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Venoarterial extracorporeal life support (VA-ECLS) is a powerful tool that can provide complete cardiopulmonary support for patients with refractory cardiogenic shock. However, VA-ECLS increases left ventricular (LV) afterload, resulting in greater myocardial oxygen demand, which can impair myocardial recovery and worsen pulmonary edema. These complications can be ameliorated by various LV venting strategies to unload the LV. Evidence suggests that LV venting improves outcomes in VA-ECLS, but there is a paucity of randomized trials to help guide optimal strategy and the timing of venting. In this review, we discuss the available evidence regarding LV venting in VA-ECLS, explain important hemodynamic principles involved, and propose a practical approach to LV venting in VA-ECLS.
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Oxigenación por Membrana Extracorpórea , Insuficiencia Cardíaca , Oxigenación por Membrana Extracorpórea/métodos , Insuficiencia Cardíaca/terapia , Ventrículos Cardíacos , Hemodinámica , Humanos , Choque Cardiogénico/terapiaRESUMEN
Rationale: Respiratory support (noninvasive ventilation or high-flow nasal cannula) applied at the time of extubation has been reported to reduce reintubation rates, but concerns regarding effectiveness have limited uptake into practice.Objectives: To determine if providing postextubation respiratory support to all patients undergoing extubation in a medical ICU would decrease the incidence of reintubation.Methods: We conducted a pragmatic, two-armed, cluster-crossover trial of adults undergoing extubation from invasive mechanical ventilation between October 1, 2017, and March 31, 2019, in the medical ICU of an academic medical center. Patients were assigned to either protocolized postextubation respiratory support (a respiratory therapist-driven protocol in which patients with suspected hypercapnia received noninvasive ventilation and patients without suspected hypercapnia received high-flow nasal cannula) or usual care (postextubation management at the discretion of treating clinicians). The primary outcome was reintubation within 96 hours of extubation.Measurements and Main Results: A total of 751 patients were enrolled. Of the 359 patients assigned to protocolized support, 331 (92.2%) received postextubation respiratory support compared with 66 of 392 patients (16.8%) assigned to usual care, a difference driven by differential use of high-flow nasal cannula (74.7% vs. 2.8%). A total of 57 patients (15.9%) in the protocolized support group experienced reintubation compared with 52 patients (13.3%) in the usual care group (odds ratio, 1.23; 95% confidence interval, 0.82 to 1.84; P = 0.32).Conclusions: Among a broad population of critically ill adults undergoing extubation from invasive mechanical ventilation at an academic medical center, protocolized postextubation respiratory support, primarily characterized by an increase in the use of high-flow nasal cannula, did not prevent reintubation compared with usual care.Clinical trial registered with www.clinicaltrials.gov (NCT0328831).
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Extubación Traqueal/métodos , Cánula , Hipercapnia/terapia , Hipoxia/terapia , Intubación Intratraqueal/estadística & datos numéricos , Ventilación no Invasiva/métodos , Terapia por Inhalación de Oxígeno/métodos , Insuficiencia Respiratoria/terapia , Adulto , Anciano , Protocolos Clínicos , Trastornos de la Conciencia/terapia , Estudios Cruzados , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Atención Perioperativa , Resultado del TratamientoRESUMEN
Identifying reforms that minimize US healthcare costs is imperative. This commentary explores one intervention with potential cost-saving implications that has received comparably minimal consideration: spiritual care provision. It highlights the staff and patient costing benefits of spiritual care in addressing spiritual distress and urges practical policy and research initiatives to maximize its impact.
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Espiritualidad , HumanosRESUMEN
Raf1/c-Raf is a well-characterized serine/threonine-protein kinase that links Ras family members with the MAPK/ERK signaling cascade. We have identified a novel splice isoform of human Raf1 that causes protein truncation and loss of the C-terminal kinase domain (Raf1-tr). We found that Raf1-tr has increased nuclear localization compared with full-length Raf1, and this finding was secondary to reduced binding of Raf1-tr to the cytoplasmic chaperone FK506 binding protein 5. We show that Raf1-tr has increased binding to DNA-dependent protein kinase (DNA-PK), which inhibits DNA-PK function and causes amplification of irradiation- and bleomycin-induced DNA damage. We found that the human colorectal cancer cell line, HCT-116, displayed reduced expression of Raf1-tr, and reintroduction of Raf1-tr sensitized the cells to bleomycin-induced apoptosis. Furthermore, we identified differential Raf1-tr expression in breast cancer cell lines and showed that breast cancer cells with increased Raf1-tr expression become sensitized to bleomycin-induced apoptosis. Collectively, these results demonstrate a novel Raf1 isoform in humans that has a unique noncanonical role in regulating the double-stranded DNA damage response pathway through modulation of DNA-PK function.-Nixon, B. R., Sebag, S. C., Glennon, M. S., Hall, E. J., Kounlavong, E. S., Freeman, M. L., Becker, J. R. Nuclear localized Raf1 isoform alters DNA-dependent protein kinase activity and the DNA damage response.
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Núcleo Celular/metabolismo , Daño del ADN , Proteína Quinasa Activada por ADN/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-raf/metabolismo , Empalme Alternativo , Antibióticos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Bleomicina/farmacología , Línea Celular Tumoral , ADN/efectos de los fármacos , ADN/efectos de la radiación , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células HEK293 , Humanos , Unión Proteica , Transducción de Señal , Proteínas de Unión a Tacrolimus/metabolismo , Proteínas ras/metabolismoRESUMEN
We present efficient finite difference estimators for goal-oriented sensitivity indices with applications to the generalized Langevin equation (GLE). In particular, we apply these estimators to analyze an extended variable formulation of the GLE where other well known sensitivity analysis techniques such as the likelihood ratio method are not applicable to key parameters of interest. These easily implemented estimators are formed by coupling the nominal and perturbed dynamics appearing in the finite difference through a common driving noise or common random path. After developing a general framework for variance reduction via coupling, we demonstrate the optimality of the common random path coupling in the sense that it produces a minimal variance surrogate for the difference estimator relative to sampling dynamics driven by independent paths. In order to build intuition for the common random path coupling, we evaluate the efficiency of the proposed estimators for a comprehensive set of examples of interest in particle dynamics. These reduced variance difference estimators are also a useful tool for performing global sensitivity analysis and for investigating non-local perturbations of parameters, such as increasing the number of Prony modes active in an extended variable GLE.
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Health effects of space radiation are a serious concern for astronauts on long-duration missions. The lens of the eye is one of the most radiosensitive tissues in the body and, therefore, ocular health risks for astronauts is a significant concern. Studies in humans and animals indicate that ionizing radiation exposure to the eye produces characteristic lens changes, termed "radiation cataract," that can affect visual function. Animal models of radiation cataractogenesis have previously utilized inbred mouse or rat strains. These studies were essential for determining morphological changes and dose-response relationships between radiation exposure and cataract. However, the relevance of these studies to human radiosensitivity is limited by the narrow phenotypic range of genetically homogeneous animal models. To model radiation cataract in genetically diverse populations, longitudinal cataract phenotyping was nested within a lifetime carcinogenesis study in male and female heterogeneous stock (HS/Npt) mice exposed to 0.4 Gy HZE ions (n = 609) or 3.0 Gy γ-rays (n = 602) and in unirradiated controls (n = 603). Cataractous change was quantified in each eye for up to 2 years using Merriam-Focht grading criteria by dilated slit lamp examination. Virtual Optomotry™ measurement of visual acuity and contrast sensitivity was utilized to assess visual function in a subgroup of mice. Prevalence and severity of posterior lens opacifications were 2.6-fold higher in HZE ion and 2.3-fold higher in γ-ray irradiated mice compared to unirradiated controls. Male mice were at greater risk for spontaneous and radiation associated cataracts. Risk for cataractogenesis was associated with family structure, demonstrating that HS/Npt mice are well-suited to evaluate genetic determinants of ocular radiosensitivity. Last, mice were extensively evaluated for cataract and tumor formation, which revealed an overlap between individual susceptibility to both cancer and cataract.
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Catarata , Cristalino , Traumatismos por Radiación , Ratones , Ratas , Masculino , Femenino , Humanos , Animales , Catarata/etiología , Catarata/epidemiología , Catarata/patología , Traumatismos por Radiación/epidemiología , Cristalino/patología , Cristalino/efectos de la radiación , Rayos gamma/efectos adversos , Iones , Relación Dosis-Respuesta en la RadiaciónRESUMEN
Over the twentieth century the discipline of radiation oncology has developed from an experimental application of X-rays to a highly sophisticated treatment of cancer. Experts from many disciplines - chiefly clinicians, physicists and biologists - have contributed to these advances. Whereas the emphasis in the past was on refining techniques to ensure the accurate delivery of radiation, the future of radiation oncology lies in exploiting the genetics or the microenvironment of the tumour to turn cancer from an acute disease to a chronic disease that can be treated effectively with radiation.
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Neoplasias/radioterapia , Oncología por Radiación/historia , Fraccionamiento de la Dosis de Radiación , Física Sanitaria/historia , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Oncología por Radiación/tendencias , Radiobiología/historiaRESUMEN
The value of screening for cognitive impairment, including dementia and Alzheimer's disease, has been debated for decades. Recent research on causes of and treatments for cognitive impairment has converged to challenge previous thinking about screening for cognitive impairment. Consequently, changes have occurred in health care policies and priorities, including the establishment of the annual wellness visit, which requires detection of any cognitive impairment for Medicare enrollees. In response to these changes, the Alzheimer's Foundation of America and the Alzheimer's Drug Discovery Foundation convened a workgroup to review evidence for screening implementation and to evaluate the implications of routine dementia detection for health care redesign. The primary domains reviewed were consideration of the benefits, harms, and impact of cognitive screening on health care quality. In conference, the workgroup developed 10 recommendations for realizing the national policy goals of early detection as the first step in improving clinical care and ensuring proactive, patient-centered management of dementia.
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Trastornos del Conocimiento/diagnóstico , Demencia/diagnóstico , Diagnóstico Precoz , Tamizaje Masivo/métodos , Humanos , Tamizaje Masivo/economía , Tamizaje Masivo/normas , Medicare , Calidad de la Atención de Salud/economía , Calidad de la Atención de Salud/normas , Estados UnidosRESUMEN
This clinical image vignette describes the inadvertent placement of a balloon pump in the vena cava during a "code blue" scenario, and the lessons to be learned from that experience. The hemodynamic benefits of intra-aortic balloon pump during experimental cardiac arrest include shorter circulation time and increases in end-tidal CO2 and coronary perfusion pressure. However, the hemodynamic effects of venous diastolic augmentation during experimental cardiogenic shock vary, being detrimental in cases of low preload, and possibly beneficial in a high preload state. When performed emergently at the bedside, inadvertent intra-caval placement of a balloon pump can occur due to elevated venous pressures, in the presence of severe tricuspid regurgitation, or through an arteriovenous fistula. A similar radiographic appearance can also be seen in the presence of a right-sided aortic arch. Clues to improper position include an abnormal pressure waveform and the absence of hemodynamic changes or blood pressure augmentation.
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Corazón Auxiliar , Insuficiencia de la Válvula Tricúspide , Humanos , Hemodinámica , Choque Cardiogénico/diagnóstico , Choque Cardiogénico/terapia , Contrapulsador Intraaórtico/efectos adversos , Contrapulsador Intraaórtico/métodosRESUMEN
BACKGROUND: The COVID-19 pandemic has evolved through multiple phases characterized by new viral variants, vaccine development, and changes in therapies. It is unknown whether rates of cardiovascular disease (CVD) risk factor profiles and complications have changed over time. METHODS: We analyzed the American Heart Association COVID-19 CVD registry, a national multicenter registry of hospitalized adults with active COVID-19 infection. The time period from April 2020 to December 2021 was divided into 3-month epochs, with March 2020 analyzed separately as a potential outlier. Participating centers varied over the study period. Trends in all-cause in-hospital mortality, CVD risk factors, and in-hospital CVD outcomes, including a composite primary outcome of cardiovascular death, cardiogenic shock, new heart failure, stroke, and myocardial infarction, were evaluated across time epochs. Risk-adjusted analyses were performed using generalized linear mixed-effects models. RESULTS: A total of 46 007 patient admissions from 134 hospitals were included (mean patient age 61.8 years, 53% male, 22% Black race). Patients admitted later in the pandemic were younger, more likely obese, and less likely to have existing CVD (Ptrend ≤0.001 for each). The incidence of the primary outcome increased from 7.0% in March 2020 to 9.8% in October to December 2021 (risk-adjusted Ptrend=0.006). This was driven by an increase in the diagnosis of myocardial infarction and stroke (Ptrend<0.0001 for each). The overall rate of in-hospital mortality was 14.2%, which declined over time (20.8% in March 2020 versus 10.8% in the last epoch; adjusted Ptrend<0.0001). When the analysis was restricted to July 2020 to December 2021, no temporal change in all-cause mortality was seen (adjusted Ptrend=0.63). CONCLUSIONS: Despite a shifting risk factor profile toward a younger population with lower rates of established CVD, the incidence of diagnosed cardiovascular complications of COVID increased from the onset of the pandemic through December 2021. All-cause mortality decreased during the initial months of the pandemic and thereafter remained consistently high through December 2021.
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COVID-19 , Enfermedades Cardiovasculares , Infarto del Miocardio , Accidente Cerebrovascular , Adulto , Estados Unidos/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Femenino , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/terapia , Factores de Riesgo , Pandemias , American Heart Association , COVID-19/diagnóstico , COVID-19/terapia , COVID-19/epidemiología , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/epidemiología , Infarto del Miocardio/terapia , Sistema de Registros , Mortalidad Hospitalaria , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/terapia , Factores de Riesgo de Enfermedad CardiacaRESUMEN
AIMS: The cardiac natriuretic peptides [atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP)] are important regulators of cardiovascular physiology, with reduced natriuretic peptide (NP) activity linked to multiple human cardiovascular diseases. We hypothesized that deficiency of either ANP or BNP would lead to similar changes in left ventricular structure and function given their shared receptor affinities. METHODS AND RESULTS: We directly compared murine models deficient of ANP or BNP in the same genetic backgrounds (C57BL6/J) and environments. We evaluated control, ANP-deficient (Nppa-/-) or BNP-deficient (Nppb-/-) mice under unstressed conditions and multiple forms of pathological myocardial stress. Survival, myocardial structure, function and electrophysiology, tissue histology, and biochemical analyses were evaluated in the groups. In vitro validation of our findings was performed using human-derived induced pluripotent stem cell cardiomyocytes (iPS-CMs). In the unstressed state, both ANP- and BNP-deficient mice displayed mild ventricular hypertrophy which did not increase up to 1 year of life. NP-deficient mice exposed to acute myocardial stress secondary to thoracic aortic constriction (TAC) had similar pathological myocardial remodelling but a significant increase in sudden death. We discovered that the NP-deficient mice are more susceptible to stress-induced ventricular arrhythmias using both in vivo and ex vivo models. Mechanistically, deficiency of either ANP or BNP led to reduced myocardial cGMP levels and reduced phosphorylation of the cAMP response element-binding protein (CREBS133) transcriptional regulator. Selective CREB inhibition sensitized wild-type hearts to stress-induced ventricular arrhythmias. ANP and BNP regulate cardiomyocyte CREBS133 phosphorylation through a cGMP-dependent protein kinase 1 (PKG1) and p38 mitogen-activated protein kinase (p38 MAPK) signalling cascade. CONCLUSIONS: Our data show that ANP and BNP act in a non-redundant fashion to maintain myocardial cGMP levels to regulate cardiomyocyte p38 MAPK and CREB activity. Cardiac natriuretic peptide deficiency leads to a reduction in CREB signalling which sensitizes the heart to stress-induced ventricular arrhythmias.
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Arritmias Cardíacas , Factor Natriurético Atrial , Péptido Natriurético Encefálico , Animales , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , GMP Cíclico , Ratones , Miocitos Cardíacos/metabolismo , Péptido Natriurético Encefálico/genética , Péptido Natriurético Encefálico/metabolismo , Péptidos Natriuréticos/metabolismo , Vasodilatadores , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
This special report aims to inform the medical community about the many challenges involved in managing radiation exposure in a way that maximizes the benefit-risk ratio. The report discusses the state of current knowledge and key questions in regard to sources of medical imaging radiation exposure, radiation risk estimation, dose reduction strategies, and regulatory options.
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Diagnóstico por Imagen/efectos adversos , Traumatismos por Radiación/prevención & control , Fluoroscopía/efectos adversos , Humanos , Neoplasias Inducidas por Radiación/prevención & control , Dosis de Radiación , Protección Radiológica , Radiografía Intervencional/efectos adversos , Medición de Riesgo , Factores de Riesgo , Factores SexualesRESUMEN
Background. While uncommon, heart failure (HF) can present in young adults from a variety of causes. Identifying HF in a young patient presents many challenges, the foremost of which is recognition of the signs and symptoms of HF. Case Summary. We present four cases of new diagnosis of HF (due to familial cardiomyopathy, tachycardia-induced cardiomyopathy, spontaneous coronary artery dissection, and peripartum cardiomyopathy) to highlight the range of etiologies and presentations requiring recognition in this patient population. Discussion. A high index of suspicion is needed to diagnose HF in young adults, who may not present with classic signs and symptoms. Young adults represent a unique patient population that differs from the older patients with HF. Young adults with newly diagnosed HF should be promptly referred to a center offering full diagnostic capabilities and advanced cardiac therapies.
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PURPOSE: Treatment of fast-growing, human papillomavirus-negative, head and neck cancers (HNCs) remains challenging from the perspectives of both tumor control and late sequelae. In this study, we use systematic radiobiological optimization to identify fractionation schemes that markedly improve the radiotherapeutic effectiveness balance between tumor control probability (TCP) and late normal tissue complication probability (LNTCP), as compared with standard fractionation. METHODS AND MATERIALS: We track the development after each treatment fraction of both tumor control and late sequelae. Toward the end of the treatment, accelerated repopulation of fast-growing HNC tumors means that further fractions minimally improve TCP but result in major LNTCP increases, providing the potential for optimization of the TCP-LNTCP balance. We used a recent improved model of accelerated repopulation, calibrated with extensive HNC clinical trials data, to identify optimally effective treatment regimens that both increase TCP and significantly decrease LNTCP. For comparison, we also used standard repopulation models. RESULTS: An optimized hypofractionated schedule of 18 × 3.0 Gy is predicted to substantially increase TCP, particularly for late-stage HNC tumors (eg, â¼35% to 49% for late-stage tumors) while decreasing high-grade LNTCP (eg, â¼13% to <2%), as compared with a standard 35 × 2.0 Gy protocol. In addition, the treatment time is reduced from 47 to 24 days. Twice-daily treatments of 1.8 Gy per fraction provide still better outcomes. The hypofractionation predictions are robust, being almost independent of the details of the repopulation model. CONCLUSIONS: Hypofractionation or its close variant, accelerated hyperfractionation, efficiently overcomes tumor repopulation in fast-growing tumors and can be optimized toward the end of treatment when repopulation causes the TCP to increase only very slowly while LNTCP increases rapidly. Radiobiological modeling suggests that optimized 3.0 Gy per fraction hypofractionation (or 1.8 Gy per fraction, 2 fractions per weekday, accelerated hyperfractionation) is considerably more effective for HNC tumor control and for reduction of late effects than standard 2.0-Gy fractionation.
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Proliferación Celular/efectos de la radiación , Neoplasias de Cabeza y Cuello/radioterapia , Órganos en Riesgo/efectos de la radiación , Hipofraccionamiento de la Dosis de Radiación/normas , Traumatismos por Radiación/prevención & control , Proliferación Celular/fisiología , Protocolos Clínicos , Neoplasias de Cabeza y Cuello/patología , Humanos , Modelos Biológicos , Método de Montecarlo , Estadificación de Neoplasias , Probabilidad , Mejoramiento de la Calidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
INTRODUCTION: Following extubation from invasive mechanical ventilation, nearly one in seven critically ill adults requires reintubation. Reintubation is independently associated with increased mortality. Postextubation respiratory support (non-invasive ventilation or high-flow nasal cannula applied at the time of extubation) has been reported in small-to-moderate-sized trials to reduce reintubation rates among hypercapnic patients, high-risk patients without hypercapnia and low-risk patients without hypercapnia. It is unknown whether protocolised provision of postextubation respiratory support to every patient undergoing extubation would reduce the overall reintubation rate, compared with usual care. METHODS AND ANALYSIS: The Protocolized Post-Extubation Respiratory Support (PROPER) trial is a pragmatic, cluster cross-over trial being conducted between 1 October 2017 and 31 March 2019 in the medical intensive care unit of Vanderbilt University Medical Center. PROPER compares usual care versus protocolized post-extubation respiratory support (a respiratory therapist-driven protocol that advises the provision of non-invasive ventilation or high-flow nasal cannula based on patient characteristics). For the duration of the trial, the unit is divided into two clusters. One cluster receives protocolised support and the other receives usual care. Each cluster crosses over between treatment group assignments every 3 months. All adults undergoing extubation from invasive mechanical ventilation are enrolled except those who received less than 12 hours of mechanical ventilation, have 'Do Not Intubate' orders, or have been previously reintubated during the hospitalisation. The anticipated enrolment is approximately 630 patients. The primary outcome is reintubation within 96 hours of extubation. ETHICS AND DISSEMINATION: The trial was approved by the Vanderbilt Institutional Review Board. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences. TRIAL REGISTRATION NUMBER: NCT03288311.
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Extubación Traqueal , Intubación Intratraqueal , Respiración Artificial/normas , Estudios Cruzados , Interpretación Estadística de Datos , Humanos , Intubación Intratraqueal/estadística & datos numéricos , Ensayos Clínicos Pragmáticos como Asunto/métodos , Retratamiento/estadística & datos numéricosRESUMEN
Hospital-based proton facilities may represent a major advance in radiation therapy, in part because of excellent dose distributions around the tumor, and in part because of the potentially lower whole-body dose compared with photon radiotherapy. Most current proton beams are spread out to cover the tumor using beam scattering and collimation techniques (passive scattering); this will necessarily result in an extra whole-body neutron dose, due to interactions of the protons with the scattering and collimating beam elements. However, the clinical significance of this whole-body low-dose neutron exposure has remained controversial. The number of proton facilities worldwide is increasing rapidly, and most of these facilities are/will be based on passive scattering. Thus it is important to assess and, ideally, minimize, the potential for second cancer induction by secondary neutrons. We discuss here the neutron doses involved, and the associated potential second cancer risks, with an emphasis on the uncertainties involved.
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Neoplasias Inducidas por Radiación/etiología , Neoplasias Inducidas por Radiación/prevención & control , Neoplasias/radioterapia , Neutrones/efectos adversos , Terapia de Protones , Oncología por Radiación/métodos , Relación Dosis-Respuesta en la Radiación , Humanos , Radioterapia de Alta Energía , Dispersión de RadiaciónRESUMEN
BACKGROUND AND PURPOSE: Accelerated repopulation (AR) can compromise tumor control after conventional radiotherapy for fast-growing tumors. Standard AR models assume it begins at a fixed time, with repopulation rates independent of the number of clonogens killed. We investigate the validity and significance of an alternative model where onset-time and rate of AR depend on the number of clonogens killed, and thus on dose and dose-fractionation. MATERIALS AND METHODS: We analyzed tumor control (TCP) from randomized trials for head and neck cancer (HNC, 7283 patients), featuring wide ranges of doses, times, and fractionation-schemes. We used the linear-quadratic model with the standard dose-independent AR model, or with an alternative dose-dependent model, where AR onset and rate depend on clonogen killing. RESULTS: The alternative dose-dependent model of AR provides significantly-improved descriptions of a wide range of randomized clinical data, relative to the standard dose-independent model. This preferred model predicts that, for currently-used HNC fractionation schemes, the last 5 fractions do not increase TCP, but simply compensate for increased accelerated repopulation. CONCLUSIONS: The preferred dose-dependent AR model predicts that, for standard fractionation schemes currently used to treat HNC, the final week (5 fractions) could be eliminated without compromising TCP, but resulting in significantly decreased late sequelae due to the lower overall dose.
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Neoplasias de Cabeza y Cuello/radioterapia , Modelos Biológicos , Fraccionamiento de la Dosis de Radiación , Relación Dosis-Respuesta en la Radiación , Neoplasias de Cabeza y Cuello/patología , Humanos , Funciones de Verosimilitud , Modelos Lineales , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Transplant-free survival for single right ventricle (RV) lesions remains less than 70% at 3 years. Arrhythmia burden, influence of shunt type at Norwood procedure (RV-to-pulmonary artery shunt [RVPAS] versus Blalock-Taussig shunt [BTS]), and implications for mortality risk are not well defined. METHODS: The authors performed a single-center retrospective analysis of patients with single RV lesions enrolled in a prospective study of arrhythmias after congenital heart surgery. RESULTS: Fifty-eight patients received a RVPAS and 62 received a BTS, with a median follow-up of 773 days. Overall arrhythmia incidence was 78%, two-thirds of which prompted intervention. Among all types of arrhythmias, only ventricular arrhythmias (VAs) differed by shunt type, which were more common in patients receiving an RVPAS (29% RVPAS versus 14% BTS; p = 0.049). The majority of VAs were transient (69% less than 1 minute), and typically occurred early post-Norwood procedure (median 12 days). No additional variables were associated with development of VAs. Shunt type did not influence transplant-free survival. Within the entire cohort, there was a trend toward increased mortality with prior history of VA (odds ratio, 2.90; 95% confidence interval, 0.99 to 8.90; p = 0.052). For interstage survivors to Glenn palliation, any VA associated with a 14-fold increased risk of death or transplant (hazard ratio, 14.00; 95% confidence interval, 3.66 to 53.40; p < .001). No other tachyarrhythmia or bradyarrhythmia was associated with mortality. CONCLUSIONS: In this cohort with single RV lesions and prospective rhythm surveillance, patients receiving an RVPAS at Norwood surgery had an increased incidence of VAs compared with patients with a BTS. VAs correlated with late mortality in patients who survived the interstage period.
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Arritmias Cardíacas/etiología , Ventrículos Cardíacos/cirugía , Síndrome del Corazón Izquierdo Hipoplásico/cirugía , Procedimientos de Norwood/efectos adversos , Complicaciones Posoperatorias , Arteria Pulmonar/cirugía , Femenino , Ventrículos Cardíacos/anomalías , Humanos , Recién Nacido , Masculino , Estudios Prospectivos , Arteria Pulmonar/anomalías , Resultado del TratamientoAsunto(s)
Medicina Basada en la Evidencia , Neoplasias Inducidas por Radiación/epidemiología , Neoplasias Inducidas por Radiación/prevención & control , Dosis de Radiación , Protección Radiológica/métodos , Protección Radiológica/estadística & datos numéricos , Tomografía Computarizada por Rayos X/estadística & datos numéricos , Humanos , Incidencia , Medición de RiesgoRESUMEN
Rad9 and Atm regulate multiple cellular responses to DNA damage, including cell cycle checkpoints, DNA repair and apoptosis. However, the impact of dual heterozygosity for Atm and Rad9 is unknown. Using 50 cGy of X rays as an environmental insult and cataractogenesis as an end point, this study examined the effect of heterozygosity for one or both genes in mice. Posterior subcapsular cataracts, characteristic of radiation exposure, developed earlier in X-irradiated double heterozygotes than in single heterozygotes, which were more prone to cataractogenesis than wild-type controls. Cataract onset time and progression in single or double heterozygotes were accelerated even in unirradiated eyes. These findings indicate that the cataractogenic effect of combined heterozygosity is greater than for each gene alone and are the first to demonstrate the impact of multiple haploinsufficiency on radiation effects in an intact mammal. These observations may help explain observed interindividual differential radiosensitivity in human populations and have important implications for those undergoing radiotherapy or exposed to elevated levels of cosmic radiation, such as the astronaut corps. These findings demonstrate that Mrad9 and Atm are important determinants of lens opacification and, given the roles of Atm and Rad9 in maintaining genomic stability, are consistent with a genotoxic basis for radiation cataractogenesis.