RESUMEN
The α-synuclein protein can adopt several different conformations that cause neurodegeneration. Different α-synuclein conformers cause at least three distinct α-synucleinopathies: multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and Parkinson's disease (PD). In earlier studies, we transmitted MSA to transgenic (Tg) mice and cultured HEK cells both expressing mutant α-synuclein (A53T) but not to cells expressing α-synuclein (E46K). Now, we report that DLB is caused by a strain of α-synuclein prions that is distinct from MSA. Using cultured HEK cells expressing mutant α-synuclein (E46K), we found that DLB prions could be transmitted to these HEK cells. Our results argue that a third strain of α-synuclein prions likely causes PD, but further studies are needed to identify cells and/or Tg mice that express a mutant α-synuclein protein that is permissive for PD prion replication. Our findings suggest that other α-synuclein mutants should give further insights into α-synuclein prion replication, strain formation, and disease pathogenesis, all of which are likely required to discover effective drugs for the treatment of PD as well as the other α-synucleinopathies.
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Demencia/metabolismo , Enfermedad por Cuerpos de Lewy/metabolismo , Atrofia de Múltiples Sistemas/metabolismo , Priones/metabolismo , alfa-Sinucleína/metabolismo , Anciano , Línea Celular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Sinucleinopatías/metabolismoRESUMEN
PURPOSE: Clinical management of disc degeneration in patients with chronic low back pain (cLBP) is hampered by the challenge of distinguishing pathologic changes relating to pain from physiologic changes related to aging. The goal of this study was to use imaging biomarkers of disc biochemical composition to distinguish degenerative changes associated with cLBP from normal aging. METHODS: T1ρ MRI data were acquired from 133 prospectively enrolled subjects for this observational study (80 cLBP, 53 controls; mean ± SD age = 43.9 ± 13.4 years; 61 females, 72 males). The mean T1ρ relaxation time in the nucleus pulposus (NP-T1ρ; n = 650 discs) was used as a quantitative biomarker of disc biochemical composition. Linear regression was used to assess associations between NP-T1ρ and age, sex, spinal level, and study group, and their interactions. RESULTS: NP-T1ρ values were lower in cLBP patients than controls (70.8 ± 22.8 vs. 76.4 ± 22.2 ms, p = 0.009). Group differences were largest at L5-S1 (ΔT1ρcLBP-control = -11.3 ms, p < 0.0001), representing biochemical deterioration typically observed over a 9-12 year period (NP-T1ρ declined by 0.8-1.1 ms per year [95% CI]). Group differences were large in younger patients and diminished with age. Finally, the age-dependence of disc degeneration was stronger in controls than cLBP patients. CONCLUSION: Aging effects on the biochemical composition of the L5-S1 disc may involve a relatively uniform set of factors from which many cLBP patients deviate. NP-T1ρ values at L5-S1 may be highly relevant to clinical phenotyping, particularly in younger individuals.
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Degeneración del Disco Intervertebral , Disco Intervertebral , Dolor de la Región Lumbar , Masculino , Femenino , Humanos , Adulto , Persona de Mediana Edad , Degeneración del Disco Intervertebral/diagnóstico por imagen , Degeneración del Disco Intervertebral/patología , Dolor de la Región Lumbar/patología , Disco Intervertebral/diagnóstico por imagen , Disco Intervertebral/patología , Imagen por Resonancia Magnética/métodos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/patología , BioingenieríaRESUMEN
BACKGROUND: Abnormal uterine bleeding (AUB) is a common but understudied gynaecological problem, and data are lacking on emergency department (ED) visits and associated ED-to-inpatient admissions for AUB. This project aims to further understanding of the burden of AUB on patients and the healthcare system by establishing the number and characteristics of women with AUB in the ED and evaluating predictors of AUB-related inpatient hospitalisation in the USA. METHODS: This is a cross-sectional study of women presenting to the ED with non-malignant AUB in the 2016 US Nationwide Emergency Department Sample (NEDS). Clinical, demographic and hospital system factors were evaluated. χ2 and Mann-Whitney tests were used to compare the proportion of visits with each characteristic, resulting in inpatient admission versus discharge from the ED. Multivariable logistic regression models were used to analyse predictors of AUB in the ED and of AUB-related hospitalisations. RESULTS: There were 1.03 million AUB-related visits in the 2016 NEDS, of which 11.2% resulted in inpatient admission. Clinical as well as demographic and hospital system factors influenced ED disposition. Women with AUB tended to be of reproductive age, be underinsured, live in lower income and urban areas, and present to urban and public hospitals. However, older age, higher income, better insurance, presentation to private hospitals and rural residence predicted inpatient admission. CONCLUSIONS: Our study highlights the ED as an essential place of care for women with AUB while also demonstrating the importance of access to outpatient gynaecology services as some AUB-related ED visits may be preventable with outpatient care. The significant demographic and hospital system differences, as well as expected clinical differences, between women with AUB admitted to inpatient and women discharged from the ED imply structural biases impacting AUB-related ED care and add to the deepening understanding of health disparities.
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Hospitalización , Pacientes Internos , Humanos , Femenino , Estados Unidos/epidemiología , Estudios Transversales , Servicio de Urgencia en Hospital , Hemorragia Uterina/epidemiología , Hemorragia Uterina/terapiaRESUMEN
BACKGROUND & AIMS: Early liver transplantation (LT) for alcoholic hepatitis (AH) is lifesaving but concerns regarding return to harmful alcohol use remain. We sought to identify distinct patterns of alcohol use post-LT to inform pre-LT candidate selection and post-LT addiction care. METHODS: Detailed post-LT alcohol use data was gathered retrospectively from consecutive patients with severe AH at 11 ACCELERATE-AH sites from 2006-2018. Latent class analysis identified longitudinal patterns of alcohol use post-LT. Logistic and Cox regression evaluated associations between patterns of alcohol use with pre-LT variables and post-LT survival. A microsimulation model estimated the effect of selection criteria on overall outcomes. RESULTS: Of 153 LT recipients, 1-, 3-, and 5-year survival were 95%, 88% and 82%. Of 146 LT recipients surviving to home discharge, 4 distinct longitudinal patterns of post-LT alcohol use were identified: Pattern 1 [abstinent](n = 103; 71%), pattern 2 [late/non-heavy](n = 9; 6.2%), pattern 3 [early/non-heavy](n = 22; 15%), pattern 4 [early/heavy](n = 12; 8.2%). One-year survival was similar among the 4 patterns (100%), but patients with early post-LT alcohol use had lower 5-year survival (62% and 53%) compared to abstinent and late/non-heavy patterns (95% and 100%). Early alcohol use patterns were associated with younger age, multiple prior rehabilitation attempts, and overt encephalopathy. In simulation models, the pattern of post-LT alcohol use changed the average life-expectancy after early LT for AH. CONCLUSIONS: A significant majority of LT recipients for AH maintain longer-term abstinence, but there are distinct patterns of alcohol use associated with higher risk of 3- and 5-year mortality. Pre-LT characteristics are associated with post-LT alcohol use patterns and may inform candidate selection and post-LT addiction care.
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Hepatitis Alcohólica , Trasplante de Hígado , Abstinencia de Alcohol , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Hepatitis Alcohólica/cirugía , Humanos , Trasplante de Hígado/efectos adversos , Recurrencia , Estudios RetrospectivosRESUMEN
BACKGROUND: Risk of ovarian cancer in women with frequent perineal talcum powder product is not well understood. Prior systematic reviews focused on ever use. The purpose of this study is to estimate the association between frequent (at least 2 times per week) perineal talcum powder use and ovarian cancer. METHODS: A systematic review and meta-analysis was conducted according to meta-analysis of observational studies in epidemiology guidelines. Study protocol was prospectively registered at PROSPERO (registration number CRD42020172720). Searches were performed in PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials databases from their inception to August 2, 2021. Case-control and cohort studies were included if they reported frequent perineal talcum powder use and an adjusted odds ratio or hazard ratio for ovarian cancer. Review for inclusion, data extraction, and quality assessment (using the Newcastle-Ottawa Scale [NOS]) were performed independently by two reviewers. Pooled adjusted odds ratios with 95% confidence intervals were generated from the random effects model. Heterogeneity was quantified with I2 statistic. Funnel plot and Eger's test were performed to assess publication bias. Subgroup and sensitivity analyses were performed for testing the robustness of the overall findings. RESULTS: Initial database searches returned 761 unique citations and after review, eleven studies describing 66,876 patients, and 6542 cancers were included (Cohen's κ = 0.88). Publication quality was high (median NOS = 8, range: 4 to 9). Frequent talcum powder use was associated with an elevated risk of ovarian cancer (adjusted pooled summary odds ratio 1.47 (95% CI 1.31, 1.65, P<0.0001). There was no evidence of bias and low heterogeneity (I2= 24%, P=0.22). There was no meaningful difference limiting analysis to publications with a NOS quality score of 8 or 9 or limiting studies based on study design. CONCLUSIONS: This review suggests an increased risk of ovarian cancer associated with frequent perineal powder exposure of 31-65%.
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Neoplasias Ováricas , Talco , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Oportunidad Relativa , Neoplasias Ováricas/inducido químicamente , Neoplasias Ováricas/epidemiología , Talco/efectos adversosRESUMEN
BACKGROUND: Paraspinal musculature (PSM) is increasingly recognized as a contributor to low back pain (LBP), but with conventional MRI sequences, assessment is limited. Chemical shift encoding-based water-fat MRI (CSE-MRI) enables the measurement of PSM fat fraction (FF), which may assist investigations of chronic LBP. PURPOSE: To investigate associations between PSM parameters from conventional MRI and CSE-MRI and between PSM parameters and pain. STUDY TYPE: Prospective, cross-sectional. POPULATION: Eighty-four adults with chronic LBP (44.6 ± 13.4 years; 48 males). FIELD STRENGTH/SEQUENCE: 3-T, T1-weighted fast spin-echo and iterative decomposition of water and fat with echo asymmetry and least squares estimation sequences. ASSESSMENT: T1-weighted images for Goutallier classification (GC), muscle volume, lumbar indentation value, and muscle-fat index, CSE-MRI for FF extraction (L1/2-L5/S1). Pain was self-reported using a visual analogue scale (VAS). Intra- and/or interreader agreement was assessed for MRI-derived parameters. STATISTICAL TESTS: Mixed-effects and linear regression models to 1) assess relationships between PSM parameters (entire cohort and subgroup with GC grades 0 and 1; statistical significance α = 0.0025) and 2) evaluate associations of PSM parameters with pain (α = 0.05). Intraclass correlation coefficients (ICCs) for intra- and/or interreader agreement. RESULTS: The FF showed excellent intra- and interreader agreement (ICC range: 0.97-0.99) and was significantly associated with GC at all spinal levels. Subgroup analysis suggested that early/subtle changes in PSM are detectable with FF but not with GC, given the absence of significant associations between FF and GC (P-value range: 0.036 at L5/S1 to 0.784 at L2/L3). Averaged over all spinal levels, FF and GC were significantly associated with VAS scores. DATA CONCLUSION: In the absence of FF, GC may be the best surrogate for PSM quality. Given the ability of CSE-MRI to detect muscle alterations at early stages of PSM degeneration, this technique may have potential for further investigations of the role of PSM in chronic LBP. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.
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Dolor de la Región Lumbar , Músculos Paraespinales , Adulto , Estudios Transversales , Humanos , Dolor de la Región Lumbar/diagnóstico por imagen , Vértebras Lumbares , Imagen por Resonancia Magnética/métodos , Masculino , Músculos Paraespinales/diagnóstico por imagen , Músculos Paraespinales/fisiología , Estudios Prospectivos , AguaRESUMEN
AIMS: The study examined the prevalence and degree of lactate elevation in diabetic ketoacidosis, and explored which biochemical abnormalities predicted L-lactate levels. METHODS: We reviewed episodes of diabetic ketoacidosis from 79 diabetes patients (one episode per patient). Separate univariate linear regression models were specified to predict lactate level from each of nine biochemical variables. Significant predictors from the univariate models were included in a final multivariate linear regression model to predict lactate levels. RESULTS: Mean (SD) lactate level was 3.05 (1.66) mmol/L; about 65% of patients had lactate levels >2 mmol/L. In the final multivariate linear regression model (R2 = 0.45), higher lactate levels were associated with greater hydrogen ion concentration (standardised ß = .60, t = 4.16, p < 0.0001), higher blood glucose (standardised ß = .28, t = 2.67, p = 0.009) and lower glomerular filtration rate estimated from creatinine (standardised ß = -.23, t = 2.29, p = 0.025). Bicarbonate, beta-hydroxybutyrate, body mass index, mean arterial pressure and calculated osmolality were not significant predictors of lactate level. There were three distinct patterns of lactate levels with treatment of diabetic ketoacidosis: group 1 = gradual decline, group 2 = initial increase and then decline and group 3 = initial decline followed by a transient peak and subsequent decline. CONCLUSIONS: Elevated lactate level is the norm in patients with diabetic ketoacidosis. Higher blood glucose levels and higher hydrogen ion concentrations are related to greater lactate. With treatment, there are different patterns of decline in lactate levels.
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Diabetes Mellitus , Cetoacidosis Diabética , Hiperglucemia , Hiperlactatemia , Ácido 3-Hidroxibutírico , Glucemia , Cetoacidosis Diabética/complicaciones , Cetoacidosis Diabética/epidemiología , Humanos , Hiperglucemia/complicaciones , Hiperlactatemia/complicaciones , Hiperlactatemia/etiología , Ácido LácticoRESUMEN
STUDY OBJECTIVE: To identify drivers of disparities among patients undergoing surgical management of myomas when stratified by self-identified patient race. DESIGN: This is a retrospective institutional review board-approved chart review of all patients who underwent a myomectomy at a large academic center. Surgical approach to myomectomy was classified as abdominal, laparoscopic, or robotic-assisted laparoscopic. Myoma burden was quantified preoperatively using uterine volume, intraoperatively by number of myomas listed on operative report, and postoperatively by myoma weight from pathology reports. SETTING: A large tertiary care hospital containing a comprehensive myoma treatment center. PATIENTS: A total of 265 white patients and 121 African American patients who underwent a myomectomy between January 2012 and October 2018 were included in the study population. INTERVENTIONS: Abdominal, laparoscopic, and robotic-assisted myomectomy. Laparoscopic and robotic-assisted myomectomy were classified as minimally invasive myomectomy. Multivariable logistic regression models and a propensity score matching algorithm were used to match African American (AA) women and white women for myoma burden. MEASUREMENTS AND MAIN RESULTS: A total of 386 women were included in the study. AA women (31%; nâ¯=â¯121) had higher myoma burden than white women by preoperative imaging (AA: 36% with 3 or more myomas; white: 19% with 3 or more myomas; p <.01) and operative report (>8 AA: 31% vs white 13%; p <.01). Despite this, AA women underwent minimally invasive myomectomy at similar rates as compared with white women when adjusted for myoma burden, body mass index, preoperative hematocrit, hypertension, and surgical indication (adjusted odds ratio 1.3; 95% confidence interval, 0.8-2.2 myomas; p <.01). Sensitivity analysis using propensity score matching found similar results. CONCLUSION: In this population, AA women had a higher myoma burden than white women. When matched for myoma burden, however, there was no statistically significant difference between rates of minimally invasive myomectomy and abdominal myomectomy. This finding was consistent when controlling for myoma burden measured by preoperative, intraoperative, or postoperative methods of measurement. Further studies are needed to better characterize this disparity at other hospitals and to investigate ways to increase access and equity among patients undergoing minimally invasive myomectomy.
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Laparoscopía , Leiomioma , Miomectomía Uterina , Neoplasias Uterinas , Negro o Afroamericano , Femenino , Humanos , Leiomioma/cirugía , Estudios Retrospectivos , Neoplasias Uterinas/cirugíaRESUMEN
PURPOSE: The composition of the subchondral bone marrow and cartilage endplate (CEP) could affect intervertebral disc health by influencing vertebral perfusion and nutrient diffusion. However, the relative contributions of these factors to disc degeneration in patients with chronic low back pain (cLBP) have not been quantified. The goal of this study was to use compositional biomarkers derived from quantitative MRI to establish how CEP composition (surrogate for permeability) and vertebral bone marrow fat fraction (BMFF, surrogate for perfusion) relate to disc degeneration. METHODS: MRI data from 60 patients with cLBP were included in this prospective observational study (28 female, 32 male; age = 40.0 ± 11.9 years, 19-65 [mean ± SD, min-max]). Ultra-short echo-time MRI was used to calculate CEP T2* relaxation times (reflecting biochemical composition), water-fat MRI was used to calculate vertebral BMFF, and T1ρ MRI was used to calculate T1ρ relaxation times in the nucleus pulposus (NP T1ρ, reflecting proteoglycan content and degenerative grade). Univariate linear regression was used to assess the independent effects of CEP T2* and vertebral BMFF on NP T1ρ. Mixed effects multivariable linear regression accounting for age, sex, and BMI was used to assess the combined relationship between variables. RESULTS: CEP T2* and vertebral BMFF were independently associated with NP T1ρ (p = 0.003 and 0.0001, respectively). After adjusting for age, sex, and BMI, NP T1ρ remained significantly associated with CEP T2* (p = 0.0001) but not vertebral BMFF (p = 0.43). CONCLUSION: Poor CEP composition plays a significant role in disc degeneration severity and can affect disc health both with and without deficits in vertebral perfusion.
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Degeneración del Disco Intervertebral , Disco Intervertebral , Dolor de la Región Lumbar , Adulto , Médula Ósea/diagnóstico por imagen , Cartílago , Femenino , Humanos , Disco Intervertebral/diagnóstico por imagen , Degeneración del Disco Intervertebral/complicaciones , Degeneración del Disco Intervertebral/diagnóstico por imagen , Dolor de la Región Lumbar/diagnóstico por imagen , Dolor de la Región Lumbar/etiología , Vértebras Lumbares/química , Vértebras Lumbares/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Anal squamous cell carcinoma (ASCC) is uncommon, yet seen more frequently in the setting of the human immunodeficiency virus (HIV). Chemoradiotherapy is the definitive modality of treatment for patients with ASCC; this study examines factors impacting clinical outcomes in a large cohort of HIV-positive and HIV-negative patients. METHODS: A retrospective review was conducted of patients treated for nonmetastatic ASCC at a single institution between 2005 and 2018. Freedom from local recurrence (FFLR), freedom from distant metastasis, and overall survival (OS) were calculated using the Kaplan-Meier method, and univariate and multivariate analysis were performed using the Cox proportional hazards model. RESULTS: During the study period, 111 patients initiated definitive treatment for ASCC. Median age of the entire cohort was 56.7 years (interquartile range, 51.5-63.5), with 52 patients (46.8%) being HIV-positive. At median follow-up of 28.0 months, the 2- and 5-year FFLR were 78.2% (95% confidence interval [CI], 70.4-87.0) and 74.6% (95% CI, 65.8-84.5), respectively. Multivariate analysis revealed time from diagnosis to treatment initiation (median, 8 weeks; hazard ratio, 1.06; 95% CI, 1.03-1.10) to be significantly associated with worse FFLR and OS. HIV-positive patients had a trend toward worse FFLR (log-ranked p = .06). For HIV-positive patients with post-treatment CD4 less than 150 cells per mm3 , there was significantly worse OS (log-ranked p = .015). CONCLUSION: A trend toward worse FFLR was seen in HIV-positive patients, despite similar baseline disease characteristics as HIV-negative patients. Worse FFLR and OS was significantly associated with increased time from diagnosis to treatment initiation. Poorer OS was seen in HIV-positive patients with a post-treatment CD4 count less than 150 cells per mm3 . IMPLICATIONS FOR PRACTICE: Human immunodeficiency virus (HIV)-positive patients with anal squamous cell carcinoma can represent a difficult clinical scenario. Definitive radiation with concurrent chemotherapy is highly effective but can result in significant toxicity and a decrease in CD4 count that could predispose to HIV-related complications. As HIV-positive patients have largely been excluded from prospective clinical trials, this study seeks to provide greater understanding of their outcomes with radiation therapy, potential predictors of worse local control and overall survival, and those most at risk after completion of treatment.
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Neoplasias del Ano , Infecciones por VIH , Quimioradioterapia , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estudios Prospectivos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
RATIONALE & OBJECTIVE: Patients receiving dialysis report very low physical activity. We implemented a pilot trial to assess the feasibility of a pedometer-based intervention to gather preliminary evidence about its impact on physical activity, symptoms, and surrogates of cardiovascular risk. STUDY DESIGN: Pilot randomized controlled trial. SETTING & PARTICIPANTS: 60 dialysis patients from San Francisco dialysis clinics. INTERVENTION: Participants were randomly assigned 1:1 to receiving pedometers with weekly step goals or usual care for 3 months. OUTCOMES: The primary outcome was step counts, measured using pedometers. Secondary outcomes included physical performance using the Short Physical Performance Battery, the Physical Function and Vitality scales of the 36-Item Short Form Health Survey, the Dialysis Symptoms Index, and the Center for Epidemiologic Studies-Depression Scale, with endothelial function as a secondary and heart rate variability as an exploratory surrogate measure of cardiovascular risk. Targeted enrollment was 50% and targeted completion was 85%. RESULTS: 49% of approached patients were enrolled, and 92% completed the study. After 3 months, patients randomly assigned to the intervention (n=30) increased their average daily steps by 2,256 (95% CI, 978-3,537) more than the 30 controls (P<0.001). Heart rate variability (standard deviation of N-N intervals) increased by 14.94 (95% CI, 0.31-33.56) millisecondsin the intervention group as compared with controls (P = 0.05). There were no statistically significant differences across intervention groups in symptoms, physical performance, or endothelial function. Participants in the intervention group reverted to baseline steps during the postintervention follow-up. LIMITATIONS: The Northern California study setting may limit generalizability. Walking does not capture the full spectrum of physical activity. CONCLUSIONS: A short-term pedometer-based intervention led to increased step counts in dialysis patients, but the increase was not sustained. Pedometer-based interventions are feasible for dialysis patients, but future studies are needed to address whether more prolonged interventions can improve physical function or symptoms. FUNDING: Supported by grants from the American Kidney Fund, National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases, and International Society of Nephrology. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study identifier NCT02623348.
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Ejercicio Físico/fisiología , Monitores de Ejercicio , Promoción de la Salud/métodos , Diálisis Renal/métodos , Caminata/fisiología , Anciano , Femenino , Monitores de Ejercicio/tendencias , Estudios de Seguimiento , Promoción de la Salud/tendencias , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Diálisis Renal/tendencias , Factores de Tiempo , Caminata/tendenciasRESUMEN
OBJECTIVE: Although multimodality therapy has been shown to improve outcomes for patients with high-risk endometrial carcinoma, optimal type and timing of adjuvant therapies is unknown. METHODS: Patients with stage I-IVA endometrial carcinoma diagnosed from 2004 to 2015, and treated with surgery, chemotherapy, and radiation were identified in the National Cancer Database. Adjuvant treatment was categorized as sequential radiation followed by chemotherapy (RT-CT), concurrent chemoradiation (CCRT, RT and CT started within 7 days), or sequential chemotherapy followed by radiation (CT-RT). Analysis for propensity score matched (PSM) cohorts comparing RT-CT to CCRT and CT-RT groups was additionally performed. RESULTS: A total of 17,070 patients were identified, including 12,402 (72.7%) treated with RT-CT, 2,153 (12.6%) with CCRT, and 2,515 (14.7%) with CT-RT. Median follow-up was 44.3 months. Five-year overall-survival (OS) by adjuvant treatment regimen was 77.3% (95% CI 76.4%-78.2%), 74.3% (95% CI 72.0%-76.3%), and 74.4% (95% CI 72.5%-76.3%), respectively (p < .001). When unmatched cohorts were stratified by stage, adjuvant RT-CT was associated with improved OS in stage I and III patients. A similar survival advantage associated with RT-CT was observed in PSM cohorts comparing RT-CT group to CCRT/CT-RT group (5-year OS 77.4% vs 74.2%, p = .001). However, the difference in OS was significant only among stage III patients (RT-CT 73.9% compared to CCRT/CT-RT 69.7%, p =.002). CONCLUSION: Our findings suggest survival benefit with adjuvant RT-CT compared to CT-RT or CCRT in patients undergoing trimodality therapy for endometrial cancer. This survival benefit may be limited to stage III patients.
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Carcinoma/terapia , Quimioradioterapia Adyuvante/métodos , Neoplasias Endometriales/terapia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/diagnóstico , Carcinoma/mortalidad , Quimioradioterapia Adyuvante/estadística & datos numéricos , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Histerectomía , Estimación de Kaplan-Meier , Persona de Mediana Edad , Estadificación de Neoplasias , Selección de Paciente , Sistema de Registros/estadística & datos numéricos , Estudios Retrospectivos , Salpingooforectomía , Resultado del Tratamiento , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Postoperative delirium is a common and serious problem for older adults. To better align local practices with delirium prevention consensus guidelines, we implemented a 5-component intervention followed by a quality improvement (QI) project at our institution. METHODS: This hybrid implementation-effectiveness study took place at 2 adult hospitals within a tertiary care academic health care system. We implemented a 5-component intervention: preoperative delirium risk stratification, multidisciplinary education, written memory aids, delirium prevention postanesthesia care unit (PACU) orderset, and electronic health record enhancements between December 1, 2017 and June 30, 2018. This was followed by a department-wide QI project to increase uptake of the intervention from July 1, 2018 to June 30, 2019. We tracked process outcomes during the QI period, including frequency of preoperative delirium risk screening, percentage of "high-risk" screens, and frequency of appropriate PACU orderset use. We measured practice change after the interventions using interrupted time series analysis of perioperative medication prescribing practices during baseline (December 1, 2016 to November 30, 2017), intervention (December 1, 2017 to June 30, 2018), and QI (July 1, 2018 to June 30, 2019) periods. Participants were consecutive older patients (≥65 years of age) who underwent surgery during the above timeframes and received care in the PACU, compared to a concurrent control group <65 years of age. The a priori primary outcome was a composite of perioperative American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use (Beers PIM) medications. The secondary outcome, delirium incidence, was measured in the subset of older patients who were admitted to the hospital for at least 1 night. RESULTS: During the 12-month QI period, preoperative delirium risk stratification improved from 67% (714 of 1068 patients) in month 1 to 83% in month 12 (776 of 931 patients). Forty percent of patients were stratified as "high risk" during the 12-month period (4246 of 10,494 patients). Appropriate PACU orderset use in high-risk patients increased from 19% in month 1 to 85% in month 12. We analyzed medication use in 7212, 4416, and 8311 PACU care episodes during the baseline, intervention, and QI periods, respectively. Beers PIM administration decreased from 33% to 27% to 23% during the 3 time periods, with adjusted odds ratio (aOR) 0.97 (95% confidence interval [CI], 0.95-0.998; P = .03) per month during the QI period in comparison to baseline. Delirium incidence was 7.5%, 9.2%, and 8.5% during the 3 time periods with aOR of delirium of 0.98 (95% CI, 0.91-1.05, P = .52) per month during the QI period in comparison to baseline. CONCLUSIONS: A perioperative delirium prevention intervention was associated with reduced administration of Beers PIMs to older adults.
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Registros Electrónicos de Salud/normas , Delirio del Despertar/prevención & control , Atención Perioperativa/normas , Guías de Práctica Clínica como Asunto/normas , Anciano , Delirio del Despertar/etiología , Femenino , Humanos , Masculino , Atención Perioperativa/métodos , Resultado del TratamientoRESUMEN
To describe the international landscape of clinical trials in carbon-ion radiotherapy (CIRT), the authors reviewed the current status of 63 ongoing clinical trials (median, 47 participants) involving CIRT identified from the US clinicaltrials.gov trial registry and the World Health Organization International Clinical Trials Platform Registry. The objectives were to evaluate the potential for these trials to define the role of this modality in the treatment of specific cancer types and identify the major challenges and opportunities to advance this technology. A significant body of literature suggested the potential for advantageous dose distributions and, in preclinical biologic studies, the enhanced effectiveness for CIRT compared with photons and protons. In addition, clinical evidence from phase I/II trials, although limited, indicated the potential for CIRT to improve cancer outcomes. However, current high-level phase III randomized clinical trial evidence does not exist. Although there has been an increase in the number of trials investigating CIRT since 2010, and the number of countries and sites offering CIRT is slowly growing, this progress has excluded other countries. Several recommendations are proposed to study this modality to accelerate progress in the field, including: 1) increasing the number of multinational randomized clinical trials, 2) leveraging the existing CIRT facilities to launch larger multinational trials directed at common cancers combined with high-level quality assurance; and 3) developing more compact and less expensive next-generation treatment systems integrated with radiobiologic research and preclinical testing.
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Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Radioterapia de Iones Pesados/instrumentación , Neoplasias/radioterapia , Humanos , Estudios Multicéntricos como Asunto , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como Asunto , Sistema de Registros , Tamaño de la Muestra , Resultado del TratamientoRESUMEN
Purpose To determine the frequency of hepatobiliary infections after transarterial radioembolization (TARE) with yttrium 90 (90Y) in patients with liver malignancy and a history of biliary intervention. Materials and Methods For this retrospective study, records of all consecutive patients with liver malignancy and history of biliary intervention treated with TARE at 14 centers between 2005 and 2015 were reviewed. Data regarding liver function, 90Y dosimetry, antibiotic prophylaxis, and bowel preparation prophylaxis were collected. Primary outcome was development of hepatobiliary infection. Results One hundred twenty-six patients (84 men, 42 women; mean age, 68.8 years) with primary (n = 39) or metastatic (n = 87) liver malignancy and history of biliary intervention underwent 180 procedures with glass (92 procedures) or resin (88 procedures) microspheres. Hepatobiliary infections (liver abscesses in nine patients, cholangitis in five patients) developed in 10 of the 126 patients (7.9%) after 11 of the 180 procedures (6.1%; nine of those procedures were performed with glass microspheres). All patients required hospitalization (median stay, 12 days; range, 2-113 days). Ten patients required percutaneous abscess drainage, three patients underwent endoscopic stent placement and stone removal, and one patient needed insertion of percutaneous biliary drains. Infections resolved in five patients, four patients died (two from infection and two from cancer progression while infection was being treated), and one patient continued to receive suppressive antibiotics. Use of glass microspheres (P = .02), previous liver resection or ablation (P = .02), and younger age (P = .003) were independently predictive of higher infection risk. Conclusion Infectious complications such as liver abscess and cholangitis are uncommon but serious complications of transarterial radioembolization with 90Y in patients with liver malignancy and a history of biliary intervention.
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Braquiterapia/efectos adversos , Carcinoma Hepatocelular/radioterapia , Colangitis/etiología , Absceso Hepático/etiología , Neoplasias Hepáticas/radioterapia , Radioisótopos de Itrio/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Braquiterapia/métodos , Carcinoma Hepatocelular/complicaciones , Femenino , Vidrio , Humanos , Infecciones , Hígado/microbiología , Neoplasias Hepáticas/complicaciones , Masculino , Microesferas , Persona de Mediana Edad , Retratamiento , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: This study aimed to evaluate the effects of warm-mist humidification during and after head and neck radiation therapy (HN RT) on quality of life (QOL), as measured by the M. D. Anderson Symptom Inventory-Head and Neck (MDASI-HN) HN score. A secondary aim was to compare QOL among compliers (≥60% of protocol-recommended usage) versus non-compliers. METHODS: Twenty patients self-administered a hand-held, self-sterilizing humidification device for a recommended time of at least 15 min twice daily for 12 weeks. Patients completed the MDASI-HN instrument at RT start, after 6 weeks, and after 12 weeks. Compliance was reported weekly. RESULTS: The average HN score at baseline was 1.7 (SD = 1.8) and increased to 6.0 (SD = 1.6) after 6 weeks; this increase was much higher than anticipated and the primary endpoint could not be reached. However, compliers had an average of nearly two less HN symptoms (-1.8, 95% CI -4 to 0.2; p = 0.08) than non-compliers at 6 weeks and fewer symptoms at 12 weeks as well (-0.9, 95% CI -2.9 to 1.2; p = 0.39). The most common terms patients used to describe humidification were "helpful" and "soothing." CONCLUSIONS: Compliance with humidification during RT was associated with fewer reported HN symptoms and a strong trend to better QOL. Improvements were seen from compliance with occasional required use of a portable, inexpensive device. Our findings support continued efforts to reduce barriers to humidification, as an intervention that should be considered for standard HN RT clinical practice.
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Neoplasias de Cabeza y Cuello/radioterapia , Humidificadores/estadística & datos numéricos , Calidad de Vida/psicología , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cooperación del PacienteAsunto(s)
Asiático/estadística & datos numéricos , Melanoma/mortalidad , Nativos de Hawái y Otras Islas del Pacífico/estadística & datos numéricos , Neoplasias Cutáneas/mortalidad , Población Blanca/estadística & datos numéricos , Adulto , Anciano , Diagnóstico Tardío , Femenino , Humanos , Masculino , Melanoma/secundario , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Programa de VERF , Neoplasias Cutáneas/patología , Tasa de Supervivencia , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: For the past few decades, randomized clinical trials have provided evidence for effective treatments by comparing several competing therapies. Their successes have led to numerous new therapies to combat many diseases. However, since their conclusions are based on the entire cohort in the trial, the treatment recommendation is for everyone, and may not be the best option for an individual. Medical research is now focusing more on providing personalized care for patients, which requires investigating how patient characteristics, including novel biomarkers, modify the effect of current treatment modalities. This is known as heterogeneity of treatment effects. A better understanding of the interaction between treatment and patient-specific prognostic factors will enable practitioners to expand the availability of tailored therapies, with the ultimate goal of improving patient outcomes. The Subpopulation Treatment Effect Pattern Plot (STEPP) approach was developed to allow researchers to investigate the heterogeneity of treatment effects on survival outcomes across values of a (continuously measured) covariate, such as a biomarker measurement. METHODS: Here, we extend the Subpopulation Treatment Effect Pattern Plot approach to continuous, binary, and count outcomes, which can be easily modeled using generalized linear models. With this extension of Subpopulation Treatment Effect Pattern Plot, these additional types of treatment effects within subpopulations defined with respect to a covariate of interest can be estimated, and the statistical significance of any observed heterogeneity of treatment effect can be assessed using permutation tests. The desirable feature that commonly used models are applied to well-defined patient subgroups to estimate treatment effects is retained in this extension. RESULTS: We describe a simulation study to confirm that the proper Type I error rate is maintained when there is no treatment heterogeneity, and a power study to show that the statistics have power to detect treatment heterogeneity under alternative scenarios. As an illustration, we apply the methods to data from the Aspirin/Folate Polyp Prevention Study, a clinical trial evaluating the effect of oral aspirin, folic acid, or both as a chemoprevention agent against colorectal adenomas. The pre-existing R software package stepp has been extended to handle continuous, binary, and count data using Gaussian, Bernoulli, and Poisson models, and it is available on the Comprehensive R Archive Network. CONCLUSION: The extension of the method and the availability of new software now permit STEPP to be applied to the full range of clinical trial end points.
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Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Adenoma/prevención & control , Aspirina/administración & dosificación , Biomarcadores de Tumor , Neoplasias Colorrectales/prevención & control , Interpretación Estadística de Datos , Ácido Fólico/administración & dosificación , Humanos , Modelos Estadísticos , Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Investigators conducting randomized clinical trials often explore treatment effect heterogeneity to assess whether treatment efficacy varies according to patient characteristics. Identifying heterogeneity is central to making informed personalized healthcare decisions. Treatment effect heterogeneity can be investigated using subpopulation treatment effect pattern plot (STEPP), a non-parametric graphical approach that constructs overlapping patient subpopulations with varying values of a characteristic. Procedures for statistical testing using subpopulation treatment effect pattern plot when the endpoint of interest is survival remain an area of active investigation. METHODS: A STEPP analysis was used to explore patterns of absolute and relative treatment effects for varying levels of a breast cancer biomarker, Ki-67, in the phase III Breast International Group 1-98 randomized clinical trial, comparing letrozole to tamoxifen as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. Absolute treatment effects were measured by differences in 4-year cumulative incidence of breast cancer recurrence, while relative effects were measured by the subdistribution hazard ratio in the presence of competing risks using O-E (observed-minus-expected) methodology, an intuitive non-parametric method. While estimation of hazard ratio values based on O-E methodology has been shown, a similar development for the subdistribution hazard ratio has not. Furthermore, we observed that the subpopulation treatment effect pattern plot analysis may not produce results, even with 100 patients within each subpopulation. After further investigation through simulation studies, we observed inflation of the type I error rate of the traditional test statistic and sometimes singular variance-covariance matrix estimates that may lead to results not being produced. This is due to the lack of sufficient number of events within the subpopulations, which we refer to as instability of the subpopulation treatment effect pattern plot analysis. We introduce methodology designed to improve stability of the subpopulation treatment effect pattern plot analysis and generalize O-E methodology to the competing risks setting. Simulation studies were designed to assess the type I error rate of the tests for a variety of treatment effect measures, including subdistribution hazard ratio based on O-E estimation. This subpopulation treatment effect pattern plot methodology and standard regression modeling were used to evaluate heterogeneity of Ki-67 in the Breast International Group 1-98 randomized clinical trial. RESULTS: We introduce methodology that generalizes O-E methodology to the competing risks setting and that improves stability of the STEPP analysis by pre-specifying the number of events across subpopulations while controlling the type I error rate. The subpopulation treatment effect pattern plot analysis of the Breast International Group 1-98 randomized clinical trial showed that patients with high Ki-67 percentages may benefit most from letrozole, while heterogeneity was not detected using standard regression modeling. CONCLUSION: The STEPP methodology can be used to study complex patterns of treatment effect heterogeneity, as illustrated in the Breast International Group 1-98 randomized clinical trial. For the subpopulation treatment effect pattern plot analysis, we recommend a minimum of 20 events within each subpopulation.