This paper describes the Smart Beginnings Integrated Model, an innovative, tiered approach for addressing school readiness disparities in low-income children from birth to age 3 in the United States ...through universal engagement of low-income families and primary prevention in pediatric primary care integrated with secondary/tertiary prevention in the home. We build on both public health considerations, in which engagement, cost and scalability are paramount, and a developmental psychopathology framework (Cicchetti & Toth, Journal of Child Psychology and Psychiatry, and Allied Disciplines 50:16–25, 2009), in which the child is considered within the context of the proximal caregiving environment. Whereas existing early preventive models have shown promise in promoting children’s school readiness, the Smart Beginnings model addresses three important barriers that have limited impacts at the individual and/or population level: (1) identification and engagement of vulnerable families; (2) the challenges of scalability at low cost within existing service systems; and (3) tailoring interventions to address the heterogeneity of risk among low-income families. Smart Beginnings takes advantage of the existing platform of pediatric primary care to provide a universal primary prevention strategy for all families (Video Interaction Project) and a targeted secondary/tertiary prevention strategy (Family Check-Up) for families with additional contextual factors. We describe the theory underlying the Smart Beginnings model, some initial findings from its recent application in two cities, and implications for changing social policy to promote school readiness beginning during very early childhood.
Measurement error arises through a variety of mechanisms. A rich literature exists on the bias introduced by covariate measurement error and on methods of analysis to address this bias. By ...comparison, less attention has been given to errors in outcome assessment and nonclassical covariate measurement error. We consider an extension of the regression calibration method to settings with errors in a continuous outcome, where the errors may be correlated with prognostic covariates or with covariate measurement error. This method adjusts for the measurement error in the data and can be applied with either a validation subset, on which the true data are also observed (eg, a study audit), or a reliability subset, where a second observation of error prone measurements are available. For each case, we provide conditions under which the proposed method is identifiable and leads to consistent estimates of the regression parameter. When the second measurement on the reliability subset has no error or classical unbiased measurement error, the proposed method is consistent even when the primary outcome and exposures of interest are subject to both systematic and random error. We examine the performance of the method with simulations for a variety of measurement error scenarios and sizes of the reliability subset. We illustrate the method's application using data from the Women's Health Initiative Dietary Modification Trial.
Medical studies that depend on electronic health records (EHR) data are often subject to measurement error, as the data are not collected to support research questions under study. These data errors, ...if not accounted for in study analyses, can obscure or cause spurious associations between patient exposures and disease risk. Methodology to address covariate measurement error has been well developed; however, time‐to‐event error has also been shown to cause significant bias, but methods to address it are relatively underdeveloped. More generally, it is possible to observe errors in both the covariate and the time‐to‐event outcome that are correlated. We propose regression calibration (RC) estimators to simultaneously address correlated error in the covariates and the censored event time. Although RC can perform well in many settings with covariate measurement error, it is biased for nonlinear regression models, such as the Cox model. Thus, we additionally propose raking estimators which are consistent estimators of the parameter defined by the population estimating equation. Raking can improve upon RC in certain settings with failure‐time data, require no explicit modeling of the error structure, and can be utilized under outcome‐dependent sampling designs. We discuss features of the underlying estimation problem that affect the degree of improvement the raking estimator has over the RC approach. Detailed simulation studies are presented to examine the performance of the proposed estimators under varying levels of signal, error, and censoring. The methodology is illustrated on observational EHR data on HIV outcomes from the Vanderbilt Comprehensive Care Clinic.
Before a novel treatment can be deemed a clinical success, an assessment of its risk–benefit profile must be made. One of the inherent challenges for this assessment comes from the multiplicity that ...arises from comparing treatment groups across multiple outcomes. Composite outcomes that summarize a patient’s clinical status, or severity, across a prioritized list of safety and efficacy outcomes have become increasing popular. In this article, we review these approaches and illustrate through examples some of the challenges and complexities of a composite derived from prioritized outcomes, such as the win ratio. These challenges include the difficult tension between the analytical validity that comes from choosing a pre-specified outcome and an evaluation that is responsive to unexpected safety events that arise during the course of a trial. Other challenges include a sensitivity of the resulting test statistic to the underlying censoring distribution and other nuisance parameters. Approaches that resolve some of the difficulties of the analytical challenges associated with prioritized outcomes are then discussed. Ultimately, a composite outcome of net clinical benefit is another decision tool, but one to be used alongside more traditional analyses of efficacy and safety, and with the broader perspective that investigators, the data safety monitoring board, and regulators bring to an evaluation of risk–benefit.
There is growing evidence that racial and ethnic minorities bear a disproportionate burden from COVID-19. Temporal changes in the pandemic epidemiology and diversity in the clinical course require ...careful study to identify determinants of poor outcomes. We analyzed 6255 hospitalized individuals with PCR-confirmed SARS-CoV-2 infection from one of 5 hospitals in the University of Pennsylvania Health System between March 2020 and March 2021, using electronic health records to assess risk factors and outcomes through 8 weeks post-admission. Discharge, readmission and mortality outcomes were analyzed in a multi-state model with multivariable Cox models for each transition. Mortality varied markedly over time, with cumulative incidence (95% CI) 30 days post-admission of 19.1% (16.9, 21.3) in March-April 2020, 5.7% (4.2, 7.5) in July-October 2020 and 10.5% (9.1,12.0) in January-March 2021; 26% of deaths occurred after discharge. Average age (SD) at admission varied from 62.7 (17.6) to 54.8 (19.9) to 60.5 (18.1); mechanical ventilation use declined from 21.3% to 9-11%. Compared to Caucasian, Black race was associated with more severe disease at admission, higher rates of co-morbidities and residing in a low-income zip code. Between-race risk differences in mortality risk diminished in multivariable models; while admitting hospital, increasing age, admission early in the pandemic, and severe disease and low blood pressure at admission were associated with increased mortality hazard. Hispanic ethnicity was associated with fewer baseline co-morbidities and lower mortality hazard (0.57, 95% CI: 0.37, .087). Multi-state modeling allows for a unified framework to analyze multiple outcomes throughout the disease course. Morbidity and mortality for hospitalized COVID-19 patients varied over time but post-discharge mortality remained non-trivial. Black race was associated with more risk factors for morbidity and with treatment at hospitals with lower mortality. Multivariable models suggest there are not between-race differences in outcomes. Future work is needed to better understand the identified between-hospital differences in mortality.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In large epidemiologic studies, it is typical for an inexpensive, non-invasive procedure to be used to record disease status during regular follow-up visits, with less frequent assessment by a gold ...standard test. Inexpensive outcome measures like self-reported disease status are practical to obtain, but can be error-prone. Association analysis reliant on error-prone outcomes may lead to biased results; however, restricting analyses to only data from the less frequently observed error-free outcome could be inefficient. We have developed an augmented likelihood that incorporates data from both error-prone outcomes and a gold standard assessment. We conduct a numerical study to show how we can improve statistical efficiency by using the proposed method over standard approaches for interval-censored survival data that do not leverage auxiliary data. We extend this method for the complex survey design setting so that it can be applied in our motivating data example. Our method is applied to data from the Hispanic Community Health Study/Study of Latinos to assess the association between energy and protein intake and the risk of incident diabetes. In our application, we demonstrate how our method can be used in combination with regression calibration to additionally address the covariate measurement error in self-reported diet.
Treatment of pulmonary nontuberculous mycobacteria, especially Mycobacterium abscessus, requires prolonged, multidrug regimens with high toxicity and suboptimal efficacy. Options for refractory ...disease are limited.
We reviewed the efficacy and toxicity of inhaled amikacin in patients with treatment-refractory nontuberculous mycobacterial lung disease.
Records were queried to identify patients who had inhaled amikacin added to failing regimens. Lower airway microbiology, symptoms, and computed tomography scan changes were assessed together with reported toxicity.
The majority (80%) of the 20 patients who met entry criteria were women; all had bronchiectasis, two had cystic fibrosis and one had primary ciliary dyskinesia. At initiation of inhaled amikacin, 15 were culture positive for M. abscessus and 5 for Mycobacterium avium complex and had received a median (range) of 60 (6, 190) months of mycobacterial treatment. Patients were followed for a median of 19 (1, 50) months. Eight (40%) patients had at least one negative culture and 5 (25%) had persistently negative cultures. A decrease in smear quantity was noted in 9 of 20 (45%) and in mycobacterial culture growth for 10 of 19 (53%). Symptom scores improved in nine (45%), were unchanged in seven (35%), and worsened in four (20%). Improvement on computed tomography scans was noted in 6 (30%), unchanged in 3 (15%), and worsened in 11 (55%). Seven (35%) stopped amikacin due to: ototoxicity in two (10%), hemoptysis in two (10%), and nephrotoxicity, persistent dysphonia, and vertigo in one each.
In some patients with treatment-refractory pulmonary nontuberculous mycobacterial disease, the addition of inhaled amikacin was associated with microbiologic and/or symptomatic improvement; however, toxicity was common. Prospective evaluation of inhaled amikacin for mycobacterial disease is warranted.
Objective
To characterize the incidence and clinical characteristics of neurotoxicity in the month following CTL019 infusion in children and young adults, to define the relationship between ...neurotoxicity and cytokine release syndrome (CRS), and to identify predictive biomarkers for development of neurotoxicity following CTL019 infusion.
Methods
We analyzed data on 51 subjects, 4 to 22 years old, who received CTL019, a chimeric antigen receptor–modified T‐cell therapy against CD19, between January 1, 2010 and December 1, 2015 through a safety/feasibility clinical trial (NCT01626495) at our institution. We recorded incidence of significant neurotoxicity (encephalopathy, seizures, and focal deficits) and CRS, and compared serum cytokine levels in the first month postinfusion between subjects who did and did not develop neurotoxicity.
Results
Neurotoxicity occurred in 23 of 51 subjects (45%, 95% confidence interval = 31–60%) and was positively associated with higher CRS grade (p < 0.0001) but was not associated with demographic characteristics or prior oncologic treatment history. Serum interleukin (IL)‐2, IL‐15, soluble IL‐4, and hepatocyte growth factor concentrations were higher in subjects with neurotoxicity than those with isolated CRS. Differences in peak levels of select cytokines including IL‐12 and soluble tumor necrosis factor receptor‐1 within the first 3 days were seen in subjects with neurotoxicity.
Interpretation
Neurotoxicity is common after CTL019 infusion in children and young adults, and is associated with higher CRS grade. Differences in serum cytokine profiles between subjects with neurotoxicity and those with isolated CRS suggest unique pathophysiological mechanisms. Serum cytokine profiles in the first 3 days postinfusion may help identify children and young adults at risk for neurotoxicity, and may provide a foundation for investigation into potential mitigation strategies. Ann Neurol 2018;84:537–546
CD19-targeted chimeric antigen receptor (CAR)-modified T cells demonstrate unprecedented responses in B-cell acute lymphoblastic leukemia (B-ALL); however, relapse remains a substantial challenge. ...Short CAR T-cell persistence contributes to this risk; therefore, strategies to improve persistence are needed.
We conducted a pilot clinical trial of a humanized CD19 CAR T-cell product (huCART19) in children and young adults with relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (n = 2), treated in two cohorts: with (retreatment, n = 33) or without (CAR-naive, n = 41) prior CAR exposure. Patients were monitored for toxicity, response, and persistence of huCART19.
Seventy-four patients 1-29 years of age received huCART19. Cytokine release syndrome developed in 62 (84%) patients and was grade 4 in five (6.8%). Neurologic toxicities were reported in 29 (39%), three (4%) grade 3 or 4, and fully resolved in all cases. The overall response rate at 1 month after infusion was 98% (100% in B-ALL) in the CAR-naive cohort and 64% in the retreatment cohort. At 6 months, the probability of losing huCART19 persistence was 27% (95% CI, 14 to 41) for CAR-naive and 48% (95% CI, 30 to 64) for retreatment patients, whereas the incidence of B-cell recovery was 15% (95% CI, 6 to 28) and 58% (95% CI, 33 to 77), respectively. Relapse-free survival at 12 and 24 months, respectively, was 84% (95% CI, 72 to 97) and 74% (95% CI, 60 to 90) in CAR-naive and 74% (95% CI, 56 to 97) and 58% (95% CI, 37 to 90) in retreatment cohorts.
HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-ALL, including after failure of prior CAR T-cell therapy.
Single-site clinic-based studies suggest an increasing prevalence of pulmonary nontuberculous mycobacteria (NTM) disease, but systematic data are lacking.
To describe prevalence and trends for NTM ...lung disease at four geographically diverse integrated heath care delivery systems in the United States.
We abstracted mycobacterial culture results from electronic laboratory databases and linked to other datasets containing clinical and demographic information. Possible cases were defined as a single positive NTM pulmonary isolate, and definite cases were defined as two positive sputum cultures, or one positive culture from a bronchoalveolar lavage or lung biopsy. Annual prevalence was calculated using United States census data; average annual prevalence is presented for 2004-2006. Poisson regression models were used to estimate the annual percent change in prevalence.
A total of 28,697 samples from 7,940 patients were included in the analysis. Of these, 3,988 (50%) were defined as possible cases, and 1,865 (47%) of these were defined as definite cases. Average annual (2004-2006) site-specific prevalence ranged from 1.4 to 6.6 per 100,000. Prevalence was 1.l- to 1.6-fold higher among women relative to men across sites. The prevalence of NTM lung disease was increasing significantly at the two sites where trends were studied, by 2.6% per year among women and 2.9% per year among men. Among persons aged greater than or equal to 60 years, annual prevalence increased from 19.6 per 100,000 during 1994-1996 to 26.7 per 100,000 during 2004-2006.
The epidemiology of nontuberculous mycobacterial lung disease is changing, with a predominance of women and increasing prevalence at the sites studied.
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