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Glutamate receptors within the mammalian CNS are of prime interest since they are the major receptor type used. Invertebrate models served and still do a vital role in characterizing glutamate receptor function. Considering that Drosophila melanogaster is a true model organism with a known genome and successful rapid induction of mutations for various studies, it is important to understand the pharmacological and physiological function within this model synaptic neuromuscular preparation. There are 5 glutamate postsynaptic receptors subtypes at the Drosophila NMJ and they were deemed to be most similar to the kainate/AMPA class for vertebrates by sequence data. This lead to the receptors being labeled kainate type without pharmacological testing. We show the responses are primarily of a quisqualate subtype and not a kainate or aAMPA subtype since the muscle is not depolarized by kainate or AMPA at 1 mM. In fact, kainate might block the glutamate receptors since the excitatory postsynaptic potential (EPSP) is reduced in the presence of kainate (40% for 1 mM and 500uM but about 20% for 100uM). The reduction in the EPSP amplitude occurred without any significant change in resting membrane potential; thus, kainate did not depolarize the muscle as observed for application of glutamate or quisqualate. (NSF-IBN-0131459, RLC, KV; REU-NSF, DB)

Investigating the function of individual synapses is essential to understanding the mechanisms that influence the efficacy of chemical synaptic transmission. The known simplicity of the synaptic structure at the crayfish neuromuscular junction (NMJ) and its quantal nature of release allow an assessment of discrete synapses within the motor nerve terminals. Our goal is to investigate the effect of the stimulation frequency on the number of active release sites (n) and the probability of release (p) at those active sites. Because methods based on direct counts often provide unstable joint estimates of (n) and (p) and underestimate n, we base our analysis on mixture modeling. In particular, the mixture modeling approach is used to estimate (n) and (p) for stimulation frequencies of 1Hz, 2Hz, and 3Hz. Our results indicate that as the stimulation frequency increases, new sites are recruited (thus increasing n) and the probability of release (p) increases. The increase in (n) and (p) are not as well reflected by estimates obtained by direct counting procedures and binomial distributions. Funded by NSF grants IBN-9808631 (RLC), NSF-ILI-DUE 9850907 (RLC), NSF-DMS-9971954 (KV), and NSF-IBN-0131459 (RLC, AJS, KV).

The article presents a study which investigated the quantal signatures exhibited by neurotransmitter release at synapses and synaptic active zones (AZs). The neuromuscular junctions (NMJs) of the opener muscle in crayfish were used. Results show that quantal responses were variable, and no quantal signatures were identified.

Within-subject statistical modeling techniques were employed to investigate individual differences in the extent to which two possible indicators of processing time predicted changes in utterance complexity during spontaneous discourse for 10 children ages 7;1 to 10;1 with specific language impairments (SLI) who differed in receptive language abilities. The two indicators of processing time that were modeled were response latency and the use of a specific discourse marker (Verbal Pause) that provided children with additional time to respond. Longer response latencies were not a strong predictor of increased utterance length for any of the children. However, results indicated that children with better receptive skills used substantially more verbal pauses than children with both expressive and receptive deficits and that the use of these pauses was a strong predictor of increased utterance length for children with better comprehension skills. [ABSTRACT FROM AUTHOR]

Inferentially seamless 2/3 designs are increasingly popular in clinical trials. It is important to understand their relative advantages compared with separate phase 2 and phase 3 trials, and to understand the consequences of design choices such as the proportion of patients included in the phase 2 portion of the design. Extending previous work in this area, we perform a simulation study across multiple numbers of arms and efficacy response curves. We consider a design space crossing the choice of a separate versus seamless design with the choice of allocating 0%-100% of available patients in phase 2, with the remainder in phase 3. The seamless designs achieve greater power than their separate trial counterparts. Importantly, the optimal seamless design is more robust than the optimal separate program, meaning that one range of values for the proportion of patients used in phase 2 (30%-50% of the total phase 2/3 sample size) is nearly optimal for a wide range of response scenarios. In contrast, a percentage of patients used in phase 2 for separate trials may be optimal for some alternative scenarios but decidedly inferior for other alternative scenarios. When operationally and scientifically viable, seamless trials provide superior performance compared with separate phase 2 and phase 3 trials. The results also provide guidance for the implementation of these trials in practice., (© 2024 John Wiley & Sons Ltd.)

Objectives: Respiratory management for pediatric acute respiratory distress syndrome (PARDS) remains largely supportive without data to support one approach over another, including supine versus prone positioning (PP) and conventional mechanical ventilation (CMV) versus high-frequency oscillatory ventilation (HFOV)., Design: We present the research methodology of a global, multicenter, two-by-two factorial, response-adaptive, randomized controlled trial of supine versus PP and CMV versus HFOV in high moderate-severe PARDS, the Prone and Oscillation Pediatric Clinical Trial ( PROSpect , www.ClinicalTrials.gov , NCT03896763)., Setting: Approximately 60 PICUs with on-site extracorporeal membrane oxygenation support in North and South America, Europe, Asia, and Oceania with experience using PP and HFOV in the care of patients with PARDS., Patients: Eligible pediatric patients (2 wk old or older and younger than 21 yr) are randomized within 48 h of meeting eligibility criteria occurring within 96 h of endotracheal intubation., Interventions: One of four arms, including supine/CMV, prone/CMV, supine/HFOV, or prone/HFOV. We hypothesize that children with high moderate-severe PARDS treated with PP or HFOV will demonstrate greater than or equal to 2 additional ventilator-free days (VFD)., Measurements and Main Results: The primary outcome is VFD through day 28; nonsurvivors receive zero VFD. Secondary and exploratory outcomes include nonpulmonary organ failure-free days, interaction effects of PP with HFOV on VFD, 90-day in-hospital mortality, and among survivors, duration of mechanical ventilation, PICU and hospital length of stay, and post-PICU functional status and health-related quality of life. Up to 600 patients will be randomized, stratified by age group and direct/indirect lung injury. Adaptive randomization will first occur 28 days after 300 patients are randomized and every 100 patients thereafter. At these randomization updates, new allocation probabilities will be computed based on intention-to-treat trial results, increasing allocation to well-performing arms and decreasing allocation to poorly performing arms. Data will be analyzed per intention-to-treat for the primary analyses and per-protocol for primary, secondary, and exploratory analyses., Conclusions: PROSpect will provide clinicians with data to inform the practice of PP and HFOV in PARDS., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Introduction: Implementation of enhanced recovery pathways (ERPs) has resulted in improved patient-centred outcomes and decreased costs. However, there is a lack of high-level evidence for many ERP elements. We have designed a randomised, embedded, multifactorial, adaptive platform perioperative medicine (REMAP Periop) trial to evaluate the effectiveness of several perioperative therapies for patients undergoing complex abdominal surgery as part of an ERP. This trial will begin with two domains: postoperative nausea/vomiting (PONV) prophylaxis and regional/neuraxial analgesia. Patients enrolled in the trial will be randomised to arms within both domains, with the possibility of adding additional domains in the future., Methods and Analysis: In the PONV domain, patients are randomised to optimal versus supraoptimal prophylactic regimens. In the regional/neuraxial domain, patients are randomised to one of five different single-injection techniques/combination of techniques. The primary study endpoint is hospital-free days at 30 days, with additional domain-specific secondary endpoints of PONV incidence and postoperative opioid consumption. The efficacy of an intervention arm within a given domain will be evaluated at regular interim analyses using Bayesian statistical analysis. At the beginning of the trial, participants will have an equal probability of being allocated to any given intervention within a domain (ie, simple 1:1 randomisation), with response adaptive randomisation guiding changes to allocation ratios after interim analyses when applicable based on prespecified statistical triggers. Triggers met at interim analysis may also result in intervention dropping., Ethics and Dissemination: The core protocol and domain-specific appendices were approved by the University of Pittsburgh Institutional Review Board. A waiver of informed consent was obtained for this trial. Trial results will be announced to the public and healthcare providers once prespecified statistical triggers of interest are reached as described in the core protocol, and the most favourable interventions will then be implemented as a standardised institutional protocol., Trial Registration Number: NCT04606264., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Platform trials, with arms entering and leaving the trial over time, are complex. In addition to trial changes over time, certain arms in a platform may come with patient restrictions. Both of these issues (time and eligibility) can create biases in comparing active arms to control. The largest of these biases, using non-concurrent controls or including control patients that were ineligible for an active arm, have been extensively discussed in the literature. Here we show that even restricting to concurrent, eligible controls can induce biases if proper allocation ratios are not maintained throughout the platform. We also build on results in Ventz et al. Biostat., 19:199-215, 2018 to describe an algorithm that guarantees comparability between active and control groups in arm analyses in both time and eligibility, and allows for both re-randomization of patients and two-stage randomization procedures. The resulting method is both flexible and easily implemented, allowing robust comparisons when assumptions that underlie alternative randomization methods are in doubt., (© 2023 John Wiley & Sons Ltd.)

Background: Platelet transfusion is a potentially life-saving therapy for actively bleeding patients, ranging from those undergoing planned surgical procedures to those suffering unexpected traumatic injuries. Platelets are currently stored at room temperature (20°C-24°C) with a maximum storage duration of 7 days after donation. The CHIlled Platelet Study trial will compare the efficacy and safety of standard room temperature-stored platelets with platelets that are cold-stored (1°C-6°C), that is, chilled, with a maximum of storage up to 21 days in adult and pediatric patients undergoing complex cardiac surgical procedures., Methods/results: CHIlled Platelet Study will use a Bayesian adaptive design to identify the range of cold storage durations for platelets that are non-inferior to standard room temperature-stored platelets. If cold-stored platelets are non-inferior at durations greater than 7 days, a gated superiority analysis will identify durations for which cold-stored platelets may be superior to standard platelets. We present example simulations of the CHIlled Platelet Study design and discuss unique challenges in trial implementation. The CHIlled Platelet Study trial has been funded and will be implemented in approximately 20 clinical centers. Early randomization to enable procurement of cold-stored platelets with different storage durations will be required, as well as a platelet tracking system to eliminate platelet wastage and maximize trial efficiency and economy., Discussion: The CHIlled Platelet Study trial will determine whether cold-stored platelets are non-inferior to platelets stored at room temperature, and if so, will determine the maximum duration (up to 21 days) of storage that maintains non-inferiority., Trial Registration: ClinicalTrials.gov, NCT04834414.

Background: Multi-arm platform trials investigate multiple agents simultaneously, typically with staggered entry and exit of experimental treatment arms versus a shared control arm. In such settings, there is considerable debate whether to limit analyses for a treatment arm to concurrent randomized control subjects or to allow comparisons to both concurrent and non-concurrent (pooled) control subjects. The potential bias from temporal drift over time is at the core of this debate., Methods: We propose time-adjusted analyses, including a "Bayesian Time Machine," to model potential temporal drift in the entire study population, such that primary analyses can incorporate all randomized control subjects from the platform trial. We conduct a simulation study to assess performance relative to utilizing concurrent or pooled controls., Results: In multi-arm platform trials with staggered entry, analyses adjusting for temporal drift (either Bayesian or frequentist) have superior estimation of treatment effects and favorable testing properties compared to analyses using either concurrent or pooled controls. The Bayesian Time Machine generally provides estimates with greater precision and smaller mean square error than alternative approaches, at the risk of small bias and small Type I error inflation., Conclusions: The Bayesian Time Machine provides a compromise between bias and precision by smoothing estimates across time and leveraging all available data for the estimation of treatment effects. Prior distributions controlling the behavior of dynamic smoothing across time must be pre-specified and carefully calibrated to the unique context of each trial, appropriately accounting for the population, disease, and endpoints.

Background: Platform trials can evaluate the efficacy of several experimental treatments compared to a control. The number of experimental treatments is not fixed, as arms may be added or removed as the trial progresses. Platform trials are more efficient than independent parallel group trials because of using shared control groups. However, for a treatment entering the trial at a later time point, the control group is divided into concurrent controls, consisting of patients randomised to control when that treatment arm is in the platform, and non-concurrent controls, patients randomised before. Using non-concurrent controls in addition to concurrent controls can improve the trial's efficiency by increasing power and reducing the required sample size, but can introduce bias due to time trends., Methods: We focus on a platform trial with two treatment arms and a common control arm. Assuming that the second treatment arm is added at a later time, we assess the robustness of recently proposed model-based approaches to adjust for time trends when utilizing non-concurrent controls. In particular, we consider approaches where time trends are modeled either as linear in time or as a step function, with steps at time points where treatments enter or leave the platform trial. For trials with continuous or binary outcomes, we investigate the type 1 error rate and power of testing the efficacy of the newly added arm, as well as the bias and root mean squared error of treatment effect estimates under a range of scenarios. In addition to scenarios where time trends are equal across arms, we investigate settings with different time trends or time trends that are not additive in the scale of the model., Results: A step function model, fitted on data from all treatment arms, gives increased power while controlling the type 1 error, as long as the time trends are equal for the different arms and additive on the model scale. This holds even if the shape of the time trend deviates from a step function when patients are allocated to arms by block randomisation. However, if time trends differ between arms or are not additive to treatment effects in the scale of the model, the type 1 error rate may be inflated., Conclusions: The efficiency gained by using step function models to incorporate non-concurrent controls can outweigh potential risks of biases, especially in settings with small sample sizes. Such biases may arise if the model assumptions of equality and additivity of time trends are not satisfied. However, the specifics of the trial, scientific plausibility of different time trends, and robustness of results should be carefully considered., (© 2022. The Author(s).)

National Institutes of Health Stroke Scale (NIHSS), measured a few hours to days after stroke onset, is an attractive outcome measure for stroke research. NIHSS at the time of presentation (baseline NIHSS) strongly predicts the follow-up NIHSS. Because of the need to account for the baseline NIHSS in the analysis of follow-up NIHSS as an outcome measure, a common and intuitive approach is to define study outcome as the change in NIHSS from baseline to follow-up (ΔNIHSS). However, this approach has important limitations. Analyzing ΔNIHSS implies a very strong assumption about the relationship between baseline and follow-up NIHSS that is unlikely to be satisfied, drawing into question the validity of the resulting statistical analysis. This reduces the precision of the estimates of treatment effects and the power of clinical trials that use this approach to analysis. ANCOVA allows for the analysis of follow-up NIHSS as the dependent variable while adjusting for baseline NIHSS as a covariate in the model and addresses several challenges of using ΔNIHSS outcome using simple bivariate comparisons (eg, a t test, Wilcoxon rank-sum, linear regression without adjustment for baseline) for stroke research. In this article, we use clinical trial simulations to illustrate that variability in NIHSS outcome is less when follow-up NIHSS is adjusted for baseline compared to ΔNIHSS and how a reduction in this variability improves the power. We outline additional, important clinical and statistical arguments to support the superiority of ANCOVA using the final measurement of the NIHSS adjusted for baseline over, and caution against using, the simple bivariate comparison of absolute NIHSS change (ie, delta).

Background: Hypothermia is neuroprotective in some ischemia-reperfusion injuries. Ischemia-reperfusion injury may occur with traumatic subdural hematoma (SDH). This study aimed to determine whether early induction and maintenance of hypothermia in patients with acute SDH would lead to decreased ischemia-reperfusion injury and improve global neurologic outcome., Methods: This international, multicenter randomized controlled trial enrolled adult patients with SDH requiring evacuation of hematoma within 6 h of injury. The intervention was controlled temperature management of hypothermia to 35 °C prior to dura opening followed by 33 °C for 48 h compared with normothermia (37 °C). Investigators randomly assigned patients at a 1:1 ratio between hypothermia and normothermia. Blinded evaluators assessed outcome using a 6-month Glasgow Outcome Scale Extended score. Investigators measured circulating glial fibrillary acidic protein and ubiquitin C-terminal hydrolase L1 levels., Results: Independent statisticians performed an interim analysis of 31 patients to assess the predictive probability of success and the Data and Safety Monitoring Board recommended the early termination of the study because of futility. Thirty-two patients, 16 per arm, were analyzed. Favorable 6-month Glasgow Outcome Scale Extended outcomes were not statistically significantly different between hypothermia vs. normothermia groups (6 of 16, 38% vs. 4 of 16, 25%; odds ratio 1.8 [95% confidence interval 0.39 to ∞], p = .35). Plasma levels of glial fibrillary acidic protein (p = .036), but not ubiquitin C-terminal hydrolase L1 (p = .26), were lower in the patients with favorable outcome compared with those with unfavorable outcome, but differences were not identified by temperature group. Adverse events were similar between groups., Conclusions: This trial of hypothermia after acute SDH evacuation was terminated because of a low predictive probability of meeting the study objectives. There was no statistically significant difference in functional outcome identified between temperature groups., (© 2021. The Author(s).)

Importance: Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis., Objective: To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis., Design, Setting, and Participants: Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020., Interventions: Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone., Main Outcomes and Measures: The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality., Results: Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group., Conclusions and Relevance: Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference., Trial Registration: ClinicalTrials.gov Identifier: NCT03509350.

Introduction: As the population ages, there is interest in strategies to promote resiliency, especially for frail patients at risk of its complications. The physiological stress of surgery in high-risk individuals has been proposed both as an important cause of accelerated age-related decline in health and as a model testing the effectiveness of strategies to improve resiliency to age-related health decline. We describe a randomised, embedded, multifactorial, adaptative platform (REMAP) trial to investigate multiple perioperative interventions, the first of which is metformin and selected for its anti-inflammatory and anti-ageing properties beyond its traditional blood glucose control features., Methods and Analysis: Within a multihospital, single healthcare system, the Core Protocol for Strategies to Promote ResiliencY (SPRY) will be embedded within both the electronic health record (EHR) and the healthcare culture generating a continuously self-learning healthcare system. Embedding reduces the administrative burden of a traditional trial while accessing and rapidly analysing routine patient care EHR data. SPRY-Metformin is a placebo-controlled trial and is the first SPRY domain evaluating the effectiveness of three metformin dosages across three preoperative durations within a heterogeneous set of major surgical procedures. The primary outcome is 90-day hospital-free days. Bayesian posterior probabilities guide interim decision-making with predefined rules to determine stopping for futility or superior dosing selection. Using response adaptative randomisation, a maximum of 2500 patients allows 77%-92% power, detecting >15% primary outcome improvement. Secondary outcomes include mortality, readmission and postoperative complications. A subset of patients will be selected for substudies evaluating the microbiome, cognition, postoperative delirium and strength., Ethics and Dissemination: The Core Protocol of SPRY REMAP and associated SPRY-Metformin Domain-Specific Appendix have been ethically approved by the Institutional Review Board and are publicly registered. Results will be publicly available to healthcare providers, patients and trial participants following achieving predetermined platform conclusions., Trial Registration Number: NCT03861767., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We investigate multiple features of response adaptive randomization (RAR) in the context of a multiple arm randomized trial with control, where the primary goal is the identification of the best arm for use in a broader patient population. We maintain constant control allocation and vary the length of time until RAR is started, interim frequency, the underlying quantity used to calculate the randomization probabilities, and a threshold resulting in temporary arm dropping. We evaluate the designs on five metrics measuring benefit to the internal trial population, the future external population, and statistical estimation. Our results indicate these features have minimal interaction within the space explored, with preference for earlier activation of RAR, more frequent interim analyses, randomizing in proportion to the probability each arm is the best, and aggressive thresholding for temporarily dropping arms. The results illustrate useful principles for maximizing the benefit of RAR in practice., (© 2020 John Wiley & Sons Ltd.)

Background: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAF V600E -mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAF V600E -mutated biliary tract cancer., Methods: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAF V600E -mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAF V600E -mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting., Findings: Between March 12, 2014, and July 18, 2018, 43 patients with BRAF V600E -mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6-15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported., Interpretation: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAF V600E -mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAF V600E mutations should be considered in patients with biliary tract cancer., Funding: GlaxoSmithKline and Novartis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Historical data have been used to augment or replace control arms in some rare disease and pediatric clinical trials. With greater availability of historical data and new methodology such as dynamic borrowing, the inclusion of historical data in clinical trials is an increasingly appealing approach for larger disease areas as well, as this can result in increased power and precision and can minimize the burden on patients in clinical trials. However, sponsors must assess whether the potential biases incurred with this approach outweigh the benefits and discuss this trade-off with the regulatory agencies. This paper discusses important points for the appropriate selection of historical controls for inclusion in the analysis of primary and/or key secondary endpoint(s) in clinical trials. The general steps are as follows: (1) Assess whether a trial is a suitable candidate for this approach. (2) If it is, then carefully identify appropriate historical trials to minimize selection bias. (3) Refine the historical control set if appropriate, for example, by selecting subsets of studies or patients. Identification of trial settings that are amenable to historical borrowing and selection of appropriate historical data using the principles discussed in this paper has the potential to lead to more efficient estimation and decision making. Ultimately, this efficiency gain results in lower patient burden and gets effective drugs to patients more quickly.

Background/aims: Response adaptive randomization has many polarizing properties in two-arm settings comparing control to a single treatment. The generalization of these features to the multiple arm setting has been less explored, and existing comparisons in the literature reach disparate conclusions. We investigate several generalizations of two-arm response adaptive randomization methods relating to control allocation in multiple arm trials, exploring how critiques of response adaptive randomization generalize to the multiple arm setting., Methods: We perform a simulation study to investigate multiple control allocation schemes within response adaptive randomization, comparing the designs on metrics such as power, arm selection, mean square error, and the treatment of patients within the trial., Results: The results indicate that the generalization of two-arm response adaptive randomization concerns is variable and depends on the form of control allocation employed. The concerns are amplified when control allocation may be reduced over the course of the trial but are mitigated in the methods considered when control allocation is maintained or increased during the trial. In our chosen example, we find minimal advantage to increasing, as opposed to maintaining, control allocation; however, this result reflects an extremely limited exploration of methods for increasing control allocation., Conclusion: Selection of control allocation in multiple arm response adaptive randomization has a large effect on the performance of the design. Some disparate comparisons of response adaptive randomization to alternative paradigms may be partially explained by these results. In future comparisons, control allocation for multiple arm response adaptive randomization should be chosen to keep in mind the appropriate match between control allocation in response adaptive randomization and the metric or metrics of interest.

Background: Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM-1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma., Methods: Part 1 was an open-label, dose-finding, safety lead-in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m 2 gemcitabine on days 1 and 8 and 75 mg/m 2 docetaxel on day 8). In part 2, patients were randomized in a double-blind fashion in 2:1 ratio to ontuxizumab (8 mg/kg) or a placebo with G/D. Randomization was stratified by 4 histological cohorts., Results: In part 2 with 209 patients, no significant difference in progression-free survival between ontuxizumab plus G/D (4.3 months; 95% confidence interval [CI], 2.7-6.3 months) and the placebo plus G/D (5.6 months; 95% CI, 2.6-8.3 months) was observed (P = .67; hazard ratio [HR], 1.07; 95% CI, 0.77-1.49). Similarly, there was no significant difference in median overall survival between the 2 groups: 18.3 months for the ontuxizumab plus G/D group (95% CI, 16.2-21.1 months) and 21.1 months for the placebo plus G/D group (95% CI, 14.2 months to not reached; P = .32; HR, 1.23; 95% CI, 0.82-1.82). No significant differences between the treatment groups occurred for any efficacy parameter by sarcoma cohort. The combination of ontuxizumab plus G/D was generally well tolerated., Conclusions: Ontuxizumab plus G/D showed no enhanced activity over chemotherapy alone in soft-tissue sarcomas, whereas the safety profile of the combination was consistent with G/D alone., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Background: Bayesian adaptive designs can improve the efficiency of trials, and lead to trials that can produce high quality evidence more quickly, with fewer patients and lower costs than traditional methods. The aim of this work was to determine how Bayesian adaptive designs can be constructed for phase III clinical trials in critical care, and to assess the influence that Bayesian designs would have on trial efficiency and study results., Methods: We re-designed the High Frequency OSCillation in Acute Respiratory distress syndrome (OSCAR) trial using Bayesian adaptive design methods, to allow for the possibility of early stopping for success or futility. We constructed several alternative designs and studied their operating characteristics via simulation. We then performed virtual re-executions by applying the Bayesian adaptive designs using the OSCAR data to demonstrate the practical applicability of the designs., Results: We constructed five alternative Bayesian adaptive designs and identified a preferred design based on the simulated operating characteristics, which had similar power to the original design but recruited fewer patients on average. The virtual re-executions showed the Bayesian sequential approach and original OSCAR trial yielded similar trial conclusions. However, using a Bayesian sequential design could have led to a reduced sample size and earlier completion of the trial., Conclusions: Using the OSCAR trial as an example, this case study found that Bayesian adaptive designs can be constructed for phase III critical care trials. If the OSCAR trial had been run using one of the proposed Bayesian adaptive designs, it would have terminated at a smaller sample size with fewer deaths in the trial, whilst reaching the same conclusions. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials., Trial Registration: OSCAR Trial registration ISRCTN, ISRCTN10416500 . Retrospectively registered 13 June 2007.

Background: Sepsis accounts for 30% to 50% of all in-hospital deaths in the United States. Other than antibiotics and source control, management strategies are largely supportive with fluid resuscitation and respiratory, renal, and circulatory support. Intravenous vitamin C in conjunction with thiamine and hydrocortisone has recently been suggested to improve outcomes in patients with sepsis in a single-center before-and-after study. However, before this therapeutic strategy is adopted, a rigorous assessment of its efficacy is needed., Methods: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial. It will enroll patients with sepsis causing respiratory or circulatory compromise or both. Patients will be randomly assigned (1:1) to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 h or matching placebos until a total of 16 administrations have been completed or intensive care unit discharge occurs (whichever is first). Patients randomly assigned to the comparator group are permitted to receive open-label stress-dose steroids at the discretion of the treating clinical team. The primary outcome is consecutive days free of ventilator and vasopressor support (VVFDs) in the 30 days following randomization. The key secondary outcome is mortality at 30 days. Sample size will be determined adaptively by using interim analyses with pre-stated stopping rules to allow the early recognition of a large mortality benefit if one exists and to refocus on the more sensitive outcome of VVFDs if an early large mortality benefit is not observed., Discussion: VICTAS is a large, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled trial that will test the efficacy of vitamin C, thiamine, and hydrocortisone as a combined therapy in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. Because the components of this therapy are inexpensive and readily available and have very favorable risk profiles, demonstrated efficacy would have immediate implications for the management of sepsis worldwide., Trial Registration: ClinicalTrials.gov Identifier: NCT03509350 . First registered on April 26, 2018, and last verified on December 20, 2018. Protocol version: 1.4, January 9, 2019.

Importance: Sepsis induces profound metabolic derangements, while exogenous levocarnitine mitigates metabolic dysfunction by enhancing glucose and lactate oxidation and increasing fatty acid shuttling. Previous trials in sepsis suggest beneficial effects of levocarnitine on patient-centered outcomes., Objectives: To test the hypothesis that levocarnitine reduces cumulative organ failure in patients with septic shock at 48 hours and, if present, to estimate the probability that the most efficacious dose will decrease 28-day mortality in a pivotal phase 3 clinical trial., Design, Setting, and Participants: Multicenter adaptive, randomized, blinded, dose-finding, phase 2 clinical trial (Rapid Administration of Carnitine in Sepsis [RACE]). The setting was 16 urban US medical centers. Participants were patients aged 18 years or older admitted from March 5, 2013, to February 5, 2018, with septic shock and moderate organ dysfunction., Interventions: Within 24 hours of identification, patients were assigned to 1 of the following 4 treatments: low (6 g), medium (12 g), or high (18 g) doses of levocarnitine or an equivalent volume of saline placebo administered as a 12-hour infusion., Main Outcomes and Measures: The primary outcome required, first, a greater than 90% posterior probability that the most promising levocarnitine dose decreases the Sequential Organ Failure Assessment (SOFA) score at 48 hours and, second (given having met the first condition), at least a 30% predictive probability of success in reducing 28-day mortality in a subsequent traditional superiority trial to test efficacy., Results: Of the 250 enrolled participants (mean [SD] age, 61.7 [14.8] years; 56.8% male), 35, 34, and 106 patients were adaptively randomized to the low, medium, and high levocarnitine doses, respectively, while 75 patients were randomized to placebo. In the intent-to-treat analysis, the fitted mean (SD) changes in the SOFA score for the low, medium, and high levocarnitine groups were -1.27 (0.49), -1.66 (0.38), and -1.97 (0.32), respectively, vs -1.63 (0.35) in the placebo group. The posterior probability that the 18-g dose is superior to placebo was 0.78, which did not meet the a priori threshold of 0.90. Mortality at 28 days was 45.9% (34 of 74) in the placebo group compared with 43.3% (45 of 104) for the most promising levocarnitine dose (18 g). Similar findings were noted in the per-protocol analysis., Conclusions and Relevance: In this dose-finding, phase 2 adaptive randomized trial, the most efficacious dose of levocarnitine (18 g) did not meaningfully reduce cumulative organ failure at 48 hours., Trial Registration: ClinicalTrials.gov Identifier: NCT01665092.

New antimicrobial drugs for treatment of complicated urinary tract infection (cUTI) are generally assessed in randomized, double-blind, noninferiority clinical trials. Robust historical data for the active comparator inform on treatment effect estimation, yet typically do not substitute for the active comparator data in the proposed trial. We report design options for a phase 3 trial of cUTI using a Bayesian hierarchical model and historical data from 2 well-executed phase 3 registrational trials of doripenem. The methodology is directly applicable to other phase 3 noninferiority settings. In addition to the research design application, we provide a novel methodology for assessing the robustness of type I error control. The model borrows heavily from the prior data when the current active comparator parameter estimate approximated the historical estimate. In contrast, the model had restricted borrowing when the 2 estimates were very different. The alternative trial design, with or without the inclusion of futility stopping criteria, provides a framework for future cUTI phase 3 trials., (© 2018 John Wiley & Sons, Ltd.)

Background: Storage of platelets at 4°C compared with 22°C may increase both hemostatic activity and storage duration; however, the maximum duration of cold storage is unknown. We report the design of an innovative, prospective, randomized, Bayesian adaptive, "duration finding" clinical trial to evaluate the efficacy and maximum duration of storage of platelets at 4°C., Methods: Patients undergoing cardiac surgery and requiring platelet transfusions will be enrolled. Patients will be randomized to receive platelets stored at 22°C up to 5 days or platelets stored at 4°C up to 5 days, 10 days, or 15 days. Longer durations of cold storage will only be used if shorter durations at 4°C appear noninferior to standard storage, based on a four-level clinical hemostatic efficacy score with a NIM of a half level. A Bayesian linear model is used to estimate the hemostatic efficacy of platelet transfusions based on the actual duration of storage at 4°C., Results: The type I error rate, if platelets stored at 4°C are inferior, is 0.0247 with an 82% probability of early stopping for futility. With a maximum sample size of 1,500, the adaptive trial design has a power of over 90% to detect noninferiority and a high probability of correctly identifying the maximum duration of storage at 4°C that is noninferior to 22°C., Conclusion: An adaptive, duration-finding trial design will generate Level I evidence and allow the determination of the maximum duration platelet storage at 4°C that is noninferior to standard storage at 22°C, with respect to hemostatic efficacy. The adaptive trial design helps to ensure that longer cold storage durations are only explored once substantial supportive data are available for the shorter duration(s) and that the trial stops early if continuation is likely to be futile.

Context: The ability to generate, absorb, and transmit forces through the proximal segments of the pelvis, spine, and trunk has been proposed to influence sport performance, yet traditional training techniques targeting the proximal segments have had limited success improving sport-specific performance., Objective: To investigate the effects of a traditional endurance-training program and a sport-specific power-training program targeting the muscles that support the proximal segments and throwing velocity., Design: Randomized controlled clinical trial., Setting: University research laboratory and gymnasium., Patients or Other Participants: A total of 46 (age = 20 ± 1.3 years, height = 175.7 ± 8.7 cm) healthy National Collegiate Athletic Association Division III female softball (n = 17) and male baseball (n = 29) players., Intervention(s): Blocked stratification for sex and position was used to randomly assign participants to 1 of 2 training groups for 7 weeks: a traditional endurance-training group (ET group; n = 21) or a power-stability-training group (PS group; n = 25). Mean Outcome Measure(s) : The change score in peak throwing velocity (km/h) normalized for body weight (BW; kilograms) and change score in tests that challenge the muscles of the proximal segments normalized for BW (kilograms). We used 2-tailed independent-samples t tests to compare differences between the change scores., Results: The peak throwing velocity (ET group = 0.01 ± 0.1 km/h/kg of BW, PS group = 0.08 ± 0.03 km/h/kg of BW; P < .001) and muscle power outputs for the chop (ET group = 0.22 ± 0.91 W/kg of BW, PS group = 1.3 ± 0.91 W/kg of BW; P < .001) and lift (ET group = 0.59 ± 0.67 W/kg of BW, PS group = 1.4 ± 0.87 W/kg of BW; P < .001) tests were higher at postintervention in the PT than in the ET group., Conclusions: An improvement in throwing velocity occurred simultaneously with measures of muscular endurance and power after a sport-specific training regimen targeting the proximal segments.

Low back pain (LBP), is a common musculoskeletal problem, affecting 75-85% of adults in their lifetime. Direct costs of LBP in the USA were estimated over 85 billion dollars in 2005 resulting in a significant economic burden for the healthcare system. LBP classification systems and outcome measures are available to guide physical therapy assessments and intervention. However, little is known about which, if any, physical therapists use in clinical practice. The purpose of this study was to identify the use of and barriers to LBP classification systems and outcome measures among physical therapists in one state. A mixed methods study using a cross-sectional cohort design with descriptive qualitative methods was performed. A survey collected both quantitative and qualitative data relevant to classification systems and outcome measures used by physical therapists working with patients with LBP. Physical therapists responded using classification systems designed to direct treatment predominantly. The McKenzie method was the most frequent approach to classify LBP. Barriers to use of classification systems and outcome measures were lack of knowledge, too limiting and time. Classification systems are being used for decision-making in physical therapy practice for patients with LBP. Lack of knowledge and training seems to be the main barrier to the use of classification systems in practice. The Oswestry Disability Index and Numerical Pain Scale were the most commonly used outcome measures. The main barrier to their use was lack of time. Continuing education and reading the literature were identified as important tools to teach evidence-based practice to physical therapists in practice.

Clinical trials rarely, if ever, occur in a vacuum. Generally, large amounts of clinical data are available prior to the start of a study, particularly on the current study's control arm. There is obvious appeal in using (i.e., 'borrowing') this information. With historical data providing information on the control arm, more trial resources can be devoted to the novel treatment while retaining accurate estimates of the current control arm parameters. This can result in more accurate point estimates, increased power, and reduced type I error in clinical trials, provided the historical information is sufficiently similar to the current control data. If this assumption of similarity is not satisfied, however, one can acquire increased mean square error of point estimates due to bias and either reduced power or increased type I error depending on the direction of the bias. In this manuscript, we review several methods for historical borrowing, illustrating how key parameters in each method affect borrowing behavior, and then, we compare these methods on the basis of mean square error, power and type I error. We emphasize two main themes. First, we discuss the idea of 'dynamic' (versus 'static') borrowing. Second, we emphasize the decision process involved in determining whether or not to include historical borrowing in terms of the perceived likelihood that the current control arm is sufficiently similar to the historical data. Our goal is to provide a clear review of the key issues involved in historical borrowing and provide a comparison of several methods useful for practitioners., (Copyright © 2013 John Wiley & Sons, Ltd.)

This mixed method study was designed to investigate self-perceptions before and after experiencing an activity that dynamically and statically challenges proximal stability of the pelvis, spine, and trunk. Twenty-eight, healthy Division II female soccer and volleyball collegiate players (17 soccer, 11 volleyball) completed a self-reported Tegner activity scale, pretest questionnaire and posttest interview. A self-perceived numeric rating of the athletes' proximal stability and performance on a functional movement screen (FMS) were recorded. A guided interview was used to examine the self-perceptions of proximal stability after the FMS testing session. Differences and correlations between the pretest and posttest ratings of proximal stability and FMS scores were analyzed using a 1-sample Kolmogorov-Smirnov test and Spearman's rank order correlation test, respectively. Residual standard error from a 1-way analysis of variance was used to explore the association between variables. Qualitative data were recorded and transcribed. There were significant differences between the pretest (3.4 ± 0.63) and posttest ratings (3.1 ± 0.49) of proximal stability (p = 0.01). The relationship between the pretest proximal stability ratings and the FMS scores was low (r = 0.19, p = 0.33), whereas posttest rating and FMS scores had a moderately high (r = 0.68, p = 0.00) correlation. There was a smaller residual standard error for the posttest ratings (1.7) when compared with the pretest ratings (3.2) with the FMS. Four qualitative themes emerged: (a) wanting to do well, (b) expectations of performance, (c) focused mental mindset, and (d) body control. Self-perceptions of proximal stability in female athletes were influenced by undergoing a test that stressed the proximal stabilizers. Combining assessments of self-perceptions and proximal stability may assist clinicians and athletes in targeting components of training.

Objectives: Sepsis is the tenth leading cause of death in the United States. Despite extensive research, mortality rates for sepsis have not substantially improved in the last several decades. We describe an innovative phase II clinical trial design for evaluating the addition of L-carnitine to the treatment of vasopressor-dependent septic shock., Design: The design incorporates a variety of features to increase efficiency, including a normal dynamic linear dose-response model, adaptive randomization, and early stopping for futility or success based on the probability that a future phase III trial using a 28-day mortality outcome would be successful., Setting: Trial design and computer simulation of a trial to be conducted in the emergency department and ICU., Interventions: Proposed to study intravenous L-carnitine., Measurements: The proposed trial uses an early endpoint, the 48-hour change in Sequential Organ Failure Assessment score, to drive adaptive randomization and dose selection., Main Results: We use existing data to model the expected relationship between the Sequential Organ Failure Assessment change and the 28-day mortality to determine the trial's operating characteristics using Monte Carlo simulation., Conclusions: The resulting trial efficiently identifies the best dose of L-carnitine and provides clear guidance regarding whether to continue development into phase III.

In classical conditioning, an alteration in response occurs when two stimuli are regularly paired in close succession. An area of particular research interest is classical conditioning with a chemical signal and visual and/or tactile stimuli as the unconditional stimuli, to test manipulative and motor behaviors in a learning paradigm. A classical learning task chamber was developed to examine learning trends in a sighted surface-dwelling crayfish, Procambarus clarkii, and in a blind cave-dwelling crayfish, Orconectes australis packardi. We examined whether learning is influenced by environmental factors and/or reliance on different primary sensory modalities. Crayfish were trained to manipulate a large, cumbersome cheliped through a small access point to obtain a food reward. In both species, acquisition of the learning task was rapid when they were in nonstressed conditions. The blind crayfish tested in low white light did not successfully complete the task, suggesting a stress response.

Over the past 2 decades, there have been revolutionary developments in life science technologies characterized by high throughput, high efficiency, and rapid computation. Nutritionists now have the advanced methodologies for the analysis of DNA, RNA, protein, low-molecular-weight metabolites, as well as access to bioinformatics databases. Statistics, which can be defined as the process of making scientific inferences from data that contain variability, has historically played an integral role in advancing nutritional sciences. Currently, in the era of systems biology, statistics has become an increasingly important tool to quantitatively analyze information about biological macromolecules. This article describes general terms used in statistical analysis of large, complex experimental data. These terms include experimental design, power analysis, sample size calculation, and experimental errors (Type I and II errors) for nutritional studies at population, tissue, cellular, and molecular levels. In addition, we highlighted various sources of experimental variations in studies involving microarray gene expression, real-time polymerase chain reaction, proteomics, and other bioinformatics technologies. Moreover, we provided guidelines for nutritionists and other biomedical scientists to plan and conduct studies and to analyze the complex data. Appropriate statistical analyses are expected to make an important contribution to solving major nutrition-associated problems in humans and animals (including obesity, diabetes, cardiovascular disease, cancer, ageing, and intrauterine growth retardation)., ((c) 2010 Elsevier Inc. All rights reserved.)

Summary: Accurate determination of extracted ion chromatographic peak areas in isotope-labeled quantitative proteomics is difficult to automate. Manual validation of identified peaks is typically required. We have integrated a peak confidence scoring algorithm into existing tools which are compatible with analysis pipelines based on the standards from the Institute for Systems Biology. This algorithm automatically excludes incorrectly identified peaks, improving the accuracy of the final protein expression ratio calculation., Source and Supplementary Information: http://www.chem.uky.edu/research/lynn/Nelson.pdf.

The effects of para-chlorophenylalanine (PCPA) and 3,4 methylenedioxy-methamphetamine (MDMA, 'ecstasy') were investigated in relation to development, behavior and physiology in larval Drosophila. PCPA blocks the synthesis of serotonin (5-HT) and MDMA is known to deplete 5-HT in mammalian neurons; thus these studies were conducted primarily to target the serotonergic system. Treatment with PCPA and MDMA delayed time to pupation and eclosion. The developmental rate was investigated with a survival analysis statistical approach that is unique for Drosophila studies. Locomotion and eating were reduced in animals exposed to MDMA or PCPA. Sensitivity to exogenously applied 5-HT on an evoked sensory-central nervous system (CNS)-motor circuit showed that the CNS is sensitive to 5-HT but that when depleted of 5-HT by PCPA a decreased sensitivity occurred. A diet with MDMA produced an enhanced response to exogenous 5-HT on the central circuit. Larvae eating MDMA from the first to third instar did not show a reduction in 5-HT within the CNS; however, eating PCPA reduced 5-HT as well as dopamine content as measured by high performance liquid chromatography from larval brains. As the heart serves as a good bioindex of 5-HT exposure, it was used in larvae fed PCPA and MDMA but no significant effects occurred with exogenous 5-HT. In summary, the action of these pharmacological compounds altered larval behaviors and development. PCPA treatment changed the sensitivity in the CNS to 5-HT, suggesting that 5-HT receptor regulation is modulated by neural activity of the serotonergic neurons. The actions of acute MDMA exposure suggest a 5-HT agonist action or possible dumping of 5-HT from neurons.

We provide both theoretical and computational improvements to the analysis of synaptic transmission data. Theoretically, we demonstrate the correlation structure of observations within evoked postsynaptic potentials (EPSP) are consistent with multiple random draws from a common autoregressive moving-average (ARMA) process of order (2, 2). We use this observation and standard time series results to construct a statistical hypothesis testing procedure for determining whether a given trace is an EPSP. Computationally, we implement this method in R, a freeware statistical language, which reduces the amount of time required for the investigator to classify traces into EPSPs or non-EPSPs and eliminates investigator subjectivity from this classification. In addition, we provide a computational method for calculating common functionals of EPSPs (peak amplitude, decay rate, etc.). The methodology is freely available over the internet. The automated procedure to index the quantal characteristics greatly facilitates determining if any one or multiple parameters are changing due to experimental conditions. In our experience, the software reduces the time required to perform these analyses from hours to minutes.