Search

When seriously ill patients have exhausted all treatment options available as part of usual care, the use of investigational agents may be warranted. Food and Drug Administration’s (FDA) Expanded Access (EA) pathway provides a mechanism for these patient’s physicians to pursue use of an investigational agent outside of a clinical trial when trial enrollment is not a feasible option. Though FDA has recently implemented processes to significantly streamline the regulatory portion of the process, the overall pathway has several time-consuming components including communication with the pharmaceutical company and the associated institutional requirements for EA use (contracting, Institutional Review Board [IRB], pharmacy, billing). Here, we present our experience building infrastructure at the Vanderbilt University Medical Center (VUMC) to support physicians and patients in pursuing EA, called the Access to Investigational Medicines (AIM) Platform, aligning the needs and responsibilities of institutional stakeholders and streamlining to ensure efficiency and regulatory compliance. Since its launch, the AIM team has experienced steady growth, supporting 40 EA cases for drugs/biologics, including both single patient cases and intermediate-size EA protocols in the emergent and non-emergent setting. As the EA pathway is a complex process that requires expert facilitation, we propose prioritizing EA support infrastructure at major academic medical centers as an essential regulatory knowledge function.

Direct modulation of the gut microbiota via rearing environments and fecal microbiota transplantation in a bleomycin-induced murine model suggests that a functional gut-lung axis modulates lung fibrosis.

Improving the quality and conduct of multi-center clinical trials is essential to the generation of generalizable knowledge about the safety and efficacy of healthcare treatments. Despite significant effort and expense, many clinical trials are unsuccessful. The National Center for Advancing Translational Science launched the Trial Innovation Network to address critical roadblocks in multi-center trials by leveraging existing infrastructure and developing operational innovations. We provide an overview of the roadblocks that led to opportunities for operational innovation, our work to develop, define, and map innovations across the network, and how we implemented and disseminated mature innovations.

Contracting delays remain a challenge to the successful initiation of multisite clinical research in the US. The Clinical and Translational Science Awards (CTSA) Contracts Processing Study showed average contract negotiation duration of > 100 days for industry-sponsored or investigator-initiated contracts. Such delays create enormous costs to sponsors and to patients waiting to use new evidence-based treatments. With support from the National Institutes of Health’s National Center for Advancing Translational Sciences, the Accelerated Clinical Trial Agreement (ACTA) was developed by 25 major academic institutions and medical centers engaged in clinical research in collaboration with the University-Industry Demonstration Partnership and with input from pharmaceutical companies. The ACTA also informed the development of subsequent agreements, including the Federal Demonstration Partnership Clinical Trial Subaward Agreement (FDP-CTSA); both ACTA and the FDP-CTSA are largely non-negotiable agreements that represent pre-negotiated compromises in contract terms agreed upon by industry and/or medical center stakeholders. When the involved parties agree to use the CTSA-developed and supported standard agreement templates as a starting point for negotiations, there can be significant time savings for trials. Use of the ACTA resulted in an average savings of 48 days and use of the FDP-CTSA saved an average of 57 days of negotiation duration.

New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or “hybrid” trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology.

One challenge for multisite clinical trials is ensuring that the conditions of an informative trial are incorporated into all aspects of trial planning and execution. The multicenter model can provide the potential for a more informative environment, but it can also place a trial at risk of becoming uninformative due to lack of rigor, quality control, or effective recruitment, resulting in premature discontinuation and/or non-publication. Key factors that support informativeness are having the right team and resources during study planning and implementation and adequate funding to support performance activities. This communication draws on the experience of the National Center for Advancing Translational Science (NCATS) Trial Innovation Network (TIN) to develop approaches for enhancing the informativeness of clinical trials. We distilled this information into three principles: (1) assemble a diverse team, (2) leverage existing processes and systems, and (3) carefully consider budgets and contracts. The TIN, comprised of NCATS, three Trial Innovation Centers, a Recruitment Innovation Center, and 60+ CTSA Program hubs, provides resources to investigators who are proposing multicenter collaborations. In addition to sharing principles that support the informativeness of clinical trials, we highlight TIN-developed resources relevant for multicenter trial initiation and conduct.

Background Whether the composition of intravenous crystalloid solutions affects outcomes in adults with aneurysmal subarachnoid hemorrhage (aSAH) remains unknown. Therefore, we determined whether the use of saline is associated with a lower risk of disability and death in patients with aSAH compared with balanced crystalloids. Methods We conducted a post hoc subgroup analysis of SMART (Isotonic Solutions and Major Adverse Renal Events Trial), a pragmatic, unblinded, cluster‐randomized, multiple‐crossover clinical trial that enrolled 15 802 adults between June 2015 and April 2017. We compared IV administration of saline to balanced crystalloids in consecutively enrolled patients with aSAH aged 18 years or older whose ruptured aneurysm was procedurally secured at a single academic center in the United States. The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms]–6 [death]) at 90 days obtained from a prospective institutional stroke registry. Secondary outcome included death by 90 days. Logistic or proportional odds regression models were used to test for between‐group differences adjusted for age, hypertension, aSAH grade, and procedure type. Results Of the 79 patients with aSAH procedurally treated during the Isotonic Solutions and Major Adverse Renal Events Trial study period, 78 were enrolled (median age, 58 years; interquartile range, 49–64.5; 64% female), with 41 (53%) assigned to saline and 37 (47%) to balanced crystalloids. Plasma‐Lyte was the primary balanced crystalloid used. Among 72 patients with 90‐day modified Rankin scale assessment, the adjusted common odds ratio, for the modified Rankin scale was 0.68 (95% CI, 0.28–1.63; P=0.39), with values

Abstract Background Convalescent plasma is being used widely as a treatment for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of COVID-19 convalescent plasma is unclear. Methods The Passive Immunity Trial for Our Nation (PassITON) is a multicenter, placebo-controlled, blinded, randomized clinical trial being conducted in the USA to provide high-quality evidence on the efficacy of COVID-19 convalescent plasma as a treatment for adults hospitalized with symptomatic disease. Adults hospitalized with COVID-19 with respiratory symptoms for less than 14 days are eligible. Enrolled patients are randomized in a 1:1 ratio to 1 unit (200–399 mL) of COVID-19 convalescent plasma that has demonstrated neutralizing function using a SARS-CoV-2 chimeric virus neutralization assay. Study treatments are administered in a blinded fashion and patients are followed for 28 days. The primary outcome is clinical status 14 days after study treatment as measured on a 7-category ordinal scale assessing mortality, respiratory support, and return to normal activities of daily living. Key secondary outcomes include mortality and oxygen-free days. The trial is projected to enroll 1000 patients and is designed to detect an odds ratio ≤ 0.73 for the primary outcome. Discussion This trial will provide the most robust data available to date on the efficacy of COVID-19 convalescent plasma for the treatment of adults hospitalized with acute moderate to severe COVID-19. These data will be useful to guide the treatment of COVID-19 patients in the current pandemic and for informing decisions about whether developing a standardized infrastructure for collecting and disseminating convalescent plasma to prepare for future viral pandemics is indicated. Trial registration ClinicalTrials.gov NCT04362176 . Registered on 24 April 2020.

Abstract Background Recent trials have suggested use of balanced crystalloids may decrease the incidence of major adverse kidney events compared to saline in critically ill adults. The effect of crystalloid composition on biomarkers of early acute kidney injury remains unknown. Methods From February 15 to July 15, 2016, we conducted an ancillary study to the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) comparing the effect of balanced crystalloids versus saline on urinary levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) among 261 consecutively-enrolled critically ill adults admitted from the emergency department to the medical ICU. After informed consent, we collected urine 36 ± 12 h after hospital admission and measured NGAL and KIM-1 levels using commercially available ELISAs. Levels of NGAL and KIM-1 at 36 ± 12 h were compared between patients assigned to balanced crystalloids versus saline using a Mann-Whitney U test. Results The 131 patients (50.2%) assigned to the balanced crystalloid group and the 130 patients (49.8%) assigned to the saline group were similar at baseline. Urinary NGAL levels were significantly lower in the balanced crystalloid group (median, 39.4 ng/mg [IQR 9.9 to 133.2]) compared with the saline group (median, 64.4 ng/mg [IQR 27.6 to 339.9]) (P

Background Prior observational studies indicate that lower systolic blood pressure (SBP) after successful endovascular treatment (EVT) is associated with better functional outcomes in patients with acute ischemic stroke. However, whether targeting SBP to levels below the guideline‐recommended target of ≤180 mm Hg is safe and efficacious remains to be determined. Methods The BEST (Blood Pressure After Endovascular Stroke Therapy)‐II trial (NCT04116112) is a pragmatic, phase 2, multisite, prospective, randomized, open‐label trial with blinded end‐point assessment designed to (1) compare the safety of lower SBP targets with higher SBP targets in successfully EVT‐treated patients with stroke and (2) inform the design and estimate the probability of success of a future phase 3 trial. A total of 120 patients with acute ischemic stroke who undergo successful EVT (final modified Thrombolysis in Cerebral Infarction score ≥2b) for intracranial internal carotid artery or M1 or M2 segment of the middle cerebral artery will be randomized to the SBP targets of ≤180,

Introduction Mechanical ventilation of intensive care unit (ICU) patients universally involves titration of the fraction of inspired oxygen to maintain arterial oxygen saturation (SpO2). However, the optimal SpO2 target remains unknown.Methods and analysis The Pragmatic Investigation of optimaL Oxygen Targets (PILOT) trial is a prospective, unblinded, pragmatic, cluster-crossover trial being conducted in the emergency department (ED) and medical ICU at Vanderbilt University Medical Center in Nashville, Tennessee, USA. PILOT compares use of a lower SpO2 target (target 90% and goal range: 88%–92%), an intermediate SpO2 target (target 94% and goal range: 92%–96%) and a higher SpO2 target (target 98% and goal range: 96%–100%). The study units are assigned to a single SpO2 target (cluster-level allocation) for each 2-month study block, and the assigned SpO2 target switches every 2 months in a randomly generated sequence (cluster-level crossover). The primary outcome is ventilator-free days (VFDs) to study day 28, defined as the number of days alive and free of invasive mechanical ventilation from the final receipt of invasive mechanical ventilation through 28 days after enrolment.Ethics and dissemination The trial was approved by the Vanderbilt Institutional Review Board. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences.Trial registration number The trial protocol was registered with ClinicalTrials.gov on 25 May 2018 prior to initiation of patient enrolment (ClinicalTrials.gov identifier: NCT03537937).

For decades, the research community called for streamlined Institutional Review Board (IRB) review processes for multisite studies. Department of Health and Human Services and National Institutes of Health (NIH) recognized this need and implemented single IRB (sIRB) of record mandates. However, announcing mandates without sufficient operational guidance and tools is insufficient to foster the desired change. Nearly 4 years into implementation of the NIH’s sIRB mandate, operational challenges remain. Fortunately, NIH supports a web-based sIRB platform, the IRB Reliance Exchange (IREx), to facilitate sIRB communication and documentation. IREx has received continuous NIH funding supporting its evolution since 2011 and is now used by over 5,000 Human Research Protection Program and research personnel, 35 sIRBs, and 415 participating sites to operationalize sIRB review and approval on over 400 studies. IREx supports over 2300 reliance relationships with an average of 7 sites per study. The platform is continually used by sIRBs and relying sites, providing a valuable centralized portal for promoting a harmonized sIRB review process. IREx can promote transparency, standardize practice, minimize workflow variation, and mitigate the need for sIRBs to implement significant technical changes to their local electronic systems. IREx has proven to be nimble and adaptable with practice and policy changes over the past decade, as evidenced by continually increasing platform utilization.

The Trial Innovation Network has established an infrastructure for single IRB review in response to federal policies. The Network’s single IRB (sIRBs) have successfully supported over 70 multisite studies via more than 800 reliance arrangements. This has generated several lessons learned that can benefit the national clinical research enterprise, as we work to improve the conduct of clinical trials. These lessons include distinguishing the roles of the single IRB from institutional Human Research Protections programs, establishing a consistent sIRB review model, standardizing collection of local context and supplemental, study-specific information, and educating and empowering lead study teams to support their sites.

Abstract Introduction: As clinical trials were rapidly initiated in response to the COVID-19 pandemic, Data and Safety Monitoring Boards (DSMBs) faced unique challenges overseeing trials of therapies never tested in a disease not yet characterized. Traditionally, individual DSMBs do not interact or have the benefit of seeing data from other accruing trials for an aggregated analysis to meaningfully interpret safety signals of similar therapeutics. In response, we developed a compliant DSMB Coordination (DSMBc) framework to allow the DSMB from one study investigating the use of SARS-CoV-2 convalescent plasma to treat COVID-19 to review data from similar ongoing studies for the purpose of safety monitoring. Methods: The DSMBc process included engagement of DSMB chairs and board members, execution of contractual agreements, secure data acquisition, generation of harmonized reports utilizing statistical graphics, and secure report sharing with DSMB members. Detailed process maps, a secure portal for managing DSMB reports, and templates for data sharing and confidentiality agreements were developed. Results: Four trials participated. Data from one trial were successfully harmonized with that of an ongoing trial. Harmonized reports allowing for visualization and drill down into the data were presented to the ongoing trial’s DSMB. While DSMB deliberations are confidential, the Chair confirmed successful review of the harmonized report. Conclusion: It is feasible to coordinate DSMB reviews of multiple independent studies of a similar therapeutic in similar patient cohorts. The materials presented mitigate challenges to DSMBc and will help expand these initiatives so DSMBs may make more informed decisions with all available information.

Summary: The COVID-19 pandemic revealed an urgent need for rapid profiling of neutralizing antibody responses and development of antibody therapeutics. The current Food and Drug Administration-approved serological tests do not measure antibody-mediated viral neutralization, and there is a need for standardized quantitative neutralization assays. We report a high-throughput two-step profiling approach for identifying neutralizing convalescent plasma. Screening and downselection for serum antibody binding to the receptor-binding domain are followed by quantitative neutralization testing using a chimeric vesicular stomatitis virus expressing spike protein of SARS-CoV-2 in a real-time cell analysis assay. This approach enables a predictive screening process for identifying plasma units that neutralize SARS-CoV-2. To calibrate antibody neutralizing activity in serum from convalescent plasma donors, we introduce a neutralizing antibody standard reagent composed of two human antibodies that neutralize SARS-CoV strains, including SARS-CoV-2 variants of concern. Our results provide a framework for establishing a standardized assessment of antibody-based interventions against COVID-19.

Background: There is wide heterogeneity in sepsis in causative pathogens, host response, organ dysfunction, and outcomes. Clinical and biologic phenotypes of sepsis are proposed, but the role of pathogen data on sepsis classification is unknown.Methods: We conducted a secondary analysis of the Recombinant Human Activated Protein C (rhAPC) Worldwide Evaluation in Severe Sepsis (PROWESS) Study. We used latent class analysis (LCA) to identify sepsis phenotypes using, (i) only clinical variables (“host model”) and, (ii) combining clinical with microbiology variables (e.g., site of infection, culture-derived pathogen type, and anti-microbial resistance characteristics, “host-pathogen model”). We describe clinical characteristics, serum biomarkers, and outcomes of host and host-pathogen models. We tested the treatment effects of rhAPC by phenotype using Kaplan-Meier curves.Results: Among 1,690 subjects with severe sepsis, latent class modeling derived a 4-class host model and a 4-class host-pathogen model. In the host model, alpha type (N = 327, 19%) was younger and had less shock; beta type (N=518, 31%) was older with more comorbidities; gamma type (N = 532, 32%) had more pulmonary dysfunction; delta type (N = 313, 19%) had more liver, renal and hematologic dysfunction and shock. After the addition of microbiologic variables, 772 (46%) patients changed phenotype membership, and the median probability of phenotype membership increased from 0.95 to 0.97 (P < 0.01). When microbiology data were added, the contribution of individual variables to phenotypes showed greater change for beta and gamma types. In beta type, the proportion of abdominal infections (from 20 to 40%) increased, while gamma type patients had an increased rate of lung infections (from 50 to 78%) with worsening pulmonary function. Markers of coagulation such as d-dimer and plasminogen activator inhibitor (PAI)-1 were greater in the beta type and lower in the gamma type. The 28 day mortality was significantly different for individual phenotypes in host and host-pathogen models (both P < 0.01). The treatment effect of rhAPC obviously changed in gamma type when microbiology data were added (P-values of log rank test changed from 0.047 to 0.780).Conclusions: Sepsis host phenotype assignment was significantly modified when microbiology data were added to clinical variables, increasing cluster cohesiveness and homogeneity.

Abstract Background Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. Methods and design The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. Trial registration ClinicalTrials.gov, NCT03509350 . Registered on 26 April 2018.

Abstract 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

Abstract Background Finding the optimal treatment for a chronic condition can be a complex and lengthy endeavor for both the patient and the clinician. To address this challenge, we developed an “N-of-1” quality improvement infrastructure to aid providers and patients in personalized treatment decision-making using systematic assessment of patient-reported outcomes during routine care. Methods Using the REDCap data management infrastructure, we implemented three pediatric pilots of the Treatment Assessments in the Individual Leading to Optimal Regimens (TAILOR) tool, including children receiving early intervention, children with attention deficit hyperactivity disorder, and children with challenging behaviors in the classroom setting. This retrospective review of data summarizes utilization and satisfaction data during our pilot experience with the tool. Results The three pilots included a combined total of 109 children and 39 healthcare providers, with 67 parents and 77 teachers invited to share data using brief surveys administered using TAILOR. Overall survey response rates ranged from 38% to 84% across the three pilots, with response rates notably higher among teachers as compared with parents. Satisfaction data indicated positive impressions of the tool’s utility. Discussion These experiences show the utility of the TAILOR framework for supporting collection and incorporation of patient-reported outcomes into the care of individuals with chronic conditions.

Summary: A detailed understanding of the adaptive host response to SARS-CoV-2 infection in humans is urgently needed. We developed a sensitive, high-throughput, and efficient assay using liquid bead array technology. We observed advantages over traditional ELISA for the detection and quantification of binding IgG against the receptor binding domain (RBD) of SARS-CoV-2. To determine whether COVID-19 symptom severity correlates with SARS-CoV-2 IgG, we measured anti-RBD IgG levels from 67 subjects recovered from PCR-confirmed COVID-19. We found that COVID-19 symptom severity strongly correlated with RBD IgG level (p < 0.001). These findings have substantial implications for public policy surrounding assessments of antibody responses and possible immunity, as not all cases of COVID-19 can be assumed to generate a protective antibody response, and mild disease in particular is capable of generating very low-level anti-RBD IgG levels. These findings also have important implications for the selection of donors for convalescent plasma to be used therapeutically.

Abstract Objective From the perspective of percutaneous coronary intervention (PCI) centers, locations of ST‐segment elevation myocardial infarction (STEMI) diagnosis can include a referring facility, emergency medical services (EMS) transporting to a PCI center, or the PCI center's emergency department (ED). This challenges the use of door‐to‐balloon‐time as the primary evaluative measure of STEMI treatment pathways. Our objective was to identify opportunities to improve care by quantifying differences in the timeliness of STEMI treatment mobilization based on the location of the diagnostic ECG. Methods This 3‐year, single‐center, retrospective cohort study classified patients by diagnostic ECG location: referring facility, EMS, or PCI center ED. We quantified door‐to‐balloon‐time and diagnosis‐to‐balloon‐time with its care subintervals. Results Of 207 ED STEMI patients, 180 (87%) received PCI. Median diagnosis‐to‐balloon‐times were shortest among the ED‐diagnosed (78 minutes [interquartile range (IQR), 61‐92]), followed by EMS‐identified patients (89 minutes [IQR, 78‐122]), and longest among those referred (140 minutes [IQR, 119‐160]), reflecting time for transport to the PCI center. Conversely, referred patients had the shortest median door‐to‐balloon‐times (38 minutes [IQR, 34‐43]), followed by the EMS‐identified (64 minutes [IQR, 47‐77]), whereas ED‐diagnosed patients had the longest (89 minutes [IQR, 70‐114]), reflecting diagnosis and catheterization lab activation frequently occurring before PCI center ED arrival for referred and EMS‐identified patients. Conclusions Diagnosis‐to‐balloon‐time and its care subintervals are complementary to the traditional door‐to‐balloon‐times as measures of the STEMI treatment process. Together, they highlight opportunities to improve timely identification among ED‐diagnosed patients, use of out‐of‐hospital cath lab activation for EMS‐identified patients, and encourage pathways for referred patients to bypass PCI center EDs.

Clinical trials continue to face significant challenges in participant recruitment and retention. The Recruitment Innovation Center (RIC), part of the Trial Innovation Network (TIN), has been funded by the National Center for Advancing Translational Sciences of the National Institutes of Health to develop innovative strategies and technologies to enhance participant engagement in all stages of multicenter clinical trials. In collaboration with investigator teams and liaisons at Clinical and Translational Science Award institutions, the RIC is charged with the mission to design, field-test, and refine novel resources in the context of individual clinical trials. These innovations are disseminated via newsletters, publications, a virtual toolbox on the TIN website, and RIC-hosted collaboration webinars. The RIC has designed, implemented, and promised customized recruitment support for 173 studies across many diverse disease areas. This support has incorporated site feasibility assessments, community input sessions, recruitment materials recommendations, social media campaigns, and an array of study-specific suggestions. The RIC’s goal is to evaluate the efficacy of these resources and provide access to all investigating teams, so that more trials can be completed on time, within budget, with diverse participation, and with enough accrual to power statistical analyses and make substantive contributions to the advancement of healthcare.

Inefficiencies in the national clinical research infrastructure have been apparent for decades. The National Center for Advancing Translational Science—sponsored Clinical and Translational Science Award (CTSA) program is able to address such inefficiencies. The Trial Innovation Network (TIN) is a collaborative initiative with the CTSA program and other National Institutes of Health (NIH) Institutes and Centers that addresses critical roadblocks to accelerate the translation of novel interventions to clinical practice. The TIN’s mission is to execute high-quality trials in a quick, cost-efficient manner. The TIN awardees are composed of 3 Trial Innovation Centers, the Recruitment Innovation Center, and the individual CTSA institutions that have identified TIN Liaison units. The TIN has launched a national scale single (central) Institutional Review Board system, master contracting agreements, quality-by-design approaches, novel recruitment support methods, and applies evidence-based strategies to recruitment and patient engagement. The TIN has received 113 submissions from 39 different CTSA institutions and 8 non-CTSA Institutions, with projects associated with 12 different NIH Institutes and Centers across a wide range of clinical/disease areas. Already more than 150 unique health systems/organizations are involved as sites in TIN-related multisite studies. The TIN will begin to capture data and metrics that quantify increased efficiency and quality improvement during operations.

Potential participants seek information about clinical trials for many reasons, but the process can be challenging. We analyzed 101,249 searches in ResearchMatch Trials Today, a free interface to recruiting trials from ClinicalTrials.gov. Searches from March 2015 to November 2016 included a broad range of conditions and healthy volunteer concepts, including 12,649 unique topics. Trials Today data indicate that it is being used to identify trials on a variety of topics.

Abstract Background As Twitter has become an active data source for health surveillance research, it is important that efficient and effective methods are developed to identify tweets related to personal health experience. Conventional classification algorithms rely on features engineered by human domain experts, and engineering such features is a challenging task and requires much human intelligence. The resultant features may not be optimal for the classification problem, and can make it challenging for conventional classifiers to correctly predict personal experience tweets (PETs) due to the various ways to express and/or describe personal experience in tweets. In this study, we developed a method that combines word embedding and long short-term memory (LSTM) model without the need to engineer any specific features. Through word embedding, tweet texts were represented as dense vectors which in turn were fed to the LSTM neural network as sequences. Results Statistical analyses of the results of 10-fold cross-validations of our method and conventional methods indicate that there exist significant differences (p

Abstract Background Prior studies in critically ill patients suggest the supra-physiologic chloride concentration of 0.9% (“normal”) saline may be associated with higher risk of renal failure and death compared to physiologically balanced crystalloids. However, the comparative effects of 0.9% saline and balanced fluids are largely unexamined among patients outside the intensive care unit, who represent the vast majority of patients treated with intravenous fluids. Methods/design This study, entitled Saline Against Lactated Ringer’s or Plasma-Lyte in the Emergency Department (SALT-ED), is a pragmatic, cluster, multiple-crossover trial at a single institution evaluating clinical outcomes of adults treated with 0.9% saline versus balanced crystalloids for intravenous fluid resuscitation in the emergency department. All adults treated in the study emergency department receiving at least 500 mL of isotonic crystalloid solution during usual clinical care and subsequently hospitalized outside the intensive care unit are included. Treatment allocation of 0.9% saline versus balanced crystalloids is assigned by calendar month, with study patients treated during the same month assigned to the same fluid type. The first month (January 2016) was randomly assigned to balanced crystalloids, with each subsequent month alternating between 0.9% saline and balanced crystalloids. For balanced crystalloid treatment, clinicians can choose either Lactated Ringer’s or Plasma-Lyte A©. The study period is set at 16 months, which will result in an anticipated estimated sample size of 15,000 patients. The primary outcome is hospital-free days to day 28, defined as the number of days alive and out of the hospital from the index emergency department visit until 28 days later. Major secondary outcomes include proportion of patients who develop acute kidney injury by creatinine measurements; major adverse kidney events by hospital discharge or day 30 (MAKE30), which is a composite outcome of death, new renal replacement therapy, and persistent creatinine elevation >200% of baseline; and in-hospital mortality. Discussion This ongoing pragmatic trial will provide the most comprehensive evaluation to date of clinical outcomes associated with 0.9% saline compared to physiologically balanced fluids in patients outside the intensive care unit. Trial registration ClinicalTrials.gov, NCT02614040 . Registered on 18 November 2015.

Trial registration ClinicalTrials.gov : NCT03509350 . Registered on 26 April 2018.

The clinical process of severe sepsis is characterized by extreme inflammation interlinked with potent stimulation of the coagulation cascade often followed by a state of relative immune paralysis. In this paper, we will review many of the potential therapies directed at various steps along the inflammatory cascade from modulation of inflammatory mediators eliciting the immune response, alteration of the host's immune response in both a stimulatory and depressive manner, and taming the overexuberant coagulation response triggered by the fierce coagulation-inflammation cycle. Finally, we will discuss further opportunities for research to improve our ability to design effective therapies.