No evidence that arousal affects reactivated memories.

Memory for inherently neutral elements of emotional events is often enhanced on delayed tests - an effect that has been attributed to noradrenergic arousal. Reactivation of a memory is thought to return its corresponding neural ensemble to a state that is similar to when it was originally experienced. Therefore, we hypothesized that neutral elements of memories, too, can be enhanced through reactivation concurrent with heightened arousal. Participants (n = 94) visited the lab for three sessions. During the first session, they encoded 120 neutral memories consisting of an object presented in unique context images. In session two, the 80 objects were reactivated by presenting their corresponding context images, 40 of which were immediately followed by an arousal-inducing shock. Finally, recognition memory for all objects was tested. It was found that memory for reactivated objects was enhanced, but even though the shocks elicited elevations in arousal as indexed by skin conductance, there was no difference between memory of objects reactivated with and without heightened arousal. We thus conclude that arousal, when isolated from other cognitive and affective variables that might impact memory, has no enhancing effect on reactivated memories.

Reliability and Accuracy of the Pediatric Swiss Emergency Triage Scale-the SETSped Study.

BACKGROUND AND IMPORTANCE: The Swiss Emergency Triage Scale (SETS) is an adult triage tool used in several emergency departments. It has been recently adapted to the pediatric population but, before advocating for its use, performance assessment of this tool is needed. OBJECTIVES: The purpose of this study was to assess the reliability and the accuracy of the pediatric version of the SETS for the triage of pediatric patients. DESIGN, SETTING, AND PARTICIPANTS: This study was a cross-sectional study among a sample of emergency triage nurses (ETNs) exposed to 17 clinical scenarios using a computerized simulator. OUTCOME MEASURES AND ANALYSIS: The primary outcome was the reliability of the triage level performed by the ETNs. It was assessed using an intraclass correlation coefficient.Secondary outcomes included accuracy of triage compared with expert-based triage levels and factors associated with accurate triage. MAIN RESULTS: Eighteen ETNs participated in the study and completed the evaluation of all scenarios, for a total of 306 triage decisions. The intraclass correlation coefficient was 0.80 (95% confidence interval, 0.69-0.91), with an agreement by scenario ranging from 61.1% to 100%. The overall accuracy was 85.8%, and nurses were more likely to undertriage (16.0%) than to overtriage (4.3%). No factor for accurate triage was identified. CONCLUSIONS: This simulator-based study showed that the SETS is reliable and accurate among a pediatric population. Future research is needed to confirm these results, compare this triage scale head-to-head with other recognized international tools, and study the SETSped in real-life setting.

Assessing IRS performance in a gender-integrated vector control programme on Bioko Island, Equatorial Guinea, 2010-2021.

BACKGROUND: Indoor residual spraying (IRS) is a common vector control strategy in countries with high malaria burden. Historically, social norms have prevented women from working in IRS programmes. The Bioko Island Malaria Elimination Project has actively sought to reduce gender inequality in malaria control operations for many years by promoting women's participation in IRS. METHODS: This study investigated the progress of female engagement and compared spray productivity by gender from 2010 to 2021, using inferential tests and multivariable regression. Spray productivity was measured by rooms sprayed by spray operator per day (RSOD), houses sprayed by spray operator per day (HSOD), and the daily productivity ratio (DPR), defined as the ratio of RSOD to HSOD, which standardized productivity by house size. RESULTS: The percentage of women participating in IRS has increased over time. The difference in DPR comparing male and female spray operators was only statistically significant (p < 0.05) for two rounds, where the value was higher for women compared to men. Regression analyses showed marginal, significant differences in DPR between men and women, but beta coefficients were extremely small and thus not indicative of a measurable effect of gender on operational performance. CONCLUSIONS: The quantitative analyses of spray productivity are counter to stigmatizing beliefs that women are less capable than male counterparts during IRS spray rounds. The findings from this research support the participation of women in IRS campaigns, and a renewed effort to implement equitable policies and practices that intentionally engage women in vector control activities.

Context reexposure to bolster contextual dependency of emotional episodic memory.

Contextual overgeneralization of emotional memory is a core aspect of anxiety disorders. Identifying methods to enhance contextual dependency of emotional memory is therefore of significant clinical interest. Animal research points to a promising approach: reexposure to the context in which fear is acquired reduces generalization to other contexts. However, the exact conditions for this effect are unknown, complicating translation to effective interventions. Most notably, exposure to a context that resembles-but is not identical to-the learning context may diminish contextual dependency of memory by integration of additional contextual cues. Here, we therefore assessed in a large-scale study (N = 180) whether context reexposure enhances contextual dependency of emotional episodic memory whereas exposure to a similar context impairs it. We also tested whether relatively strong memory retrieval during context (re)exposure amplifies these effects. We replicated prior research showing that correct recognition depends on context and contextual dependency is lower for emotional than neutral memories. However, exposure to the encoding context or a similar context did not affect contextual dependency of memory, and retrieval strength did not interact with such effects. Thorough insight into factors underlying the effects of context (re)exposure on contextual dependency seems key to eventually attain a memory recontextualization intervention.

Innovative three-dimensional models for understanding mechanisms underlying lung diseases: powerful tools for translational research.

Chronic lung diseases result from alteration and/or destruction of lung tissue, inevitably causing decreased breathing capacity and quality of life for patients. While animal models have paved the way for our understanding of pathobiology and the development of therapeutic strategies for disease management, their translational capacity is limited. There is, therefore, a well-recognised need for innovative in vitro models to reflect chronic lung diseases, which will facilitate mechanism investigation and the advancement of new treatment strategies. In the last decades, lungs have been modelled in healthy and diseased conditions using precision-cut lung slices, organoids, extracellular matrix-derived hydrogels and lung-on-chip systems. These three-dimensional models together provide a wide spectrum of applicability and mimicry of the lung microenvironment. While each system has its own limitations, their advantages over traditional two-dimensional culture systems, or even over animal models, increases the value of in vitro models. Generating new and advanced models with increased translational capacity will not only benefit our understanding of the pathobiology of lung diseases but should also shorten the timelines required for discovery and generation of new therapeutics. This article summarises and provides an outline of the European Respiratory Society research seminar "Innovative 3D models for understanding mechanisms underlying lung diseases: powerful tools for translational research", held in Lisbon, Portugal, in April 2022. Current in vitro models developed for recapitulating healthy and diseased lungs are outlined and discussed with respect to the challenges associated with them, efforts to develop best practices for model generation, characterisation and utilisation of models and state-of-the-art translational potential.

Integration of immune cells in organs-on-chips: a tutorial.

Viral and bacterial infections continue to pose significant challenges for numerous individuals globally. To develop novel therapies to combat infections, more insight into the actions of the human innate and adaptive immune system during infection is necessary. Human in vitro models, such as organs-on-chip (OOC) models, have proven to be a valuable addition to the tissue modeling toolbox. The incorporation of an immune component is needed to bring OOC models to the next level and enable them to mimic complex biological responses. The immune system affects many (patho)physiological processes in the human body, such as those taking place during an infection. This tutorial review introduces the reader to the building blocks of an OOC model of acute infection to investigate recruitment of circulating immune cells into the infected tissue. The multi-step extravasation cascade in vivo is described, followed by an in-depth guide on how to model this process on a chip. Next to chip design, creation of a chemotactic gradient and incorporation of endothelial, epithelial, and immune cells, the review focuses on the hydrogel extracellular matrix (ECM) to accurately model the interstitial space through which extravasated immune cells migrate towards the site of infection. Overall, this tutorial review is a practical guide for developing an OOC model of immune cell migration from the blood into the interstitial space during infection.

Immune cell extravasation in an organ-on-chip to model lung inflammation.

Acute respiratory distress syndrome (ARDS) is a severe lung condition with high mortality and various causes, including lung infection. No specific treatment is currently available and more research aimed at better understanding the pathophysiology of ARDS is needed. Most lung-on-chip models that aim at mimicking the air-blood barrier are designed with a horizontal barrier through which immune cells can migrate vertically, making it challenging to visualize and investigate their migration. In addition, these models often lack a barrier of natural protein-derived extracellular matrix (ECM) suitable for live cell imaging to investigate ECM-dependent migration of immune cells as seen in ARDS. This study reports a novel inflammation-on-chip model with live cell imaging of immune cell extravasation and migration during lung inflammation. The three-channel perfusable inflammation-on-chip system mimics the lung endothelial barrier, the ECM environment and the (inflamed) lung epithelial barrier. A chemotactic gradient was established across the ECM hydrogel, leading to the migration of immune cells through the endothelial barrier. We found that immune cell extravasation depends on the presence of an endothelial barrier, on the ECM density and stiffness, and on the flow profile. In particular, bidirectional flow, broadly used in association with rocking platforms, was found to significantly delay extravasation of immune cells in contrast to unidirectional flow. Extravasation was increased in the presence of lung epithelial tissue. This model is currently used to study inflammation-induced immune cell migration but can be used to study infection-induced immune cell migration under different conditions, such as ECM composition, density and stiffness, type of infectious agents used, and the presence of organ-specific cell types.

Lung-on-a-Chip Models of the Lung Parenchyma.

Since the publication of the first lung-on-a-chip in 2010, research has made tremendous progress in mimicking the cellular environment of healthy and diseased alveoli. As the first lung-on-a-chip products have recently reached the market, innovative solutions to even better mimic the alveolar barrier are paving the way for the next generation lung-on-chips. The original polymeric membranes made of PDMS are being replaced by hydrogel membranes made of proteins from the lung extracellular matrix, whose chemical and physical properties exceed those of the original membranes. Other aspects of the alveolar environment are replicated, such as the size of the alveoli, their three-dimensional structure, and their arrangement. By tuning the properties of this environment, the phenotype of alveolar cells can be tuned, and the functions of the air-blood barrier can be reproduced, allowing complex biological processes to be mimicked. Lung-on-a-chip technologies also provide the possibility of obtaining biological information that was not possible with conventional in vitro systems. Pulmonary edema leaking through a damaged alveolar barrier and barrier stiffening due to excessive accumulation of extracellular matrix proteins can now be reproduced. Provided that the challenges of this young technology are overcome, there is no doubt that many application areas will benefit greatly.

Autologous tumor lysate-loaded dendritic cell vaccination in glioblastoma: What happened to the evidence?

In patients with glioblastoma, the "DCVax-L" trial reported a survival benefit with the addition of autologous tumor lysate-loaded denditric cell vaccination to the standard-of-care (SoC) in patients with glioblastoma. The trial presented as a phase 3 externally controlled trial is showing an improvement in overall survival (OS) in patients receiving the vaccine therapy as compared to externally controlled patients, both in the newly diagnosed setting (median OS = 19.3 months versus 16.5 months; HR = 0.80; 98% CI, 0.00-0.94; P = 0.002) and in the recurrent setting (median OS = 13.2 months versus 7.8 months; HR = 0.58; 98% CI, 0.00-0.76; P < 0.001). Interestingly, the original endpoint, progression-free survival (PFS), was not improved by the experimental therapy. While we praise efforts to improve outcomes in a population representing a true unmet need, the trial's design, methods and report raise several issues undermining the ability to derive meaningful conclusion. These limitations are mainly driven by multiple changes occurring years after the trial ended. External controls were used in a trial originally randomizing patients, the primary endpoint was modified (OS instead of PFS), a new study population (recurrent glioblastoma) was added, and unplanned analyses were conducted, among several other changes. Additionally, due to inclusion criteria, the external controls likely selected patients with less favorable outcome as compared with patients enrolled in the trial, potentially biasing the reported survival benefit. In the absence of data sharing, these shortcomings will not be clarified. Dendritic cell vaccination remains a promising approach for GBM. It is therefore disappointing that due to key methodological limitations, the DCVax-L trial ultimately failed to provide sound conclusions about the potential efficacy of such approach for patients with glioblastoma.

Identifying individual, household and environmental risk factors for malaria infection on Bioko Island to inform interventions.

BACKGROUND: Since 2004, malaria transmission on Bioko Island has declined significantly as a result of the scaling-up of control interventions. The aim of eliminating malaria from the Island remains elusive, however, underscoring the need to adapt control to the local context. Understanding the factors driving the risk of malaria infection is critical to inform optimal suits of interventions in this adaptive approach. METHODS: This study used individual and household-level data from the 2015 and 2018 annual malaria indicator surveys on Bioko Island, as well as remotely-sensed environmental data in multilevel logistic regression models to quantify the odds of malaria infection. The analyses were stratified by urban and rural settings and by survey year. RESULTS: Malaria prevalence was higher in 10-14-year-old children and similar between female and male individuals. After adjusting for demographic factors and other covariates, many of the variables investigated showed no significant association with malaria infection. The factor most strongly associated was history of travel to mainland Equatorial Guinea (mEG), which increased the odds significantly both in urban and rural settings (people who travelled had 4 times the odds of infection). Sleeping under a long-lasting insecticidal net decreased significantly the odds of malaria across urban and rural settings and survey years (net users had around 30% less odds of infection), highlighting their contribution to malaria control on the Island. Improved housing conditions indicated some protection, though this was not consistent across settings and survey year. CONCLUSIONS: Malaria risk on Bioko Island is heterogeneous and determined by a combination of factors interacting with local mosquito ecology. These interactions grant further investigation in order to better adapt control according to need. The single most important risk factor identified was travel to mEG, in line with previous investigations, and represents a great challenge for the success of malaria control on the Island.

Effects of biomechanical and biochemical stimuli on angio- and vasculogenesis in a complex microvasculature-on-chip.

The endothelium of blood vessels is a vital organ that reacts differently to subtle changes in stiffness and mechanical forces exerted on its environment (extracellular matrix (ECM)). Upon alteration of these biomechanical cues, endothelial cells initiate signaling pathways that govern vascular remodeling. The emerging organs-on-chip technologies allow the mimicking of complex microvasculature networks, identifying the combined or singular effects of these biomechanical or biochemical stimuli. Here, we present a microvasculature-on-chip model to investigate the singular effect of ECM stiffness and mechanical cyclic stretch on vascular development. Following two different approaches for vascular growth, the effect of ECM stiffness on sprouting angiogenesis and the effect of cyclic stretch on endothelial vasculogenesis are studied. Our results indicate that ECM hydrogel stiffness controls the size of the patterned vasculature and the density of sprouting angiogenesis. RNA sequencing shows that the cellular response to stretching is characterized by the upregulation of certain genes such as ANGPTL4+5, PDE1A, and PLEC.

A multiplex inhalation platform to model in situ like aerosol delivery in a breathing lung-on-chip.

Prolonged exposure to environmental respirable toxicants can lead to the development and worsening of severe respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and fibrosis. The limited number of FDA-approved inhaled drugs for these serious lung conditions has led to a shift from in vivo towards the use of alternative in vitro human-relevant models to better predict the toxicity of inhaled particles in preclinical research. While there are several inhalation exposure models for the upper airways, the fragile and dynamic nature of the alveolar microenvironment has limited the development of reproducible exposure models for the distal lung. Here, we present a mechanistic approach using a new generation of exposure systems, the Cloud α AX12. This novel in vitro inhalation tool consists of a cloud-based exposure chamber (VITROCELL) that integrates the breathing AXLung-on-chip system (AlveoliX). The ultrathin and porous membrane of the AX12 plate was used to create a complex multicellular model that enables key physiological culture conditions: the air-liquid interface (ALI) and the three-dimensional cyclic stretch (CS). Human-relevant cellular models were established for a) the distal alveolar-capillary interface using primary cell-derived immortalized alveolar epithelial cells (AXiAECs), macrophages (THP-1) and endothelial (HLMVEC) cells, and b) the upper-airways using Calu3 cells. Primary human alveolar epithelial cells (AXhAEpCs) were used to validate the toxicity results obtained from the immortalized cell lines. To mimic in vivo relevant aerosol exposures with the Cloud α AX12, three different models were established using: a) titanium dioxide (TiO2) and zinc oxide nanoparticles b) polyhexamethylene guanidine a toxic chemical and c) an anti-inflammatory inhaled corticosteroid, fluticasone propionate (FL). Our results suggest an important synergistic effect on the air-blood barrier sensitivity, cytotoxicity and inflammation, when air-liquid interface and cyclic stretch culture conditions are combined. To the best of our knowledge, this is the first time that an in vitro inhalation exposure system for the distal lung has been described with a breathing lung-on-chip technology. The Cloud α AX12 model thus represents a state-of-the-art pre-clinical tool to study inhalation toxicity risks, drug safety and efficacy.

Design, power, and alpha levels in randomized phase II oncology trials.

BACKGROUND: The statistical plan of a phase II trial should balance minimizing the premature termination of potentially beneficial therapies (i.e. false negatives) and the further, costly testing of ineffective drugs (i.e. false positives). We sought to examine the methodology, reporting, and bias in the interpretation of outcomes of phase II oncology trials in recent years. MATERIALS AND METHODS: In a retrospective cross-sectional analysis, we reviewed all full-length articles published on PubMed from 1 January 2021 to 20 June 2022. We searched for data regarding the sample size calculation (number, α value, power, and expected effect size), the primary and secondary outcomes and results, and the authors' conclusion of the study. RESULTS: About 5.4% of studies (n = 10) used a statistical power that was inferior to 80%, and 16.7% (n = 34) did not indicate the level of power for the sample size calculation. Approximately 16.7% (n = 31) of studies used a one-sided α level of ≤0.025; 17.7% (n = 33) of studies used a predefined threshold (no comparator effect size or difference between groups) to determine the sample size for efficacy. The percentage of studies with a positive authors' conclusion but not meeting the primary endpoint, or the endpoint was equivocal, was 27.4% (n = 51). CONCLUSION: Many randomized phase II studies in oncology failed to report essential data for determining sample size calculations, many did not actually use a comparator to determine efficacy even though the studies were randomized, and many had positive conclusions even though the results were indeterminate or the primary endpoint was not met.

Preferential MGMT hypermethylation in SDH-deficient wild-type GIST.

AIMS: Wild-type gastrointestinal stromal tumours (wtGIST) are frequently caused by inherited pathogenic variants, or somatic alterations in the succinate dehydrogenase subunit genes (SDHx). Succinate dehydrogenase is a key enzyme in the citric acid cycle. SDH deficiency caused by SDHx inactivation leads to an accumulation of succinate, which inhibits DNA and histone demethylase enzymes, resulting in global hypermethylation. Epigenetic silencing of the DNA repair gene MGMT has proven utility as a positive predictor of the therapeutic efficacy of the alklyating drug temozolomide (TMZ) in tumours such as glioblastoma multiforme. The aim of this study was to examine MGMT promoter methylation status in a large cohort of GIST. METHODS: MGMT methylation analysis was performed on 65 tumour samples including 47 wtGIST (33 SDH-deficient wtGIST and 11 SDH preserved wtGIST) and 21 tyrosine kinase (TK) mutant GIST. RESULTS: MGMT promoter methylation was detected in 8 cases of SDH-deficient (dSDH) GIST but in none of the 14 SDH preserved wild-type GIST or 21 TK mutant GIST samples analysed. Mean MGMT methylation was significantly higher (p 0.0449) and MGMT expression significantly lower (p<0.0001) in dSDH wtGIST compared with TK mutant or SDH preserved GIST. No correlation was identified between SDHx subunit gene mutations or SDHC epimutation status and mean MGMT methylation levels. CONCLUSION: MGMT promoter hypermethylation occurs exclusively in a subset of dSDH wtGIST. Data from this study support testing of tumour MGMT promoter methylation in patients with dSDH wtGIST to identify those patients who may benefit from most from TMZ therapy.

Threat learning impairs subsequent associative inference.

Despite it being widely acknowledged that the most important function of memory is to facilitate the prediction of significant events in a complex world, no studies to date have investigated how our ability to infer associations across distinct but overlapping experiences is affected by the inclusion of threat memories. To address this question, participants (n = 35) encoded neutral predictive associations (A → B). The following day these memories were reactivated by pairing B with a new aversive or neutral outcome (B → CTHREAT/NEUTRAL) while pupil dilation was measured as an index of emotional arousal. Then, again 1 day later, the accuracy of indirect associations (A → C?) was tested. Associative inferences involving a threat learning memory were impaired whereas the initial memories were retroactively strengthened, but these effects were not moderated by pupil dilation at encoding. These results imply that a healthy memory system may compartmentalize episodic information of threat, and so hinders its recall when cued only indirectly. Malfunctioning of this process may cause maladaptive linkage of negative events to distant and benign memories, and thereby contribute to the development of clinical intrusions and anxiety.

Central line-associated bloodstream infections at the multidisciplinary intensive care unit of Universitas Academic Hospital, Bloemfontein, South Africa.

Background: Central line-associated bloodstream infections (CLABSIs) are frequently encountered device-related healthcare-associated infections in critically ill patients, causing substantial morbidity, mortality and prolonged hospitalisation. Objectives: To determine the incidence of CLABSI, median catheter dwell-time prior to developing CLABSI, as well as the causative microorganisms of CLABSI among patients admitted to the multidisciplinary intensive care unit (MICU) at Universitas Academic Hospital, Bloemfontein. Methods: We conducted a retrospective review of medical and laboratory records of all MICU patients who had a central line placed between January and December 2018. Results: A total of 377 patients were admitted to the MICU in 2018, of which 182 met the inclusion criteria for the present study. From the cohort of 182 patients, 16.5% (n=30) of patients presented with 32 CLABSI episodes, with two patients having had two independent episodes each. A total of 1 215 central line days were recorded, yielding a CLABSI rate of 26.3/1 000-line days. Laboratory analysis identified microorganisms in 38 blood cultures, with Gram-negative organisms (55.3%; n=21) being predominant over Gram-positive organisms (39.5%; n=15) and fungi (5.3%; n=2). Conclusion: The incidence of CLABSI at the MICU at Universitas Academic Hospital is high. Urgent intervention with strict compliance to prevention bundles is required to reduce the high incidence of CLABSI.

A New Immortalized Human Alveolar Epithelial Cell Model to Study Lung Injury and Toxicity on a Breathing Lung-On-Chip System.

The evaluation of inhalation toxicity, drug safety and efficacy assessment, as well as the investigation of complex disease pathomechanisms, are increasingly relying on in vitro lung models. This is due to the progressive shift towards human-based systems for more predictive and translational research. While several cellular models are currently available for the upper airways, modelling the distal alveolar region poses several constraints that make the standardization of reliable alveolar in vitro models relatively difficult. In this work, we present a new and reproducible alveolar in vitro model, that combines a human derived immortalized alveolar epithelial cell line (AXiAEC) and organ-on-chip technology mimicking the lung alveolar biophysical environment (AXlung-on-chip). The latter mimics key features of the in vivo alveolar milieu: breathing-like 3D cyclic stretch (10% linear strain, 0.2 Hz frequency) and an ultrathin, porous and elastic membrane. AXiAECs cultured on-chip were characterized for their alveolar epithelial cell markers by gene and protein expression. Cell barrier properties were examined by TER (Transbarrier Electrical Resistance) measurement and tight junction formation. To establish a physiological model for the distal lung, AXiAECs were cultured for long-term at air-liquid interface (ALI) on-chip. To this end, different stages of alveolar damage including inflammation (via exposure to bacterial lipopolysaccharide) and the response to a profibrotic mediator (via exposure to Transforming growth factor ß1) were analyzed. In addition, the expression of relevant host cell factors involved in SARS-CoV-2 infection was investigated to evaluate its potential application for COVID-19 studies. This study shows that AXiAECs cultured on the AXlung-on-chip exhibit an enhanced in vivo-like alveolar character which is reflected into: 1) Alveolar type 1 (AT1) and 2 (AT2) cell specific phenotypes, 2) tight barrier formation (with TER above 1,000 Ω cm2) and 3) reproducible long-term preservation of alveolar characteristics in nearly physiological conditions (co-culture, breathing, ALI). To the best of our knowledge, this is the first time that a primary derived alveolar epithelial cell line on-chip representing both AT1 and AT2 characteristics is reported. This distal lung model thereby represents a valuable in vitro tool to study inhalation toxicity, test safety and efficacy of drug compounds and characterization of xenobiotics.

Duration of treatment in oncology clinical trials: does the duration change when the same drug moves from the experimental arm to the control arm?

BACKGROUND: When a new drug comes to the market, the incentive for the sponsoring company is to maximize the treatment duration in order for the patient to reap the full therapeutic benefit of the product and achieve a positive trial result. We sought to enumerate instances when an already-approved oncology drug was used as a comparator for a newer drug seeking approval and compare the duration of treatment when it is used in the intervention arm to when it is used as a comparator. PATIENTS AND METHODS: In a cross-sectional analysis, we searched drug approval announcements for advanced, metastatic, or unresectable cancers between 2009 and 2020. We included studies reporting on an approved drug and studies reporting on when the same drug was used as a comparator for other drugs seeking Food and Drug Administration (FDA) approval. We examined median progression-free survival and duration of treatment for when the drug was initially approved and for when the drug was used as a comparator for other drugs that were seeking approval. RESULTS: Of the 23 instances when an approved drug was later used as a comparator against a newer drug seeking FDA approval, we found 11 instances (47.8%) where the drug, when used as a comparator arm, had a shorter duration of treatment than when it was used in the intervention arm. The median duration of treatment in the study initially testing the drug was 6.0 months (range: 2.2-12.7 months), whereas the median duration of treatment when the same drug was used as a comparator was 4.9 months (range: 1.7-12.0 months). CONCLUSIONS: These results suggest that there is bias in how long a patient receives a given therapy, and this bias favors the newer therapy. Clinical trialists should seek to utilize methodology that reduces bias so that the relative efficacy of newer drugs can be objectively assessed.