Ventilator-free days (VFDs) are a commonly reported composite outcome measure in acute respiratory distress syndrome trials. VFDs combine survival and duration of ventilation in a manner that ...summarizes the "net effect" of an intervention on these two outcomes. However, this combining of outcome measures makes VFDs difficult to understand and analyze, which contributes to imprecise interpretations. We discuss the strengths and limitations of VFDs and other "failure-free day" composites, and we provide a framework for when and how to use these outcome measures. We also provide a comprehensive discussion of the different analytic methods for analyzing and interpreting VFDs, including Student's
tests and rank-sum tests, as well as competing risk regressions treating extubation as the primary outcome and death as the competing risk. Using simulations, we illustrate how the statistical test with optimal power depends on the relative contributions of mortality and ventilator duration on the composite effect size. Finally, we recommend a simple analysis and reporting framework using the competing risk approach, which provides clear information on the effect size of an intervention, a statistical test and measure of confidence with the ability to adjust for baseline factors and allow interim monitoring for trials. We emphasize that any approach to analyzing a composite outcome, including other "failure-free day" constructs, should also be accompanied by an examination of the components.
Liver transplantation offers life-saving therapy for patients with decompensated liver disease or T2 hepatocellular carcinomas. In the United States, deceased donor livers are primarily allocated by ...Model for End-Stage Liver Disease (MELD) score within each of the country's more than 50 donation service areas (DSAs). Variation in DSA size, population, and organ availability have engendered concern that unequal access to deceased donor livers across DSAs contributes to geographic variability in outcome.
To determine the extent to which DSA variability in organ availability correlated with combined waitlist and posttransplant mortality, we analyzed retrospectively national waitlist and posttransplant data for a 7-year period after implementation of the current MELD-based allocation system.
Marked variation among DSAs was evident in death rate (3.3-fold), transplant rate (20-fold), and mean transplant MELD (>10 points). Death rate correlated with organ availability was assessed by transplant rate and transplant MELD. DSAs with low organ availability included the country's largest cities, had more new listings per capita, larger waitlists, more transplant centers per DSA, and a higher proportion of black and Asian patients. DSAs of organ shortage were also characterized by more frequent dual listing at another transplant center, more living donor liver transplants, and increased average length of the transplant admission.
Geographic differences in deceased donor organ availability contribute to variation in overall death rate of liver transplant patients, shape the clinical practice of transplant, and influence the resources consumed per transplant. Geographic variation in organ access results primarily from rates of listing rather than donation. Our findings highlight the need to restructure organ distribution areas to achieve equal access to deceased donor livers for transplantation in the United States.
This analysis of previously reported trials shows that low tidal volumes, a key component of safer ventilation strategies, confer a protective effect against complications only if the lower volume ...results in a lower pulmonary driving pressure.
Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (V
T
), and higher positive end-expiratory pressures (PEEPs) — collectively termed lung-protective strategies — have been associated with survival benefits in randomized clinical trials involving patients with the acute respiratory distress syndrome (ARDS).
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The different components of lung protection in those strategies, such as lower V
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, lower plateau pressure, and higher PEEP, can all reduce mechanical stresses on the lung, which are thought to induce ventilator-induced lung injury.
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Clinical trials, however, have reported conflicting responses to the manipulation of separate components of lung . . .
OBJECTIVE:--The A1C assay, expressed as the percent of hemoglobin that is glycated, measures chronic glycemia and is widely used to judge the adequacy of diabetes treatment and adjust therapy. ...Day-to-day management is guided by self-monitoring of capillary glucose concentrations (milligrams per deciliter or millimoles per liter). We sought to define the mathematical relationship between A1C and average glucose (AG) levels and determine whether A1C could be expressed and reported as AG in the same units as used in self-monitoring. RESEARCH DESIGN AND METHODS--A total of 507 subjects, including 268 patients with type 1 diabetes, 159 with type 2 diabetes, and 80 nondiabetic subjects from 10 international centers, was included in the analyses. A1C levels obtained at the end of 3 months and measured in a central laboratory were compared with the AG levels during the previous 3 months. AG was calculated by combining weighted results from at least 2 days of continuous glucose monitoring performed four times, with seven-point daily self-monitoring of capillary (fingerstick) glucose performed at least 3 days per week. RESULTS:--Approximately 2,700 glucose values were obtained by each subject during 3 months. Linear regression analysis between the A1C and AG values provided the tightest correlations (AGmg/dl = 28.7 x A1C - 46.7, R² = 0.84, P < 0.0001), allowing calculation of an estimated average glucose (eAG) for A1C values. The linear regression equations did not differ significantly across subgroups based on age, sex, diabetes type, race/ethnicity, or smoking status. CONCLUSIONS:--A1C levels can be expressed as eAG for most patients with type 1 and type 2 diabetes.
Coronary CT angiography (CCTA) in the emergency department reduced the length of hospital stay and allowed more patients to be discharged directly from the emergency department. However, CCTA ...resulted in more downstream testing and higher exposure to radiation.
Treatment of patients with acute chest pain but an inconclusive initial evaluation with the use of biomarkers and electrocardiographic (ECG) testing is often diagnostically challenging and inefficient. The majority of patients with acute coronary syndromes have underlying coronary artery disease.
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Contrast-enhanced coronary computed tomographic angiography (CCTA) has high sensitivity and specificity for the detection of clinically significant coronary artery disease, as compared with invasive coronary angiography, in patients in stable condition with suspected or known coronary artery disease.
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Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICAT-I),
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a blinded observational study involving patients in the emergency department with suspected . . .
Selection and design of individualized treatments remains a key goal in cancer therapeutics; prediction of response and tumor recurrence following a given therapy provides a basis for subsequent ...personalized treatment design. We demonstrate an approach towards this goal with the example of photodynamic therapy (PDT) as the treatment modality and photoacoustic imaging (PAI) as a non-invasive, response and disease recurrence monitor in a murine model of glioblastoma (GBM). PDT is a photochemistry-based, clinically-used technique that consumes oxygen to generate cytotoxic species, thus causing changes in blood oxygen saturation (StO2). We hypothesize that this change in StO2 can be a surrogate marker for predicting treatment efficacy and tumor recurrence. PAI is a technique that can provide a 3D atlas of tumor StO2 by measuring oxygenated and deoxygenated hemoglobin. We demonstrate that tumors responding to PDT undergo approximately 85% change in StO2 by 24-hrs post-therapy while there is no significant change in StO2 values in the non-responding group. Furthermore, the 3D tumor StO2 maps predicted whether a tumor was likely to regrow at a later time point post-therapy. Information on the likelihood of tumor regrowth that normally would have been available only upon actual regrowth (10-30 days post treatment) in a xenograft tumor model, was available within 24-hrs of treatment using PAI, thus making early intervention a possibility. Given the advances and push towards availability of PAI in the clinical settings, the results of this study encourage applicability of PAI as an important step to guide and monitor therapies (e.g. PDT, radiation, anti-angiogenic) involving a change in StO2.
Clinical trials are often designed to compare treatments on the basis of multiple outcomes. For the analysis of the treatment comparison from such a trial, in 1999, the Finkelstein‐Schoenfeld test ...was proposed, which was a generalization of the Gehan‐Wilcoxon test based on pairwise comparison of patients on a primary outcome when possible but otherwise on a secondary outcome. In 2012, Pocock and colleagues suggested an estimate based on this concept, the Win Ratio, which summarized the ratio of the number of patients who fared better versus worse on the experimental arm. However, in 2016, Oakes noted that the Win Ratio could be a function of the distribution of follow‐up times of the trial. The aim of this paper is to propose an approach to representing the Win Ratio graphically in such a way that the effect of time on the estimate would be apparent. In addition, the methods are used to display the contribution of each endpoint to the composite. We apply the methods to clinical trials in cancer, cardiology, and neurology. Software is available named winRatioAnalysis in CRAN.
Longitudinal clinical trials are often designed to compare treatments on the basis of multiple outcomes. For example in the case of cardiac trials, the outcomes of interest include mortality as well ...as cardiac events and hospitalization. For a COVID‐19 trial, the outcomes of interest include mortality, time on ventilator, and time in hospital. Earlier work by these authors proposed a non‐parametric test based on a composite of multiple endpoints referred to as the Finkelstein‐Schoenfeld (FS) test (Finkelstein and Schoenfeld. Stat Med. 1999;18(11):1341–1354.). More recently, an estimate of the treatment comparison based on multiple endpoints (related to the FS test) was proposed (Pocock et al. Eur Heart J. 2011;33(2):176–182.). This estimate, which summarized the ratio of the number of patients who fared better vs worse on the experimental arm was coined the win ratio. The aim of this article is to provide guidance in the design of a trial that will use the FS test or the win ratio. The issues that will be considered are the sample size, sequential monitoring, and adaptive designs.
Nanoscale drug delivery vehicles can facilitate multimodal therapies of cancer by promoting tumour-selective drug release. However, few are effective because cancer cells develop ways to resist and ...evade treatment. Here, we introduce a photoactivable multi-inhibitor nanoliposome (PMIL) that imparts light-induced cytotoxicity in synchrony with a photoinitiated and sustained release of inhibitors that suppress tumour regrowth and treatment escape signalling pathways. The PMIL consists of a nanoliposome doped with a photoactivable chromophore (benzoporphyrin derivative, BPD) in the lipid bilayer, and a nanoparticle containing cabozantinib (XL184)--a multikinase inhibitor--encapsulated inside. Near-infrared tumour irradiation, following intravenous PMIL administration, triggers photodynamic damage of tumour cells and microvessels, and simultaneously initiates release of XL184 inside the tumour. A single PMIL treatment achieves prolonged tumour reduction in two mouse models and suppresses metastatic escape in an orthotopic pancreatic tumour model. The PMIL offers new prospects for cancer therapy by enabling spatiotemporal control of drug release while reducing systemic drug exposure and associated toxicities.
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