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The Toll-like receptor (TLR) adaptor protein MyD88 is integral to airway inflammatory response to microbial- enriched organic dust extract (ODE) exposures. ODE-induced airway neutrophil influx and release of pro-inflammatory cytokines was essentially abrogated in global MyD88-deficient mice, yet these mice demonstrate an increase in airway epithelial cell mucin expression. To further elucidate the role of MyD88-dependent responses specific to lung airway epithelial cells in response to ODE in vivo, the surfactant protein C protein (SPC) Cre+ embryologic expressing airway epithelial cells floxed for MyD88 to disrupt MyD88 signaling were utilized. The inducible club cell secretory protein (CCSP) Cre+, MyD88 floxed, were also developed. Using an established protocol, mice were intranasally instilled with ODE or saline once or daily up to 3weeks. Mice with MyD88-deficient SPC+ lung epithelial cells exhibited decreased neutrophil influx following ODE exposure once and repetitively for 1week without modulation of classic pro-inflammatory mediators including tumor necrosis factor (TNF)-a, interleukin (IL)-6, and neutrophil chemoattractants. This protective response was lost after 3weeks of repetitive exposure. ODE-induced Muc5ac mucin expression at 1 week was also reduced in MyD88-deficient SPC+ cells. Acute ODE-induced IL-33 was reduced in MyD88-deficient SPC+ cells whereas serum IgE levels were increased at one week. In contrast, mice with inducible MyD88-deficient CCSP+ airway epithelial cells demonstrated no significant difference in experimental indices following ODE exposure. Collectively, these findings suggest that MyD88-dependent signaling targeted to all airway epithelial cells plays an important role in mediating neutrophil influx and mucin production in response to acute organic dust exposures. [ABSTRACT FROM AUTHOR]

It is healthy to periodically question things that we have long taken for granted. Randomized clinical trials are the gold standard for evaluating the benefits and harms of interventions, though often fails to provide the practical evidence to inform medical decision-making. A primary reason is failure to recognize the most important questions for treating patients in clinical practice, and using this as the motivation for the design, monitoring, analysis, and reporting of clinical trials. Our most promising opportunity is placing increased interest on questions of a pragmatic origin to match their clinical importance. Improvements to traditional approaches are needed. Standard approaches synthesizing information obtained from separate marginal analysis of each outcome, fail to incorporate associations between outcomes and recognize the cumulative nature of outcomes in individual patients, suffer from competing risk complexities during interpretation of individual outcomes, and since efficacy and safety analyses are often conducted on different populations, generalizability is unclear. The utility of clinical trials can be enhanced by: (i) using outcomes to analyze patients rather than patients to analyze the outcomes, and (ii) incorporating benefit:risk evaluation into standard trial design and conduct, rather than conducted as a post-hoc exercise. Benefit: risk outcomes such as the desirability of outcome ranking (DOOR), can become a standard, prespecified along with efficacy and safety outcomes. Inclusion and analyses of such endpoints provide important information regarding the effects on patients, unable to be obtained by marginal analyses of efficacy and safety. Prespecified procedures to identify subgroups of patients with a positive benefit:risk profile will further advance clinical trial science. [ABSTRACT FROM AUTHOR]

There is an innate desire to conduct research faster and cheaper. The desire is magnified by todays' business and political pressures. Though understandable, such desires can be dangerous threatening our objectivity and ability to reason, resulting in studies with lower integrity, replicability, and applicability. Modern ideas include: conducting observational rather than randomized studies rationalized by the increasing access to real world data and the belief that modeling can replace randomization, using surrogate rather than clinical outcomes, using surrogate rather than clinical diseases, using PP (Per Protocol) analyses instead of ITT (Intention-to-Treat), using assumptions regarding treatment effects in place of data to estimate those effects, and using adaptive designs that promise efficiencies. These trends are often labeled as "innovation." But is this progress...or regress...a fancy way of lowering the usual evidentiary standard and introducing greater uncertainty? Is it time for a market correction for these "products" that are often presented with a degree of commercialism rather than scientific objectivity? Indeed, our traditional approaches are in need in improvements. Rather than compromising on scientific rigor, can we redirect our motivation to find BETTER answers to the most important questions for patients and clinicians? Though often misunderstood, one such movement is pragmatism, the concept of truly getting closer to understanding the effects of interventions as they are experienced by patients and the value of diagnostics in real world practice. I propose that we place increased interest on questions of a pragmatic origin to match their clinical importance and utility. I present ideas for more pragmatic assessments of the effects of interventions and the yield of diagnostics. [ABSTRACT FROM AUTHOR]

Introduction: Parents of infants who undergo therapeutic hypothermia experience emotional challenges that have not been fully characterized. Comprehensive understanding of the parental experience of hypothermia is needed to provide better care to the family of the infant. This study aimed to improve the understanding of the parental emotional experience of therapeutic hypothermia in the Neonatal Intensive Care Unit (NICU).Methods: Semistructured interviews were conducted in a group setting with parents matched into groups according to the severity of the infant's presenting encephalopathy. The interviews were transcribed and coded into principal and additional subthemes.Results: Families of 15 infants, who were between 2 months and 2 years at the time of the interview, participated. Infants had a mean gestational age of 40.0 weeks and 11 (73%) were male. Eleven (73%) were transferred from other hospitals following birth and eight (53%) had seizures. Emotional Experiences was a principal theme and included subthemes of traumatic experiences, Loss of normalcy, and Separation of parent and infant. The birth was frequently described as traumatic with descriptions of chest compressions, excessive blood loss and infants not crying. Trauma was also described in the parental observations of the shivering hypothermic infant. Parents highlighted the loss of normalcy in terms of their expected birth narrative and the loss of the early opportunity to breastfeed and hold their infant. Parents reported that the physical separation imposed by hypothermia adversely impacted their ability to bond with their infant. Healing Experiences was the other principal theme with subthemes identified as Incorporation of parents into NICU care, Reclaiming parenthood and Support from other hypothermia families. Parents reported feeling a connection to their infant when they were involved in medical rounds and when asked to participate in routine care of their infant. Occasionally, parents strongly advocated for their own participation in a particular aspect of their infant's care such as a diaper change and this was perceived as reinforcing their role as parent. Lastly, parents requested greater access to peer support from parents who had experienced therapeutic hypothermia.Conclusion: Parents of infants treated with hypothermia reported the experience of their unexpected adverse delivery and their baby subsequently being treated with therapeutic hypothermia as traumatic. This trauma can be compounded by the pale, still and shivering appearance of their newborn and the delay in bonding as a result of physical separation during hypothermia treatment. Parents described feeling connected to their infant in the context of performing routine care activities and desired greater access to peer support. The themes reported in this study could be used to inform high level NICU care and raise provider awareness of the parent experience. [ABSTRACT FROM AUTHOR]

We discuss using prediction as a flexible and practical approach for monitoring futility in clinical trials with two co-primary endpoints (CPE). This approach is appealing in that it provides quantitative evaluation of potential effect sizes and associated precision, and can be combined with flexible error-spending strategies. We extend prediction of effect size estimates and the construction of predicted intervals to the two CPE case, and illustrate interim futility monitoring of treatment effects using prediction with an example. We also discuss alternative approaches based on the conditional and predictive powers, compare these methods and provide some guidance on the use of prediction for better decision in clinical trials with CPE. [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]

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]

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]

We discuss group-sequential three-arm noninferiority clinical trial designs that include active and placebo controls for evaluating both assay sensitivity and noninferiority. We extend two existing approaches, the fixed margin and fraction approaches, into a group-sequential setting with two decision-making frameworks. We investigate the operating characteristics including power, Type I error rate, maximum, and expected sample sizes, as design factors vary. In addition, we discuss sample size recalculation and its impact on the power and Type I error rate via a simulation study. [ABSTRACT FROM PUBLISHER]

Comparing diagnostic tests on accuracy alone can be inconclusive. For example, a test may have better sensitivity than another test yet worse specificity. Comparing tests on benefit risk may be more conclusive because clinical consequences of diagnostic error are considered. For benefit-risk evaluation, we propose diagnostic yield, the expected distribution of subjects with true positive, false positive, true negative, and false negative test results in a hypothetical population. We construct a table of diagnostic yield that includes the number of false positive subjects experiencing adverse consequences from unnecessary work-up. We then develop a decision theory for evaluating tests. The theory provides additional interpretation to quantities in the diagnostic yield table. It also indicates that the expected utility of a test relative to a perfect test is a weighted accuracy measure, the average of sensitivity and specificity weighted for prevalence and relative importance of false positive and false negative testing errors, also interpretable as the cost-benefit ratio of treating non-diseased and diseased subjects. We propose plots of diagnostic yield, weighted accuracy, and relative net benefit of tests as functions of prevalence or cost-benefit ratio. Concepts are illustrated with hypothetical screening tests for colorectal cancer with test positive subjects being referred to colonoscopy. [ABSTRACT FROM PUBLISHER]

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 authors comment on the study "Antimicrobial Products: Statistical Challenges and Opportunities" published in the current issue of the journal.

Sensitivity and specificity are key aspects in evaluating the performance of diagnostic tests. Accuracy and AUC are commonly used composite measures that incorporate sensitivity and specificity. Average Weighted Accuracy (AWA) is motivated by the need for a statistical measure that compares diagnostic tests from the medical costs and clinical impact point of view, while incorporating the relevant prevalence range of the disease as well as the relative importance of false-positive versus false-negative cases. We illustrate the testing procedures in four different scenarios: (i) one diagnostic test vs. the best random test, (ii) two diagnostic tests from two independent samples, (iii) two diagnostic tests from the same sample, and (iv) more than two diagnostic tests from different or the same samples. The impacts of sample size, prevalence, and relative importance on power and average medical costs/clinical loss are examined through simulation studies. Accuracy has the highest power while AWA provides a consistent criterion in selecting the optimal threshold and better diagnostic tests with direct clinical interpretations. The use of AWA is illustrated on a three-arm clinical trial evaluating three different assays in detecting Neisseria gonorrhoeae and Chlamydia trachomatis in the rectum and pharynx. [ABSTRACT FROM AUTHOR]