Search

Patient management is not based on a single decision. Rather, it is dynamic: based on a sequence of decisions, with therapeutic adjustments made over time. Adjustments are personalized: tailored to individual patients as new information becomes available. However, strategies allowing for such adjustments are infrequently studied. Traditional antibiotic trials are often nonpragmatic, comparing drugs for definitive therapy when drug susceptibilities are known. COMparing Personalized Antibiotic StrategieS (COMPASS) is a trial design that compares strategies consistent with clinical practice. Strategies are decision rules that guide empiric and definitive therapy decisions. Sequential, multiple-assignment, randomized (SMART) COMPASS allows evaluation when there are multiple, definitive therapy options. SMART COMPASS is pragmatic, mirroring clinical, antibiotic-treatment decision-making and addressing the most relevant issue for treating patients: identification of the patient-management strategy that optimizes the ultimate patient outcomes. SMART COMPASS is valuable in the setting of antibiotic resistance, when therapeutic adjustments may be necessary due to resistance. [ABSTRACT FROM AUTHOR]

Background Overcoming β-lactam resistance in pathogens such as Pseudomonas aeruginosa is a major clinical challenge. Rapid molecular diagnostics (RMDs) have the potential to inform selection of empiric therapy in patients infected by P. aeruginosa. Methods In this study, we used a heterogeneous collection of 197 P. aeruginosa that included multidrug-resistant isolates to determine whether 2 representative RMDs (Acuitas Resistome test and VERIGENE gram-negative blood culture test) could identify susceptibility to 2 newer β-lactam/β-lactamase inhibitor (BL-BLI) combinations, ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (TOL/TAZO). Results We found that the studied RMD platforms were able to correctly identify BL-BLI susceptibility (susceptibility sensitivity, 100%; 95% confidence interval [CI], 97%, 100%) for both BLs-BLIs. However, their ability to detect resistance to these BLs-BLIs was lower (resistance sensitivity, 66%; 95% CI, 52%, 78% for TOL/TAZO and 33%; 95% CI, 20%, 49% for CZA). Conclusions The diagnostic platforms studied showed the most potential in scenarios where a resistance gene was detected or in scenarios where a resistance gene was not detected and the prevalence of resistance to TOL/TAZO or CZA is known to be low. Clinicians need to be mindful of the benefits and risks that result from empiric treatment decisions that are based on resistance gene detection in P. aeruginosa, acknowledging that such decisions are impacted by the prevalence of resistance, which varies temporally and geographically. [ABSTRACT FROM AUTHOR]

Investigators can choose to analyze different patient populations in clinical trials. The different analysis populations answer different types of research questions, estimate different quantities, and evaluate the robustness of the trial results. Various analysis populations have different strengths and weaknesses depending on the type of question being addressed and the potential for bias from the selection of various groups of trial participants. We discuss analysis populations in the context of anti-infective clinical trials. [ABSTRACT FROM AUTHOR]

I thank and commend Dr. Gibson on his thoughtful and thorough discussion regarding the role of I p i -values in evaluating evidence (Gibson [8]). One could replace hypothesis testing and I p i -values with confidence interval estimation. Observed I p i -values should be reported rather than, for example, I p i < 0.05 or I p i > 0.05. Although a I p i -value of 0.06 and 0.86 each result in a failure to reject a null hypothesis when testing at 0.05, they may be interpreted quite differently in light of other evidence such as results for other outcomes. [Extracted from the article]

Response-adaptive randomization (RAR) has recently gained popularity in clinical trials. The intent is noble: minimize the number of participants randomized to inferior treatments and increase the amount of information about better treatments. Unfortunately, RAR causes many problems, including (1) bias from temporal trends, (2) inefficiency in treatment effect estimation, (3) volatility in sample-size distributions that can cause a nontrivial proportion of trials to assign more patients to an inferior arm, (4) difficulty of validly analyzing results, and (5) the potential for selection bias and other issues inherent to being unblinded to ongoing results. The problems of RAR are most acute in the very setting for which RAR has been proposed, namely long-duration “platform” trials and infectious disease settings where temporal trends are ubiquitous. Response-adaptive randomization can eliminate the benefits that randomization, the most powerful tool in clinical trials, provides. Use of RAR is discouraged. [ABSTRACT FROM AUTHOR]

We review the design, data monitoring, and analyses of clinical trials with co-primary endpoints. Recently developed methods for fixed-sample and group-sequential settings are described. Practical considerations are discussed, and guidance for the application of these methods is provided. [ABSTRACT FROM PUBLISHER]

Purpose: Whilst much is known on the multiple variables associated with a poor prognosis in soft tissue sarcomas, little evidence exists on the impact of fungation at the time of presentation. The aim of this study was to assess the impact of fungation on overall and disease free survival in soft tissue sarcomas.Methods: The study comprised a retrospective review of all patients presenting with a soft tissue sarcoma between 1996 and 2014 managed at a single institution. Over the 18-year study period, 2661 patients were diagnosed with a STS. Eighty-six patients (3.2%) presented with a fungating tumour.Results: The five year survival for all patients with a fungating sarcoma was 15.5% (95% confidence interval: 4.6-26.4), which compared to 65.6% (95% confidence interval 63.2-67.8%) (p = 0.0001) for non-fungating tumours. The incidence of metastasis at presentation in the non-fungating tumour group was 11.3% of patients, compared to 20.0% in those with a fungating tumour (p = 0.0113). Factors associated with a poor prognosis in the fungating group included size, grade and tumour-type, patient age, tumour depth, and metastases at presentation. As an independent risk factor, tumour fungation was associated with a poor prognosis when compared to non-fungating tumours. The rate of limb sacrifice as primary treatment was higher in the fungating group (23% versus 73%). In spite of this, the incidence of local recurrence was higher in the fungating group (20% versus 16.5%).Conclusions: Fungation is associated with a poor prognosis with a high incidence of metastases at presentation and a high rate of local recurrence. As an independent variable, fungation confers a poor prognosis when compared to non-fungation in soft tissue sarcomas. [ABSTRACT FROM AUTHOR]

The Ediacara Biota represents the oldest fossil evidence for the appearance of animals but linking these taxa to specific clades has proved challenging. Dickinsonia is an abundant, apparently bilaterally symmetrical Ediacara fossil with uncertain affinities. We identified and measured key morphological features of over 900 specimens of Dickinsonia costata from the Ediacara Member, South Australia to characterize patterns in growth and morphology. Here we show that development in Dickinsonia costata was surprisingly highly regulated to maintain an ovoid shape via terminal addition and the predictable expansion of modules. This result, along with other characters found in Dickinsonia suggests that it does not belong within known animal groups, but that it utilized some of the developmental gene networks of bilaterians, a result predicted by gene sequencing of basal metazoans but previously unidentified in the fossil record. Dickinsonia thus represents an extinct clade located between sponges and the last common ancestor of Protostomes and Deuterostomes, and likely belongs within the Eumetazoa. [ABSTRACT FROM AUTHOR]

Carbapenem-resistant Enterobacteriaceae (CRE) are an emerging and troublesome group of pathogens. Risk factor studies, outcome studies, and randomized trials are three types of studies conducted to answer different types of questions regarding CRE. These studies pose different types of challenges. We discuss issues in the design and analyses of case-control studies, cohort studies, and randomized trials aimed to address various research questions regarding CRE. [ABSTRACT FROM AUTHOR]

Decreased efficacy of antibiotics due to resistant pathogens has created a need for the development of more effective medical interventions. Despite the increasing prevalence of pathogens resistant to one or more drugs, identifying and enrolling participants into clinical trials that evaluate new interventions for the treatment of some diseases can be challenging given the low prevalence of disease in which there are no effective treatments. Thus researchers might be tempted to consider externally-controlled trials that may allow for a reduction of the necessary number of prospectively-identified trial participants, thus easing recruitment burden and resulting in more timely trial completion relative to randomized controlled trials. We discuss advantages and disadvantages in externally controlled trials and review requirements for a valid externally-controlled trial. As ECTs are subject to the bias of observational studies, the criteria for a valid ECT should be carefully evaluated before these designs are implemented. Given considerable variation in study results in the resistant pathogen setting, the lack of information on important patient characteristics that may confound estimates of treatment effects, as well as the improvements in medical practice and evolving antibiotic resistance, the use of ECTs in the resistant pathogen setting, is not recommended. ECTs should be should be limited to specific situations where superiority of the effect of the new intervention is dramatic, the usual course of the disease highly predictable, the endpoints are objective (e. g., all-cause mortality) and the impact of baseline and treatment variables on outcomes is well characterized. Given that the resistant pathogen setting does not satisfy these criteria, we conclude that that randomized clinical trials are needed to evaluate new treatments for resistant pathogens. Innovative approaches to trial design that may ease recruitment burden while evaluating the benefits and harms of new treatments are being developed and utilized. [ABSTRACT FROM AUTHOR]

In the future, clinical trials will have an increased emphasis on pragmatism, providing a practical description of the effects of new treatments in realistic clinical settings. Accomplishing pragmatism requires better summaries of the totality of the evidence in ways that clinical trials consumers—patients, physicians, insurers—find transparent and allow for informed benefit:risk decision-making. The current approach to the analysis of clinical trials is to analyze efficacy and safety separately and then combine these analyses into a benefit:risk assessment. Many assume that this will effectively describe the impact on patients. But this approach is suboptimal for evaluating the totality of effects on patients. We discuss methods for benefit:risk assessment that have greater pragmatism than methods that separately analyze efficacy and safety. These include the concepts ofwithin-patient analysesand composite benefit:risk endpoints with a goal of understanding how to analyze one patient before trying to figure out how to analyze many. We discuss thedesirability of outcome ranking(DOOR) and introduce thepartial credit strategyusing an example in a clinical trial evaluating the effects of a new antibiotic. As part of the example, we introduce a strategy to engage patients as a resource to inform benefit:risk analyses consistent with the goal of measuring and weighing outcomes that are most important from the patient's perspective. We describe a broad vision for the future of clinical trials consistent with increased pragmatism. Greater focus on using endpoints to analyze patients rather than patients to analyze endpoints particularly in late-phase/stage clinical trials is an important part of this vision. [ABSTRACT FROM PUBLISHER]

The medical community needs systematic and pragmatic approaches for evaluating the benefit-risk trade-offs of diagnostics that assist in medical decision making. Benefit-Risk Evaluation of Diagnostics: A Framework (BED-FRAME) is a strategy for pragmatic evaluation of diagnostics designed to supplement traditional approaches. BED-FRAME evaluates diagnostic yield and addresses 2 key issues: (1) that diagnostic yield depends on prevalence, and (2) that different diagnostic errors carry different clinical consequences. As such, evaluating and comparing diagnostics depends on prevalence and the relative importance of potential errors. BED-FRAME provides a tool for communicating the expected clinical impact of diagnostic application and the expected tradeoffs of diagnostic alternatives. BED-FRAME is a useful fundamental supplement to the standard analysis of diagnostic studies that will aid in clinical decision making. [ABSTRACT FROM AUTHOR]