List Of Clinical Trials Research Articles

TRAIL as a Warrior in Nano-Sized Trojan Horse: Anticancer and Anti-Metastatic Effects of Nano-Formulations of TRAIL in Cell Culture and Animal Model Studies

Cancer is a therapeutically challenging and genomically complicated disease. Pioneering studies have uncovered multifaceted aspects of cancer, ranging from intra- and inter-tumor heterogeneity, drug resistance, and genetic/epigenetic mutations. Loss of apoptosis is another critical aspect that makes cancer cells resistant to death. A substantial fraction of mechanistic information gleaned from cutting-edge studies has enabled researchers to develop near-to-complete resolution of the apoptotic pathway. Within the exciting frontiers of apoptosis, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) has garnered phenomenal appreciation by interdisciplinary researchers principally because of its unique capability to target cancer cells. TRAIL-based monotherapies and combinatorial therapies have reached phase II and phase III clinical trials. Rapidly upgrading the list of clinical trials substantiates the clinically valuable role of TRAIL-based therapeutics in cancer therapy. However, there is a growing concern about the poor bioavailability and rapid clearance of TRAIL-based therapeutics. Excitingly, the charismatic field of nanotechnology offers solutions for different problems, and we have witnessed remarkable breakthroughs in the efficacy of TRAIL-based therapeutics using nanotechnological approaches. In this review, we have attempted to provide a summary about different nanotechnologically assisted delivery methods for TRAIL-based therapeutics in cell culture studies and animal model studies for the inhibition/prevention of cancer.

The TB vaccine clinical trial centre directory: An inventory of clinical trial centres in Sub-Saharan Africa.

There are over ten vaccine candidates for tuberculosis (TB) in the clinical pipeline that require testing in TB-prevalent populations. To accelerate the clinical development of TB vaccines, a directory of clinical trial centres was established in sub-Saharan Africa (SSA) to assess capacity for conducting late-stage TB vaccine trials. TB vaccine-related parameters were identified, and trial centres in SSA were identified and prioritized based on whether they had experience with TB or non-TB vaccine trials. A survey was sent to identified centres, and the resulting directory presents their capacity for TB vaccine trials. Centres that identified as eligible for TB vaccine trials also had the opportunity to participate to the survey. This article provides an overview of the TB vaccine clinical trial centre directory, including the number and distribution of centres, their general characteristics, and their experience with prior TB vaccine trials. It includes information on the capacity of the centres, such as laboratory biosafety level, patient support, and community engagement. It also includes a case study to demonstrate how the directory can be used to identify trial centres with specific capabilities needed for a particular TB vaccine trial. Of the 134 identified centres, 56 provided information. Of these centres, 51 (91%) had phase 3 clinical trial experience and previous TB trials were conducted at 38 centres. Regarding TB vaccine trials, 19 centres conducted prevention of disease trials, 14 conducted prevention of infection trials, and 27 had no experience with TB vaccine clinical trials. From the respondents, 29 centers in South Africa were identified that could potentially conduct TB vaccine trials, followed by Tanzania (5), Kenya (5), Nigeria (3), and Uganda and Ethiopia (2 each). Trial sites in other countries were underrepresented, based on this survey. The establishment of a clinical trial centre directory can provide a basis for decision-making by various stakeholders. Despite some limitations in survey methodology, the findings suggest opportunities for expanding the evaluation of clinical trial capacity in other disease-prevalent countries and continents. Such data would be valuable in further enriching the Clinical Trial Community which a resource that geographically highlights clinical trial investments and capacities in African research ecosystem. New TB vaccine candidates need to be assessed in clinical trials in countries with high rates of TB in the coming years.An open-access directory of TB vaccine clinical trial centres in sub-Saharan Africa was established, providing an overview of the capacity to conduct clinical trials for TB vaccine candidates (http://www.edctp.org/our-work/coordination-tb-vaccine-funded-research/directory-tb-vaccine-clinical-trial-sites-sub-saharan-africa/).The directory is intended for clinical triallists, funders, policymakers, and researchers to accelerate the clinical development of novel TB vaccines by providing useful information.Regular updates are necessary to ensure the directory remains relevant for vaccine development and feeds into the continental Clinical Trials Community (https://ctc.africa/).

Enhancing the patient journey to clinical trial enrollment with navigation to optimize accrual: A pilot study for a pragmatic multicentre, stepped wedge, cluster randomized controlled trial (The CTN Pilot Trial).

11093 Background: Clinical trials are essential to the advancement of clinical therapies, yet accrual rates remain disappointing. Multiple challenges lead to less than 5% of cancer patients enrolled onto clinical trials. The Clinical Trials Navigator (CTN) program was established to assist patients and health care professionals identify appropriate clinical trials for patients. Methods: Between March 2019 to January 2024, a novel navigator-assisted clinical trials search program was offered to Canadian patients. Three non-medical navigators were trained to receive referrals, review medical information, and search five different clinical trial search engines. Eligibility criteria was scrutinized. A second review of the clinical trial list was conducted by two physicians. The final curated list of clinical trials was provided to patients and their oncologist. Results: A total of 373 patients were referred to the CTN program during the study period. A unique clinical trial search was performed for each patient yielding a median of only one potentially eligible trial per patient. Clinical trial enrolment occurred in 3.2% of patients in our database which translates to a 19% rate of successful enrolment of those referred to a trial by the CTN. Most patients (78%) were referred to clinical trial sites that conducted more than 100 clinical trials at any time. Compared to the Canadian cancer statistics, lung, lymphoma, pancreatic and brain cancers were overrepresented in referrals to the CTN program while prostate cancer was underrepresented. Type of cancer played a significant role in the likelihood of a successful referral (p < 0.01). Lung cancer was the most frequently reported cancer that resulted in referrals and breast cancer showed a lower frequency of referrals. The cancer type, stage and number of lines of prior therapy were not significantly associated with the patient enrollment onto a clinical trial. An increase in survival of referred patients from last analysis from 3.0 months to 5.3 months. Conclusions: The CTN program is a successful tool to identify clinical trials for cancer patients and can improve clinical trial accrual, as almost one fifth of patients (19%) who were referred to a clinical trial were enrolled. Ongoing iterative changes to the program to improve these metrics are underway and efforts to improve implementation of the CTN program across Canada are ongoing.

Engine failures: A critical analysis of current clinical trial websites' search engines.

e18537 Background: Clinical trials are critical to treatment advancement as they provide a foundation for future discoveries. Currently, only 7% of cancer patients in Ontario are enrolled in a clinical trial and 1 in 4 clinical trials fails to recruit enough patients. Enrolling patients depends on finding suitable trials for them. Lack of trial availability is the most common barrier to trial recruitment especially in non-academic hospitals since they tend to hold fewer within-center trials compared to larger centers. Most must rely on finding trials via databases such as ClinicalTrials.gov, yet there is a lack of literature that critically examines these databases for their searching capabilities emphasizing the need for critical analysis of the current search engines for delivery of a suitable list of clinical trials for patients. Methods: From June to September 2022, three individuals were trained and hired to conduct searches for 18 cancer patients across five search engines through the Clinical Trials Navigator program. Upon receiving referrals, they each searched online repositories to find eligible trials for the patient. Each navigator conducted an initial search for each patient on ClinicalTrials.gov. In addition, each searched alternative websites: Navigator 1 searched CanadianCancerTrials, Navigator 2 searched ClinicalTrialsOntario, and Navigator 3 searched Canadian Cancer Clinical Trials Network and OncoQuebec. For every search, each tracked search key words, total trials shown, total eligible trials found, and the number of eligible trials found on alternate websites that were not present in the initial ClinicalTrials.gov search. A qualitative analysis was done in tandem to identify shortcomings in the search engines. All searches were amalgamated by the lead navigator. Results: Our findings reveal pitfalls in the clinical trial search system, such as dysfunctional search filters, inconsistent results across the different websites, outdated trial information, and most importantly, lack of reproducibility as well as a lack of thoroughness of search results. On ClinicalTrials.gov, out of 54 search results, only 6 were reproducible between navigators. The only searches that were consistent between the navigators revealed zero trials for the patient. Not only was there variability in the total number of studies shown per same patient search by different navigators despite using similar or identical search terms, but there was also variability in the total number of eligible studies for the patient. Conclusions: The functionality of clinical trials search engines compromises equitable access to clinical trials, and impair clinical trials accrual. The highlighted challenges of the current clinical trials search engines available to patients and health care professions indicate an inefficient process that may be compromising clinical trial recruitment and thus potential patient outcomes.

Targeting miRNAs and Other Non-Coding RNAs as a Therapeutic Approach: An Update.

Since the discovery of the first microRNAs (miRNAs, miRs), the understanding of miRNA biology has expanded substantially. miRNAs are involved and described as master regulators of the major hallmarks of cancer, including cell differentiation, proliferation, survival, the cell cycle, invasion, and metastasis. Experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression, and because miRNAs act as tumor suppressors or oncogenes (oncomiRs), they have emerged as attractive tools and, more importantly, as a new class of targets for drug development in cancer therapeutics. With the use of miRNA mimics or molecules targeting miRNAs (i.e., small-molecule inhibitors such as anti-miRS), these therapeutics have shown promise in preclinical settings. Some miRNA-targeted therapeutics have been extended to clinical development, such as the mimic of miRNA-34 for treating cancer. Here, we discuss insights into the role of miRNAs and other non-coding RNAs in tumorigenesis and resistance and summarize some recent successful systemic delivery approaches and recent developments in miRNAs as targets for anticancer drug development. Furthermore, we provide a comprehensive overview of mimics and inhibitors that are in clinical trials and finally a list of clinical trials based on miRNAs.

390 A Mixed Methods Review of Endpoint Measures Utilized in Adult ADHD Medication Clinical Trial Design

OBJECTIVES/GOALS: To evaluate the clinical trial designs of stimulant medications approved for the treatment of adult Attention-Deficit/Hyperactivity Disorder (ADHD) and identify discrepancies between safety and efficacy outcome measure criteria. METHODS/STUDY POPULATION: There are 24 stimulants currently approved and marketed for the treatment of adult ADHD: 12 amphetamine (AMP)-based and 12 methylphenidate (MPH)-based formulations. A mixed methods review of clinical trials that have evaluated the safety and efficacy of these drugs will be performed using qualitative and quantitative data, including inclusion and exclusion criteria, primary and secondary outcome measures, manufacturer recommendations, and package inserts, as well as FDA recommendations for industry. After compiling a list of clinical trials for each of the 24 drugs, this information will be analyzed for themes and trends in the assessment of safety and efficacy with particular attention paid to differing criteria between individual drugs and/or the two subclasses of prescription stimulants. RESULTS/ANTICIPATED RESULTS: The FDA has published recommendations for ADHD medication clinical trial design, including suggested outcome measures utilizing validated assessment tools. However, the FDA notes that these assessments may be altered to fit study populations and indicate that other primary and secondary endpoint measures may be acceptable. As such, efficacy assessments for these drugs may vary greatly, and the specific criterion selected for each drug’s study population and outcome measures may suggest more specific indications and usage conditions for optimal efficacy. DISCUSSION/SIGNIFICANCE: Regulatory officials consider AMP- and MPH-based stimulants equivalent therapeutic options for the treatment of ADHD. A study of clinical trial criteria reveals that differing mechanisms have been used to evaluate safety and efficacy. This discrepancy may have implications that affect clinical decision-making and patient experiences.

Assessing the reporting quality of adult neuro-oncology protocols, abstracts, and trials: Adherence to the SPIRIT and CONSORT statements.

Comprehensive and transparent reporting of clinical trial activity is important. The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and Consolidated Standards of Reporting Trials (CONSORT) 2010 statements define the items to be reported in clinical trial protocols and randomized controlled trials, respectively. The aim of this methodological review was to assess the reporting quality of adult neuro-oncology trial protocols and trial result articles. Adult primary and secondary brain tumor phase 3 trial protocols and result articles published after the introduction of the SPIRIT 2013 statement, were identified through searches of 4 electronic bibliographic databases. Following extraction of baseline demographic data, the reporting quality of independently included trial protocols and result articles was assessed against the SPIRIT and CONSORT statements respectively. The CONSORT-A checklist, an extension of the CONSORT 2010 statement, was used to specifically assess the abstract accompanying the trial results article. Percentage adherence (standard deviation [SD]) was calculated for each article. Seven trial protocols, and 36 trial result articles were included. Mean adherence of trial protocols to the SPIRIT statement was 79.4% (SD: 0.11). Mean adherence of trial abstracts to CONSORT-A was 75.3% (SD: 0.12) and trial result articles to CONSORT was 74.5% (SD: 0.10). The reporting quality of adult neuro-oncology trial protocols and trial result articles requires improvement to ensure comprehensive and transparent communication of planned neuro-oncology clinical trials and results within the literature. Raising awareness by clinical triallists and implementing mandatory evidence of proof of adherence by journals should improve reporting quality.

Analysis of the distribution of trial sites in South Korea using social network analysis.

Location of trial sites can be a potential source of study bias. Considering that clinical trials have been mostly conducted in urban areas, the distribution of trial sites need to be evaluated. We analyzed clinical trial approval data using social network analysis to quantitatively assess the site-by-site connections. The approval list of clinical trials from the Ministry of Food and Drug Safety database between 2014 and 2021 was analyzed. The number of clinical trials per trial site was counted according to the approval year and study phase and evaluated for distribution using empirical cumulative distribution function plots. Trial sites and conducts of a clinical trial were mapped into nodes and edges in the social network analysis, and basic network parameters were obtained. The clinical trials were concentrated at several trial sites. Forty-nine to 60.6% of phase 1 and up to 30% of the other study phases of clinical trials were at the top 5 trial sites. The annual distribution of the number of clinical trials per site was comparable across the study period. Connections among the trial sites in the metropolitan area were prominent. Graph size and density were higher in phase 3 trials than in the other phases. We demonstrated that the conduct of clinical trials was concentrated in the Seoul Metropolitan Area in both number of trials and connections using social network analysis.

A Comparison of PROPr and EQ-5D-5L Value Sets.

ObjectivesThe EQ-5D-5L and its value sets are widely used internationally. However, in the US and elsewhere, there is growing use of PROMIS, which has a value set (PROPr) based on the stated preferences of the US population. This paper aims to compare the characteristics of EQ-5D-5L and PROPr value sets and to highlight potential implications for users.MethodsUS, Australian and English value sets were used for EQ-5D-5L. PROPr utilities were calculated based on PROMIS-29 + 2. We examined, in each case, (i) the characteristics (e.g. range of values, number of unique values) and distribution of all possible ‘theoretical’ utilities; (ii) dimension/domain importance ranking by the utility of corner states (i.e. health states with the worst level in one domain and the best in all others); (iii) comparisons of utilities for health states hypothesised to be comparable in terms of severity across EQ-5D-5L descriptive systems and PROMIS-29 + 2 domain scores; (iv) the changes in values of adjacent states (i.e. a one-level change in one dimension for EQ-5D-5L and a four-point change in raw scores for PROMIS-29 + 2, with the other dimensions held constant) for dimensions hypothesised to overlap conceptually or be correlated between the two instruments.ResultsEQ-5D-5L and PROPr utilities differ systematically. First, the US EQ-5D-5L utilities range from − 0.573 to 1, whereas PROPr values for PROMIS-29 + 2 range from − 0.022 to 0.954. Second, in the US (and English) EQ-5D-5L value sets, pain is the most important dimension whereas in PROPr pain is one of the least important (apart from sleep disturbance). Third, classified based on severity across EQ-5D-5L descriptive systems and PROMIS-29 + 2 domain scores, PROPr has substantially lower values than EQ-5D-5L values for comparable ‘mild’ health states, but higher values for more ‘severe’ health states. Last, when one dimension is considered across its best to worst levels and all other dimensions are held constant at their best or moderate level, in EQ-5D-5L value sets, the greatest changes in utility occur between levels 3 and 4 (moderate and severe) problems; in PROPr that occurred between the most severe states and their descriptively adjacent health states.ConclusionThere are very considerable differences between US EQ-5D-5L and PROPr utilities, despite both in principle representing utility on the same scale anchored at 0 and 1 and both representing the preferences of the US general public. It is important for decision makers and clinical triallists to be aware of these differences. Further work is needed to assess the impact of these differences in value sets using population and patient data, and in longitudinal settings.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40273-021-01109-3.

Missing trials in drug regulatory dossiers may have good reasons, but should be predefined and transparent

Boesen and colleagues have done a tremendous job in addressing the question: when I have a list of clinical trials of a class of long-acting medicinal products containing methylphenidate, and I want to see whether these trials also pop-up in the regulatory dossiers that are assumed to deal with the licensing process of these products for use in adult patients with ADHD, what do I see? [1]. At first glance a very simple and logical question for everybody interested in how regulatory processes function and whether these processes contribute to public health and patient safety.

Abstract 3638: Analysis of the clinical benefit of comprehensive genome profiling derived therapeutic associations in advanced cancer

Abstract Modern cancer care has seen an increase in the use of targeted therapies and the number of FDA-approved biomarkers. To take advantage of these options, many have turned to commercially available comprehensive genome profiling (CGP) services, like Foundation Medicine's FoundationOne assay. FoundationOne (FO) offers a list of clinically relevant genomic alterations and biomarkers, as well as a list of clinical trials, on-label and off-label therapies that may benefit the patient, that is, therapeutic associations. We performed a retrospective cohort study to assess the clinical benefit of therapy associations from FO reports. We collected demographics, therapy records, and clinical outcomes for 1004 patients who had a history of advanced cancer in the Cleveland Clinic system and had received a FO report between 2012 and 2017. FO therapy associations were considered as “applied” if a patient received an order for said therapy for the first time after their report date. We classified patients as follows: No Associated Therapy (NAT) if the patient did not receive any recommendations, Therapy Applied (TA) if at least one associated therapy was ordered after report date, and Therapy Not Applied (TNA) if none of the associated therapies were applied. We evaluated differences in demographic and clinical features among the 3 groups using Chi-squared and Kruskal-Wallis tests where appropriate. We performed survival analysis using univariate and multivariate COX Proportional Hazards regression models, and Log-Rank tests on Kaplan Meier Curves with overall survival (OS) as our metric. Our cohort demographics were 55% male, 85% white, 92% non-Hispanic, and a median age at report of 60 (IQR: 51-69). The most common diagnoses were Lung Adenocarcinoma (14%), Glioblastoma (8%), Colon Adenocarcinoma (8%), and Breast Cancer NOS (4%). Most of our patients belonged to the TNA class (64%), 21% were NAT, and 15% were TA. There was no statistical significance in the demographic distribution among the therapy classes. In the pan-cancer analysis, we found no statistically significant difference in OS among the therapy groups or any of the adjusted covariates except for metastasis status. Similarly, when evaluating the top cancer diagnoses individually, we found no significant differences in OS. The data in our study indicates that the application of FO therapy associations is not correlated with a statistically significant difference in OS for advanced cancer patients. This suggests that larger studies should be performed to better understand how CGP services provide clinical benefits to patients, and how we can maximize these benefits in the real-world community setting. Citation Format: Jean Rene Clemenceau, Sung Hak Lee, Alex Milinovich, Jian Jin, Nathan Pennell, Davendra Sohal, Tae Hyun Hwang. Analysis of the clinical benefit of comprehensive genome profiling derived therapeutic associations in advanced cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3638.

Pharmacokinetic and pharmacodynamic evidence of adrenaline administered via auto-injector for anaphylactic reactions: A review of literature.

Anaphylaxis is a severe allergic reaction that can lead to death if not treated quickly. Adrenaline (epinephrine) is the first-line treatment for anaphylaxis and its prompt administration is vital to reduce mortality. Following a number of high-profile cases, serious concerns have been raised, both about the optimal dose of intramuscular adrenaline via an auto-injector and the correct needle length to ensure maximal penetration every time. To date, the public data are sparse on the pharmacokinetics-pharmacodynamics of adrenaline administered via an auto-injector. The limited available literature showed a huge variation in the plasma concentrations of adrenaline administered through an auto-injector, as well as variations in the auto-injector needle length. Hence, delivering an effective dose during an anaphylaxis remains a challenge for both patients and healthcare professionals. Collaborative work between pharmacokinetics-pharmacodynamics experts, clinical triallists and licence holders is imperative to address this gap in evidence so that we can improve outcomes of anaphylaxis. In addition, we advise inclusion of expertise of human factors in usability studies given the necessity of carer or self-administration in the uniquely stressful nature of anaphylaxis.

Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

Where Can Patients Obtain Information on the Preapproval Access Pathway to Investigational Treatment in Japan? A Survey of Patient Advocacy Organizations' Websites.

Investigational treatments are those that have been approved for testing in humans but are not yet available as an approved treatment option. For many patients with a terminal illness who have no approved treatment option and are not eligible for a clinical trial, investigational treatments are the last resort. However, not much is known about the dissemination of information by patient advocacy organizations (PAOs). We evaluated the quantity and quality of information on preapproval access to investigational therapies provided by Japanese PAO websites between January 24 and March 29, 2019. A total of 49 PAOs were identified. Of these, 16 (33%) provided no relevant information. The most frequent information provided was the PAO's own clinical trial finder or list of clinical trials (n = 15, 31%); of the 10 cancer‐related PAOs, 5 (50%) provided this information. Nine (18%) PAOs had developed patient registries or provided a link to relevant registries. Only 1 PAO (2%) provided a link about the Ministry of Health, Labour, and Welfare trials that described the process and regulations of clinical trials. Our results indicate that PAOs do not disseminate adequate information on preapproval pathways. We suggest that the government involve PAOs in disseminating this information to both patients and physicians.

A systematic review of outcomes in postoperative pain studies in paediatric and adolescent patients: towards development of a core outcome set.

Systematic reviews of postoperative pain in children have called into question the consistency of outcomes measured by clinical triallists as well as the measurement instruments used for assessment. Core outcome set methodology may be a solution to improve standardisation. This study provides an evidence-based foundation for the development of a core outcome set for paediatric postoperative pain studies. We searched ClinicalTrials.gov to identify relevant postoperative pain studies in children. The search yielded 300 registered trials. The following data were then extracted from each of the trials: phase of trial; study type; study design; sample size; all outcomes; whether the outcome was listed as primary, secondary, or tertiary; the measurement instrument for each reported outcome; the specific metric for each outcome; and the type of clinical procedure. Following screening, 134 studies were included in our study. Pain measurement was the most commonly reported outcome (n = 123), followed by total postoperative analgesic dosage (n = 83) and side-effects (n = 25). Temporal trends indicated that pain assessment and unexpected events increased in use between 2000 and 2016, whereas postoperative analgesia measurement decreased. We found a lack of standardisation among outcomes and measurement instruments in paediatric postoperative pain studies. Development of a core outcome set may improve the quality of future trials and allow for more accurate study-to-study comparisons.

Comparative Effectiveness of Up To Three Lines of Chemotherapy Treatment Plans for Metastatic Colorectal Cancer.

Modern chemotherapy agents transformed standard care for metastatic colorectal cancer (mCRC) but raised concerns about the financial burden of the disease. We studied comparative effectiveness of treatment plans that involve up to three lines of therapies and impact of treatment sequencing on health and cost outcomes. We employed a Markov model to represent the dynamically changing health status of mCRC patients and used Monte-Carlo simulation to evaluate various treatment plans consistent with existing guidelines. We calibrated our model by a meta-analysis of published data from an extensive list of clinical trials and measured the effectiveness of each plan in terms of cost per quality-adjusted life year. We examined the sensitivity of our model and results with respect to key parameters in two scenarios serving as base case and worst case for patients’ overall and progression-free survivals. The derived efficient frontiers included seven and five treatment plans in base case and worst case, respectively. The incremental cost-effectiveness ratio (ICER) ranged between $26,260 and $152,530 when the treatment plans on the efficient frontiers were compared against the least costly efficient plan in the base case, and between $21,256 and $60,040 in the worst case. All efficient plans were expected to lead to fewer than 2.5 adverse effects and on average successive adverse effects were spaced more than 9 weeks apart from each other in the base case. Based on ICER, all efficient treatment plans exhibit at least 87% chance of being efficient. Sensitivity analyses show that the ICERs were most dependent on drug acquisition cost, distributions of progression-free and overall survivals, and health utilities. We conclude that improvements in health outcomes may come at high incremental costs and are highly dependent in the order treatments are administered.

Selective decontamination of the digestive tract in critically ill patients treated in intensive care units: a mixed-methods feasibility study (the SuDDICU study).

Hospital-acquired infections (HAIs) are a major cause of morbidity and mortality. Critically ill patients in intensive care units (ICUs) are particularly susceptible to these infections. One intervention that has gained much attention in reducing HAIs is selective decontamination of the digestive tract (SDD). SDD involves the application of topical non-absorbable antibiotics to the oropharynx and stomach and a short course of intravenous (i.v.) antibiotics. SDD may reduce infections and improve mortality, but has not been widely adopted in the UK or internationally. Hence, there is a need to identify the reasons for low uptake and whether or not further clinical research is needed before wider implementation would be considered appropriate. The project objectives were to (1) identify and describe the SDD intervention, (2) identify views about the evidence base, (3) identify acceptability of further research and (4) identify feasibility of further randomised controlled trials (RCTs). A four-stage approach involving (1) case studies of two ICUs in which SDD is delivered including observations, interviews and documentary analysis, (2) a three-round Delphi study for in-depth investigation of clinicians' views, including semi-structured interviews and two iterations of questionnaires with structured feedback, (3) a nationwide online survey of consultants in intensive care medicine and clinical microbiology and (4) semistructured interviews with international clinical triallists to identify the feasibility of further research. Case studies were set in two UK ICUs. Other stages of this research were conducted by telephone and online with NHS staff working in ICUs. (1) Staff involved in SDD adoption or delivery in two UK ICUs, (2) ICU experts (intensive care consultants, clinical microbiologists, hospital pharmacists and ICU clinical leads), (3) all intensive care consultants and clinical microbiologists in the UK with responsibility for patients in ICUs were invited and (4) international triallists, selected from their research profiles in intensive care, clinical trials and/or implementation trials. SDD involves the application of topical non-absorbable antibiotics to the oropharynx and stomach and a short course of i.v. antibiotics. Levels of support for, or opposition to, SDD in UK ICUs; views about the SDD evidence base and about barriers to implementation; and feasibility of further SDD research (e.g. likely participation rates). (1) The two case studies identified complexity in the interplay of clinical and behavioural components of SDD, involving multiple staff. However, from the perspective of individual staff, delivery of SDD was regarded as simple and straightforward. (2) The Delphi study (n = 42) identified (a) specific barriers to SDD implementation, (b) uncertainty about the evidence base and (c) bimodal distributions for key variables, e.g. support for, or opposition to, SDD. (3) The national survey (n = 468) identified uncertainty about the effect of SDD on antimicrobial resistance, infection rates, mortality and cost-effectiveness. Most participants would participate in further SDD research. (4) The triallist interviews (n = 10) focused largely on the substantial challenges of conducting a large, multinational clinical effectiveness trial. There was considerable uncertainty about possible benefits and harms of SDD. Further large-scale clinical effectiveness trials of SDD in ICUs may be required to address these uncertainties, especially relating to antimicrobial resistance. There was a general willingness to participate in a future effectiveness RCT of SDD. However, support was not unanimous. Future research should address the barriers to acceptance and participation in any trial. There was some, but a low level of, interest in adoption of SDD, or studies to encourage implementation of SDD into practice. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 25. See the NIHR Journals Library website for further project information.

Review of Tissue-Protective Cytokines

Review of Tissue-Protective Cytokines

Human Stromal (Mesenchymal) Stem Cells: Basic Biology and Current Clinical Use for Tissue Regeneration

Human stromal (mesenchymal) stem cells (hMSC) represent a group of non-hematopoietic stem cells present in the bone marrow stroma and the stroma of other organs including subcutaneous adipose tissue, placenta, and muscles. They exhibit the characteristics of somatic stem cells of self-renewal and multi-lineage differentiation into mesoderm-type of cells, e.g., to osteoblasts, adipocytes, chondrocytes and possibly other cell types including hepatocytes and astrocytes. Due to their ease of culture and multipotentiality, hMSC are increasingly employed as a source for cells suitable for a number of clinical applications, e.g., non-healing bone fractures and defects and also non-skeletal degenerative diseases like heart failure. Currently, the numbers of clinical trials that employ MSC are increasing. However, several biological and biotechnological challenges need to be overcome to benefit from the full potential of hMSC. In this current review, we present some of the most important and recent advances in understanding of the biology of hMSC and their current and potential use in therapy.

Evaluation of PubMed filters used for evidence-based searching: validation using relative recall

The research sought to determine the value of PubMed filters and combinations of filters in literature selected for systematic reviews on therapy-related clinical questions. References to 35,281 included and 48,514 excluded articles were extracted from 2,629 reviews published prior to January 2008 in the Cochrane Database of Systematic Reviews and sent to PubMed with and without filters. Sensitivity, specificity, and precision were calculated from the percentages of unfiltered and filtered references retrieved for each review and averaged over all reviews. Sensitivity of the Sensitive Clinical Queries filter was reasonable (92.7%, 92.1-93.3); specificity (16.1%, 15.1-17.1) and precision were low (49.5%, 48.5-50.5). The Specific Clinical Queries and the Single Term Medline Specific filters performed comparably (sensitivity, 78.2%, 77.2-79.2 vs. 78.0%; 77.0-79.0; specificity, 52.0%, 50.8-53.2 vs. 52.3%, 51.1-53.5; precision, 60.4%, 59.4-61.4 vs. 60.6%, 59.6-61.6). Combining the Abridged Index Medicus (AIM) and Single Term Medline Specific (65.2%, 63.8-66.6), Two Terms Medline Optimized (64.2%, 62.8-65.6), or Specific Clinical Queries filters (65.0%, 63.6-66.4) yielded the highest precision. Sensitive and Specific Clinical Queries filters used to answer questions about therapy will result in a list of clinical trials but cannot be expected to identify only methodologically sound trials. The Specific Clinical Queries filters are not suitable for questions regarding therapy that cannot be answered with randomized controlled trials. Combining AIM with specific PubMed filters yields the highest precision in the Cochrane dataset.