use of palliative care interventions in chronic obstructive pulmonary disease (COPD) has increased in recent years and inclusion criteria used to identify patients with COPD appropriate for palliative care vary widely. We evaluated the inclusion criteria to identify ways to improve enrollment opportunities for patients with COPD. OBJECTIVES: To determine inclusion criteria used to select patients with COPD for palliative care trials. METHODS: A systematic review was conducted to determine criteria used to select patients with COPD for palliative care randomized controlled trials. A narrative synthesis was conducted for all trials. RESULTS: Inclusion criteria were highly heterogeneous. Most studies (n = 11, 79%) used a combination of criteria to identify patients with COPD. Commonly used criteria included hospitalization for an acute exacerbation of COPD (n = 8, 57%), home supplemental oxygen use (n = 8, 57%), and spirometry values confirming COPD (n = 6, 43%). Three studies (21.4%) used Modified Medical Research Council score and two studies (21%) used physician prognosis or a performance scale. CONCLUSION: The most common criteria, a hospitalization for acute exacerbation of COPD or supplemental oxygen use at home, both have the benefit of selecting patients who have a higher symptom burden or higher healthcare utilization who might therefore benefit more from palliative care. By describing the landscape and variability of previously used inclusion criteria, this article serves as a resource for clinicians and researchers. Developing a consistent set of inclusion criteria in the future would help generate generalizable results that can be translated into clinical practice to improve the lives of patients with COPD. PROSPERO REGISTRATION NUMBER: CRD42022306752.
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Cuidados Paliativos , Selección de Paciente , Enfermedad Pulmonar Obstructiva Crónica , Ensayos Clínicos Controlados Aleatorios como Asunto , Enfermedad Pulmonar Obstructiva Crónica/terapia , Cuidados Paliativos/métodos , HumanosRESUMEN
BACKGROUND: Providing palliative care to patients with chronic obstructive pulmonary disease (COPD) is a priority. Spirometry demonstrating airflow limitation is a diagnostic test for COPD and a common inclusion criterion for palliative care research. However, requiring spirometry with airflow limitation may exclude appropriate patients unable to complete spirometry, or patients with preserved-ratio impaired spirometry and symptoms or imaging consistent with COPD. MEASURES: To determine differences in quality of life (QOL) and symptoms between patients with COPD identified based on International Classification of Diseases (ICD) codes and spirometry with airflow limitation compared to ICD codes only. INTERVENTION: Patients with COPD enrolled in a palliative care trial were included. Patients were at high risk of hospitalization and death and reported poor QOL. Baseline measures of QOL (Functional Assessment of Cancer Therapy-General (FACT-G), the Clinical COPD Questionnaire, and Quality of Life at the End of Life), and symptoms (Patient Health Questionnaire-8, Generalized Anxiety Disorder-7, fatigue, Insomnia Severity Index) were compared. OUTCOMES: Two hundred eight patients with COPD were predominantly male, White, and average age was 68.4. Between patients with ICD codes and spirometry with airflow limitation compared to patients with ICD codes only, there were no significant differences in FACT-G (59.0 vs. 55.0, P = 0.33), other measures of QOL, or symptoms between groups. CONCLUSION: These results imply that spirometry may not need to be a requirement for inclusion into palliative care research or clinical care for patients with poor quality of life and at high risk for adverse outcomes.
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Enfermedad Pulmonar Obstructiva Crónica , Calidad de Vida , Humanos , Masculino , Anciano , Femenino , Cuidados Paliativos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/terapia , Hospitalización , EspirometríaRESUMEN
BACKGROUND: Dyspnea is a common and debilitating symptom that affects many different patient populations. Dyspnea measures should assess multiple domains. OBJECTIVE: To evaluate the reliability, validity, and responsiveness of an ultra-brief, multi-dimensional dyspnea measure. DESIGN: We adapted the DEG from the PEG, a valid 3-item pain measure, to assess average dyspnea intensity (D), interference with enjoyment of life (E), and dyspnea burden with general activity (G). PARTICIPANTS: We used data from a multi-site randomized clinical trial among outpatients with heart failure. MAIN MEASURES: We evaluated reliability (Cronbach's alpha), concurrent validity with the Memorial-Symptom-Assessment-Scale (MSAS) shortness-of-breath distress-orbothersome item and 7-item Generalized-Anxiety-Disorder (GAD-7) scale, knowngroups validity with New-York-Heart-Association-Functional-Classification (NYHA) 1-2 or 3-4 and presence or absence of comorbid chronic obstructive pulmonary disease (COPD), responsiveness with the MSAS item as an anchor, and calculated a minimal clinically important difference (MCID) using distribution methods. KEY RESULTS: Among 312 participants, the DEG was reliable (Cronbach's alpha 0.92). The mean (standard deviation) DEG score was 5.26 (2.36) (range 0-10) points. DEG scores correlated strongly with the MSAS shortness of breath distress-or-bothersome item (r=0.66) and moderately with GAD-7 categories (ρ=0.36). DEG scores were statistically significantly lower among patients with NYHA 1-2 compared to 3-4 [mean difference (standard error): 1.22 (0.27) points, p<0.01], and those without compared to with comorbid COPD [0.87 (0.27) points, p<0.01]. The DEG was highly sensitive to change, with MCID of 0.59-1.34 points, or 11-25% change. CONCLUSIONS: The novel, ultra-brief DEG measure is reliable, valid, and highly responsive. Future studies should evaluate the DEG's sensitivity to interventions, use anchor-based methods to triangulate MCID estimates, and determine its prognostic usefulness among patients with chronic cardiopulmonary and other diseases.
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Enfermedad Pulmonar Obstructiva Crónica , Calidad de Vida , Disnea/diagnóstico , Disnea/epidemiología , Disnea/etiología , Humanos , Psicometría , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To compare the effect of preoperative intravenous (IV) acetaminophen versus oral (PO) acetaminophen or placebo on postoperative pain scores and the time to discharge in women undergoing oocyte retrieval. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Single academic fertility center. PATIENT(S): Women aged 18-43 years undergoing oocyte retrieval. INTERVENTION(S): Randomization to preoperative 1,000 mg IV acetaminophen and PO placebo (group A), IV placebo and 1,000 mg PO acetaminophen (group B), or IV and PO placebo (group C) MAIN OUTCOME MEASURE(S): Difference in patient-reported postoperative visual analog scale pain scores from baseline and the time to discharge. RESULT(S): Of the 159 women who completed the study, there were no differences in the mean postoperative pain score differences or the time to discharge. Although not statistically significant, the mean postoperative opioid dose requirement in group A was lower than that in groups B and C (0.24 vs. 0.59 vs. 0.58 mg IV morphine equivalents, respectively) due to fewer women in group A requiring rescue pain medication (8% vs. 19% vs. 15%, respectively). Group A also reported less constipation when compared with groups B and C (19% vs. 33% vs. 40%, respectively). The rates of postoperative nausea were similar, and there were no differences in embryology or early pregnancy outcomes between the study groups. CONCLUSION(S): Preoperative IV acetaminophen for women undergoing oocyte retrieval did not reduce postoperative pain scores or shorten the time to discharge when compared with PO acetaminophen or placebo and, thus, cannot currently be recommended routinely in this patient population. CLINICAL TRIAL REGISTRATION NUMBER: NCT03073980.
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Acetaminofén/administración & dosificación , Recuperación del Oocito/métodos , Manejo del Dolor/métodos , Administración Intravenosa , Adolescente , Adulto , Método Doble Ciego , Femenino , Humanos , Massachusetts/epidemiología , Recuperación del Oocito/efectos adversos , Dimensión del Dolor , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/epidemiología , Dolor Postoperatorio/etiología , Periodo Perioperatorio , Placebos , Adulto JovenRESUMEN
The importin α/ß transport machinery mediates the nuclear import of cargo proteins that bear a classical nuclear localization sequence (cNLS). These cargo proteins are linked to the major nuclear protein import factor, importin-ß, by the importin-α adapter, after which cargo/carrier complexes enter the nucleus through nuclear pores. In the nucleus, cargo is released by the action of RanGTP and the nuclear pore protein Nup2, after which the importins are recycled to the cytoplasm for further transport cycles. The nuclear export of importin-α is mediated by Cse1/CAS. Here, we exploit structures of functionally important complexes to identify residues that are critical for these interactions and provide insight into how cycles of protein import and recycling of importin-α occur in vivo using a Saccharomyces cerevisiae model. We examine how these molecular interactions impact protein localization, cargo import, function and complex formation. We show that reversing the charge of key residues in importin-α (Arg44) or Cse1 (Asp220) results in loss of function of the respective proteins and impairs complex formation both in vitro and in vivo. To extend these results, we show that basic residues in the Nup2 N-terminus are required for both Nup2 interaction with importin-α and Nup2 function. These results provide a more comprehensive mechanistic model of how Cse1, RanGTP and Nup2 function in concert to mediate cNLS-cargo release in the nucleus.
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Señales de Localización Nuclear , Proteínas de Saccharomyces cerevisiae , Transporte Activo de Núcleo Celular , Núcleo Celular/metabolismo , Carioferinas/metabolismo , Señales de Localización Nuclear/metabolismo , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Complejo Poro Nuclear/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , alfa Carioferinas/genética , alfa Carioferinas/metabolismoRESUMEN
Background: The optimal timing to introduce palliative care (PC) and end-of-life (EOL) conversations into the lives of people with cystic fibrosis (CF) has not been established. Objective: Compare EOL care practices for people with CF who died without a lung transplant (LT), are living without an LT, and those who received an LT. Design: Retrospective chart review. Setting/Subjects: People with CF who received care from 2012 to 2017 at the University of Texas Southwestern Medical Center. Measurements: Primary outcomes were (1) EOL discussion with a pulmonologist, (2) time of EOL discussion before death or LT, (3) evaluation by PC, and (4) documentation of advanced directive or medical power of attorney. Results: Twenty-three patients died without LT, 40 patients received an LT, and 222 were living without an LT. Among LT recipients, 10% had EOL conversations compared with 74% of deceased patients and 5% of living patients without LT (p = 0.001). Among deceased patients, 39% had EOL conversations more than six months before death, while 5% of transplanted patients had EOL conversation more than six months before LT (p < 0.001). Deceased patients were more likely to have seen PC (57%) than either patients who received LT (2%) or those living without LT (3%, p = 0.0001). Conclusions: Patients who died without LT were more likely to have seen PC and had an EOL conversation than patients who received LT or who are living without LT. Further research should explore the optimal timing to discuss EOL care and the best timing to involve PC.
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Fibrosis Quística , Cuidados Paliativos al Final de la Vida , Trasplante de Pulmón , Cuidado Terminal , Fibrosis Quística/cirugía , Humanos , Estudios RetrospectivosRESUMEN
We describe a case of an adult with dermatomyositis (DM) who presents with a rash, high fevers, tachycardia and hypotension, initially concerning for an infectious aetiology or a DM flare. She was found to have cytomegalovirus viraemia which improved after starting valganciclovir. After extensive workup and lack of improvement with broad-spectrum antimicrobial therapy, intravenous immunoglobulin and steroids, the patient was diagnosed with macrophage activation syndrome after bone marrow biopsy and levels of soluble CD25 (soluble interleukin (IL)-2 receptor) and IL2 were obtained. Unfortunately, despite therapy with dexamethasone, anakinra and etoposide, the patient decompensated and the patient's family opted for comfort care. The patient subsequently expired in the intensive care unit.
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Infecciones por Citomegalovirus/fisiopatología , Dermatomiositis/fisiopatología , Ganciclovir/análogos & derivados , Inmunoglobulinas Intravenosas/uso terapéutico , Síndrome de Activación Macrofágica/diagnóstico , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/tratamiento farmacológico , Dermatomiositis/sangre , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/virología , Resultado Fatal , Femenino , Ganciclovir/uso terapéutico , Humanos , Síndrome de Activación Macrofágica/fisiopatología , Síndrome de Activación Macrofágica/virología , Persona de Mediana Edad , Valganciclovir , ViremiaRESUMEN
OBJECTIVE: One approach to potential misuse of prescription opioids by patients with chronic pain is team-based collaborative primary care, with primary care visits complemented by frequent visits with nurse care managers (NCMs) specializing in addiction care. However, little is known about the communication strategies NCMs employ in these visits. This study aimed to describe strategies NCMs used with patients when discussing aberrancies encountered during opioid monitoring. DESIGN: Observational study of NCM-patient interactions. Patients' primary care providers had been randomized to the treatment arm of a study evaluating an intervention, of which NCM visits were part, to change opioid prescribing patterns. The overall intervention was found to be successful. SETTING: Four primary care settings. PARTICIPANTS: Two NCMs and 41 patients. MAIN OUTCOME MEASURE: Forty one interactions between two NCMs and 41 unique patients were directly observed, and the detailed field notes coded for strategies using conventional content analysis. RESULTS: Five themes describing strategies that NCMs use to navigate aberrant patient behavior emerged: (1) NCM develops therapeutic relationship with patient; (2) NCM encourages adherence to monitoring strategies by contextualizing intensive opioid management for patient; (3) NCM inquires into discrepancies between patient's narrative and objective data to further understand aberrancy; (4) NCM assesses patient's medication use and pain to obtain more information about aberrancy and determine risk for opioid misuse; and (5) NCM educates patient and makes recommendations to guide appropriate medication use. CONCLUSIONS: These findings provide a potential model for the replication of intensive care management strategies utilizing NCMs in primary care.
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Analgésicos Opioides/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Comunicación , Enfermeras Administradoras , Relaciones Enfermero-Paciente , Educación en Enfermería , HumanosRESUMEN
Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK family contains three members, TRKA, TRKB, and TRKC, and these proteins are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively. To activate TRK receptors, neurotrophins bind to the extracellular region stimulating dimerization, phosphorylation, and activation of downstream signaling pathways. Major known downstream pathways include RAS/MAPK/ERK, PLCγ, and PI3K/Akt. While being rare in most cancers, TRK fusions with other proteins have been well-established as oncogenic events in specific malignancies, including glioblastoma, papillary thyroid carcinoma, and secretory breast carcinomas. TRK protein amplification as well as alternative splicing events have also been described as contributors to cancer pathogenesis. For patients harboring alterations in TRK expression or activity, TRK inhibition emerges as an important therapeutic target. To date, multiple trials testing TRK-inhibiting compounds in various cancers are underway. In this review, we will summarize the current therapeutic trials for neoplasms involving NTKR gene alterations, as well as the promises and setbacks that are associated with targeting gene fusions.
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Signal transducer and activator of transcription 3 (STAT3), glioma oncogene homolog 1 (GLI1), and truncated GLI1 (tGLI1) are oncogenic transcription factors playing important roles in breast cancer. tGLI1 is a gain-of-function GLI1 isoform. Whether STAT3 physically and/or functionally interacts with GLI1/tGLI1 has not been explored. To address this knowledge gap, we analyzed 47 node-positive breast cancer specimens using immunohistochemical staining and found that phosphorylated-STAT3 (Y705), GLI1, and tGLI1 are co-overexpressed in the majority of triple-negative breast carcinomas (64%) and HER2-enriched (68%) breast carcinomas, and in lymph node metastases (65%). Using gene set enrichment analysis, we analyzed 710 breast tumors and found that STAT3 activation and GLI1/tGLI1 activation signatures are co-enriched in triple-negative subtypes of breast cancers and HER2-enriched subtypes of breast cancers, but not in luminal subtypes of breast cancers. Patients with high levels of STAT3 and GLI1/tGLI1 co-activation in their breast tumors had worse metastasis-free survival compared to those with low levels. Since these proteins co-overexpress in breast tumors, we examined whether they form complexes and observed that STAT3 interacted with both GLI1 and tGLI1. We further found that the STAT3-GLI1 and STAT3-tGLI1 complexes bind to both consensus GLI1-binding and STAT3-binding sites using chromatin immunoprecipitation (ChIP) assay, and that the co-overexpression markedly activated a promoter controlled by GLI1-binding sites. To identify genes that can be directly co-activated by STAT3 and GLI1/tGLI1, we analyzed three ChIP-seq datasets and identified 34 potential target genes. Following validations using reverse transcription polymerase chain reaction and survival analysis, we identified three genes as novel transcriptional targets of STAT3 and GLI1/tGLI1, R-Ras2, Cep70, and UPF3A. Finally, we observed that co-overexpression of STAT3 with GLI1/tGLI1 promoted the ability of breast cancer cells to form mammospheres and that STAT3 only cooperates with tGLI1 in immortalized mammary epithelial cells. In summary, our study identified novel physical and functional cooperation between two families of oncogenic transcription factors, and the interaction contributes to aggressiveness of breast cancer cells and poor prognosis of triple-negative breast cancers and HER2-enriched breast cancers.
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Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundario , Receptor ErbB-2/metabolismo , Factor de Transcripción STAT3/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Proteína con Dedos de Zinc GLI1/metabolismo , Animales , Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de la Membrana/genética , Ratones , Proteínas Asociadas a Microtúbulos/genética , Proteínas de Unión al GTP Monoméricas/genética , Trasplante de Neoplasias , Fosforilación , Pronóstico , Proteínas de Unión al ARN/genética , Esferoides Celulares/metabolismo , Esferoides Celulares/patología , Análisis de Supervivencia , Neoplasias de la Mama Triple Negativas/genética , Regulación hacia ArribaRESUMEN
Many atypical antipsychotic drugs currently prescribed for the treatment of schizophrenia have limited brain penetration due to the efflux activity of ATP-binding cassette (ABC) transporters at the blood-brain barrier (BBB), including P-glycoprotein (P-gp) and ABCG2. Herein, we describe the design and synthesis of the first class of homodimeric prodrug dual inhibitors of P-gp and ABCG2. These inhibitors are based on the structure of the atypical antipsychotic drug paliperidone (Pal), a transport substrate for both transporters. We synthesized and characterized a small library of homodimeric bivalent Pal inhibitors that contain a variety of tethers joining the two monomers via ester linkages. The majority of our compounds were low micromolar to sub-micromolar inhibitors of both P-gp and ABCG2 in cells overexpressing these transporters and in immortalized human hCMEC/D3 cells that are derived from the BBB. Our most potent dual inhibitor also contained an internal disulfide bond in the tether (Pal-8SS) that allowed for rapid reversion to monomer in the presence of reducing agents or plasma esterases. To increase stability against these esterases, we further engineered Pal-8SS to contain two hindering methyl groups alpha to the carbonyl of the ester moiety within the tether. The resulting dimer, Pal-8SSMe, was also a potent dual inhibitor that remained susceptible to reducing conditions but was more resistant to breakdown in human plasma. Importantly, Pal-8SSMe both accumulated and subsequently reverted to the therapeutic Pal monomer in the reducing environment of BBB cells. Thus, these molecules serve two purposes, acting as both inhibitors of P-gp and ABCG2 at the BBB and as prodrugs, effectively delivering therapies to the brain that would otherwise be precluded.
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Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Antipsicóticos/farmacología , Barrera Hematoencefálica/metabolismo , Proteínas de Neoplasias/metabolismo , Palmitato de Paliperidona/farmacología , Profármacos/farmacología , Transporte Biológico/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Humanos , Células MCF-7RESUMEN
BACKGROUND: Prescription opioid misuse is a significant public health problem as well as a patient safety concern. Primary care providers (PCPs) are the leading prescribers of opioids for chronic pain, yet few PCPs follow standard practice guidelines regarding assessment and monitoring. This cluster randomized controlled trial will determine whether four implementation strategies; nurse care management, use of a patient registry, academic detailing, and electronic tools, will increase PCP adherence to chronic opioid therapy guidelines and reduce opioid misuse among patients, relative to electronic tools alone. The implementation strategies and intervention content are based on the chronic care model. METHODS: We include 53 PCPs from three Boston-area community health centers and one urban safety-net hospital-based primary care practice who have at least four patients meeting the following inclusion criteria: 1) age≥18; 2) one or more completed visits to the primary care practice in the past year; 3) long-term opioid treatment defined as three or more opioid prescriptions written at least 21days apart within 6months and 4) an inpatient or outpatient ICD-9-CM diagnosis for musculoskeletal or neuropathic pain. We consider PCPs to be study subjects, and obtained a waiver of informed consent for patients because the study is promoting an established standard of care. We enrolled participants (PCPs) from December 2012 through March 2015. PCPs were randomized to receive the intervention, which includes four components: 1) nurse care management, 2) use of a patient registry, 3) academic detailing, and 4) electronic tools, or a control condition, which includes only the use of the electronic tools. The intervention PCPs receive the services of a nurse-managed registry for planning individual patient care and conducting population-based care for patients receiving opioids for chronic pain. In academic detailing visits, trained co-investigators provide intervention PCPs with individualized education to change prescribing practice. Electronic tools, located on a web site external to the EMR, www.mytopcare.org, include validated instruments to assess patient status, and management resources to facilitate PCP adherence to suggested monitoring. Electronic tools are available to PCPs in both study arms. The primary outcomes are PCP adherence to chronic opioid therapy guidelines and patient opioid misuse. Secondary outcomes include measures of substance abuse, possible opioid diversion, and level of opioid risk among patients. We will follow PCPs and their estimated 1200 chronic pain patients for 1year after study enrollment. To determine whether the intervention condition achieves greater adherence to guidelines and reduced opioid misuse after 1year compared to the control condition, we will compare the baseline and follow-up measures of the individual patients, stratifying by intervention status and noting differences that are statistically significant at the p=0.05 level. Analyses will be based on intent-to-treat. RESULTS: Randomization resulted in groups with similar baseline characteristics. The ages of PCPs are evenly distributed, with inclusion of both PCPs who have recently completed training and those who have been in practice for more than 20years. Two-thirds of enrolled PCPs are women, and one-third are non-white. DISCUSSION: The study will determine the impact of this multicomponent intervention on improving PCP adherence to guidelines and reducing opioid misuse among patients.
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Protocolos Clínicos , Adhesión a Directriz/normas , Personal de Salud/normas , Trastornos Relacionados con Opioides/prevención & control , Evaluación de Resultado en la Atención de Salud , Mal Uso de Medicamentos de Venta con Receta/prevención & control , Atención Primaria de Salud/normas , Sistema de Registros , Adulto , Boston , HumanosRESUMEN
Understanding behavioral resilience among at-risk adolescents may guide public policy decisions and future programs. We examined factors predicting behavioral resilience following intrauterine substance exposure in a prospective longitudinal birth-cohort study of 136 early adolescents (ages 12.4-15.9 years) at risk for poor behavioral outcomes. We defined behavioral resilience as a composite measure of lack of early substance use initiation (before age 14), lack of risky sexual behavior, or lack of delinquency. Intrauterine substance exposures included in this analysis were cocaine, tobacco, alcohol, and marijuana. We recruited participants from Boston Medical Center as mother-infant dyads between 1990 and 1993. The majority of the sample was African American/Caribbean (88%) and 49% female. In bivariate analyses, none and lower intrauterine cocaine exposure level predicted resilience compared with higher cocaine exposure, but this effect was not found in an adjusted model. Instead, strict caregiver supervision (adjusted odds ratio [AOR] = 6.02, 95% confidence interval (CI) [1.90, 19.00], p = .002), lower violence exposure (AOR = 4.07, 95% CI [1.77, 9.38], p < .001), and absence of intrauterine tobacco exposure (AOR = 3.71, 95% CI [1.28, 10.74], p = .02) predicted behavioral resilience. In conclusion, caregiver supervision in early adolescence, lower violence exposure in childhood, and lack of intrauterine tobacco exposure predicted behavioral resilience among a cohort of early adolescents with significant social and environmental risk. Future interventions should work to enhance parental supervision as a way to mitigate the effects of adversity on high-risk groups of adolescents. (PsycINFO Database Record