tbuckley/cabot-search huggingface dataset:
Contamination in trials: is cluster randomisation the answer?
Authors: D. J Torgerson
Journal: BMJ (2001)

Most randomised trials allocate individual participants to different treatments. However, cluster randomised trials in which groups of subjects are allocated to different treatments are becoming increasingly popular.1 Cluster randomisation is often advocated to minimise treatment “contamination” between intervention and control participants. For example, in a trial of dietary change, people in the control group might learn about the experimental diet and adopt it themselves.

Contamination of control participants has two related effects. It reduces the point estimate of an intervention's effectiveness and this apparent reduction may lead to a type II error—that is, rejection of an effective intervention as ineffective because the observed effect size was neither statistically nor clinically significant.

Although the threat of contamination is an issue in some controlled trials, it may be not be of much practical importance in many. Trialists should use individual randomisation if possible because of the drawbacks of cluster allocation. Cluster trials are associated with problems of recruitment bias and the need for larger samples than would be required in similar, individually randomised trials. In recruitment bias, different sorts of participants are selected into the various arms of the trial, thereby defeating the objective of randomisation, while a larger sample size may increase the cost of a trial, its length, or its complexity. This paper describes the difficulties of cluster trials and argues that the problem of contamination can often be dealt with by individual randomisation.

#### Summary points

Cluster trials are often used to prevent “contamination” between intervention and control groups

Cluster trials are usually very much larger than individually randomised trials and can be susceptible to recruitment bias

The problem of contamination can often be overcome by increasing the sample size

In terms of total sample size, cluster trials are only more efficient where contamination exceeds 30%

Members of clusters cannot be …
Treatment of Cancer with a Novel Dual-Targeted Conditionally Replicative Adenovirus Armed with <i>mda-7/IL-24</i> Gene
Authors: Jingjing Luo, Qingmei Xia, Rui Zhang, Chen Lv, Wei Zhang, Yingxin Wang, Qiang Cui, Li Liu, Rong Cai, Cheng Qian
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Recent studies showed that oncolytic adenoviruses not only have capacity for destruction of tumors but also can be used as potential vectors to express therapeutic genes for therapy of cancer. However, better specificity and mode of transgene expression are required to improve the efficacy and safety if this vector is applied for clinical application. Experimental Design: In this study, we have created adenoviral replication-based transgene expression system by replacement of 6.7K/gp19K of E3 genes with EGFP and IL-24 genes so that expression of transgenes should be controlled by adenoviral E3 promoter. Transgene expression, viral replication capacity, and cytotoxicity have been studied in tumor and normal cells. Antitumor efficacy was evaluated in animal model with established tumor. Results: Our data showed that expression of IL-24 could be detected at 6 h and reached the maximal level at 48 h after infection in tumor cells. The expression level was 14 times higher than that induced by cytomegalovirus promoter. Low level of IL-24 could be detected in normal cells only until 72 h after infection. The substitution of 6.7K/gp19K of E3 genes with transgenes did not affect viral replication in tumor cells. Strong cytotoxicity was observed only in tumor cells after infection with AdCN205-IL-24. Treatment of the established tumors induced high level of local expression of IL-24 in tumor cells and resulted in tumor regression. Conclusions: Our data showed that AdCN205-IL-24 can provide potent and safe vector for the therapy of cancer.
Matrix metalloproteinase 9 is involved in Crohn's disease-associated platelet hyperactivation through the release of soluble CD40 ligand
Authors: L Menchen, I Marin-Jimenez, E G Arias-Salgado, T Fontela, P Hernandez-Sampelayo, M C G. Rodriguez, N V Butta
Journal: Gut (2008)

<h3>Background:</h3> Patients with Crohn's disease have an increased risk for systemic thromboembolism. Their platelets are hyperactive and possess an elevated endogenous content of CD40 ligand (CD40L), a tumour necrosis factor α family protein member. Under basal conditions and after stimulation, these platelets express more CD40L on their surface and release higher amounts of soluble (s)CD40L than control platelets, through a mechanism that might be mediated by matrix metalloproteinases (MMPs). <h3>Objective:</h3> The aim of this work is to study whether enhanced sCD40L release secondary to changes in the platelet content of MMPs contributes to the higher state of activation of platelets from patients with Crohn's disease. <h3>Methods:</h3> State of activation, CD40L and metalloproteinases content of platelets isolated from patients with Crohn's disease and age- and sex-matched control individuals were analysed, respectively, by flow cytometry, western blot and gelatin zymography. <h3>Results:</h3> The hyperactive state of platelets from patients with Crohn's disease might rely on their enhanced release of sCD40L, since its inhibition by a broad-range inhibitor of MMPs (GM6001) reduced fibrinogen binding induced by platelet stimulation. Analysis of the content of MMPs in platelets from patients with Crohn's disease showed an exclusive increase in MMP-9 activity. Moreover, MMP-9 inhibition diminished sCD40L release and fibrinogen binding to activated platelets. <h3>Conclusions:</h3> The results suggest that platelets from patients with Crohn's disease release more sCD40L than controls as a consequence of their higher endogenous content of CD40L and of MMP-9, which is involved in CD40L shedding. The increased levels of released sCD40L might be responsible, at least in part, for the high state of activation of platelets from patients with Crohn's disease.
Loss of the miR-144/451 cluster impairs ischaemic preconditioning-mediated cardioprotection by targeting Rac-1
Authors: Xiaohong Wang, Hongyan Zhu, Xiaowei Zhang, Yong Liu, Jing Chen, Mario Medvedovic, Hongliang Li, Mitchell J. Weiss, Xiaoping Ren, Guo-Chang Fan
Journal: Cardiovascular Research (2012)

AimsWhile a wealth of data has uncovered distinct microRNA (miR) expression alterations in hypertrophic and ischaemic/reperfused (I/R) hearts, little is known about miR regulation and response to ischaemic preconditioning (IPC).
Prognostic and Predictive Values of the Immunoscore in Patients with Rectal Cancer
Authors: Maria-Gabriela Anitei, Guy Zeitoun, Bernhard Mlecnik, Florence Marliot, Nacilla Haicheur, Ana-Maria Todosi, Amos Kirilovsky, Christine Lagorce, Gabriela Bindea, Dan Ferariu, Mihai Danciu, Patrick Bruneval, Viorel Scripcariu, Jean-Marc Chevallier, Franck Zinzindohoué, Anne Berger, Jérôme Galon, Franck Pagès
Journal: Clinical Cancer Research (2014)

To determine whether the tumor immune infiltrate, as recently evaluated with the Immunoscore methodology, could be a useful prognostic marker in patients with rectal cancers.The influence of the immune infiltrate on patient's outcome was investigated in patients with or without preoperative chemoradiation therapy (pCRT). The density of total (CD3(+)) and cytotoxic (CD8(+)) T lymphocytes was evaluated by immunohistochemistry and quantified by a dedicated image analysis software in surgical specimens of patients with rectal cancer (n = 111) who did not receive pCRT and in tumor biopsies performed before pCRT from additional 55 patients. The results were correlated with tumor recurrence, patient's survival, and response to pCRT.The densities of CD3(+) and CD8(+) lymphocytes and the associated Immunoscore (from I0 to I4) were significantly correlated with differences in disease-free and overall survival (HR, 1.81 and 1.72, respectively; all P < 0.005). Cox multivariate analysis supports the advantage of the Immunoscore compared with the tumor-node-metastasis (TNM) staging in predicting recurrence and survival (all P < 0.001). Lymph node ratio added information in a prognostic model (all P < 0.05). In addition, high infiltration of CD3(+) and CD8(+) lymphocytes in tumor biopsies was associated with downstaging of the tumor after pCRT (CD3(+) cells; Fisher exact test P = 0.01).The Immunoscore could be a useful prognostic marker in patients with rectal cancer treated by primary surgery. The determination of the immune infiltrate in biopsies before treatment could be a valuable information for the prediction of response to pCRT.
Prospective Evaluation of the Functional Sling Suspension for Male Postprostatectomy Stress Urinary Incontinence: Results after 1 Year
Authors: Ricarda M. Bauer, Margit E. Mayer, Christian Gratzke, Irina Soljanik, Alexander Buchner, Patrick J. Bastian, Christian G. Stief, Christian Gozzi
Journal: European Urology (2009)
Single-Cell Profiling Identifies Aberrant STAT5 Activation in Myeloid Malignancies with Specific Clinical and Biologic Correlates
Authors: Nikesh Kotecha, Nikki J. Flores, Jonathan M. Irish, Erin F. Simonds, Debbie S. Sakai, Sophie Archambeault, Ernesto Diaz-Flores, Marc Coram, Kevin M. Shannon, Garry P. Nolan, Mignon L. Loh
Journal: Cancer Cell (2008)
Cancer Screening Among Patients With Advanced Cancer
Authors: Camelia S. Sima, Katherine S. Panageas, Deborah Schrag
Journal: JAMA (2010)

Cancer screening has been integrated into routine primary care but does not benefit patients with limited life expectancy.To evaluate the extent to which patients with advanced cancer continue to be screened for new cancers.Utilization of cancer screening procedures (mammography, Papanicolaou test, prostate-specific antigen [PSA], and lower gastrointestinal [GI] endoscopy) was assessed in 87,736 fee-for-service Medicare enrollees aged 65 years or older diagnosed with advanced lung, colorectal, pancreatic, gastroesophageal, or breast cancer between 1998 and 2005, and reported to one of the Surveillance, Epidemiology, and End Results (SEER) tumor registries. Participants were followed up until death or December 31, 2007, whichever came first. A group of 87,307 Medicare enrollees without cancer were individually matched by age, sex, race, and SEER registry to patients with cancer and observed over the same period to evaluate screening rates in context. Demographic and clinical characteristics associated with screening were also investigated.For each cancer screening test, utilization rates were defined as the percentage of patients who were screened following the diagnosis of an incurable cancer.Among women following advanced cancer diagnosis compared with controls, at least 1 screening mammogram was received by 8.9% (95% confidence interval [CI], 8.6%-9.1%) vs 22.0% (95% CI, 21.7%-22.5%); Papanicolaou test screening was received by 5.8% (95% CI, 5.6%-6.1%) vs 12.5% (95% CI, 12.2%-12.8%). Among men following advanced cancer diagnosis compared with controls, PSA test was received by 15.0% (95% CI, 14.7%-15.3%) vs 27.2% (95% CI, 26.8%-27.6%). For all patients following advanced diagnosis compared with controls, lower GI endoscopy was received by 1.7% (95% CI, 1.6%-1.8%) vs 4.7% (95% CI, 4.6%-4.9%). Screening was more frequent among patients with a recent history of screening (16.2% [95% CI, 15.4%-16.9%] of these patients had mammography, 14.7% [95% CI, 13.7%-15.6%] had a Papanicolaou test, 23.3% [95% CI, 22.6%-24.0%] had a PSA test, and 6.1% [95% CI, 5.2%-7.0%] had lower GI endoscopy).A sizeable proportion of patients with advanced cancer continue to undergo cancer screening tests that do not have a meaningful likelihood of providing benefit.
Predictors of poor outcome and benefits from antibiotics in children with acute otitis media: pragmatic randomised trial * Commentary: research directions for treatment for acute otitis media
Authors: P. Little
Journal: BMJ (2002)

# Predictors of poor outcome and benefits from antibiotics in children with acute otitis media: pragmatic randomised trial {#article-title-2} Objectives : To identify which children with acute otitis media are at risk of poor outcome and to assess benefit from antibiotics in these children. Design : Secondary analysis of randomised controlled trial cohort. Setting : Primary care. Participants : 315 children aged 6 months to 10 years. Intervention : Immediate or delayed (taken after 72 hours if necessary) antibiotics. Main outcome measure : Predictors of short term outcome: an episode of distress or night disturbance three days after child saw doctor. Results : Distress by day three was more likely in children with high temperature (adjusted odds ratio 4.5, 95% confidence interval 2.3 to 9.0), vomiting (2.6,1.3 to 5.0), and cough (2.0, 1.1 to 3.8) on day one. Night disturbance by day three was more likely with high temperature 2.4 (1.2 to 4.8), vomiting (2.1,1.1 to 4.0), cough (2.3,1.3 to 4.2), and ear discharge (2.1, 1.2 to 3.9). Among the children with high temperature or vomiting, distress by day three was less likely with immediate antibiotics (32% for immediate v 53% for delayed, χ2=4.0; P=0.045, number needed to treat 5) as was night disturbance (26% v 59%, χ2=9.3; P=0.002; number needed to treat 3). In children without higher temperature or vomiting, immediate antibiotics made little difference to distress by day three (15% v 19%, χ2=0.74; P=0.39) or night disturbance (20% v 27%, χ2=1.6; P=0.20). Addition of cough did not significantly improve prediction of benefit. Conclusion : In children with otitis media but without fever and vomiting antibiotic treatment has little benefit and a poor outcome is unlikely. # Commentary: research directions for treatment for acute otitis media {#article-title-17}
Is Visceral Fat Responsible for the Metabolic Abnormalities Associated With Obesity?
Authors: Samuel Klein
Journal: Diabetes Care (2010)

The results from both epidemiological and physiological studies have demonstrated a strong association between excess abdominal adipose tissue and the presence of metabolic risk factors for coronary heart disease (CHD), including insulin resistance, impaired glucose tolerance, type 2 diabetes, dyslipidemia, and increased circulating inflammatory proteins (1–3). Abdominal adipose tissue is a complex organ and is composed of multiple distinct compartments and subcompartments, including subcutaneous fat and intra-abdominal fat, which can be further subdivided into retroperitoneal and intraperitoneal fat, which can be divided again into mesenteric and omental fat masses. Intraperitoneal fat, which is also known as visceral adipose tissue (VAT), is considered a particularly important marker of metabolic risk (4–6).

It has been hypothesized that increased VAT is directly involved in the pathogenesis of metabolic dysfunction because VAT releases free fatty acids (FFAs) and inflammatory proteins into the portal vein, which are delivered to the liver (7). However, most FFAs in the portal circulation are derived from subcutaneous adipose tissue, and <20% of total FFAs delivered to the …
The Effect of Intermittent Antenatal Iron Supplementation on Maternal and Infant Outcomes in Rural Viet Nam: A Cluster Randomised Trial
Authors: Sarah Hanieh, Tran T. Ha, Julie A. Simpson, Gerard J. Casey, Nguyen C. Khuong, Dang D. Thoang, Tran T. Thuy, Sant-Rayn Pasricha, Thach D. Tran, Tran Tuan, Terence Dwyer, Jane Fisher, Beverley-Ann Biggs
Journal: PLoS Medicine (2013)

Beverley-Anne Biggs and colleagues conduct a community-based cluster randomized trial in rural Viet Nam to compare the effect of antenatal iron-folic acid supplementation taken daily or twice weekly on maternal and infant outcomes. Please see later in the article for the Editors' Summary
Histamine-induced end-tidal inspiratory activity and lung receptors in cats
Authors: NE Meeseen, CP van der Grinten, HT Folgering, SC Luijendijk
Journal: European Respiratory Journal (1995)

Hyperinflation in acute asthma has been associated with inspiratory muscle activity, which persist during expiration. The main objective of the present study was to evaluate the role of rapidly adapting receptors (RARs), slowly adapting receptors (SARs) and C-fibre endings in generating end-tidal inspiratory activity (ETIA). ETIA was induced by intravenous administration of histamine and continuous negative airway pressure (CNAP) in anaesthetized, spontaneously breathing cats. To differentiate between reflex activities from the three types of lung receptors, both vagus nerves were cooled to eight different temperatures (Tvg) between 4 and 37 degrees C. It is known that CNAP stimulates RARs and inhibits SARs. Histamine was used to stimulate RARs, and this was combined with continuous positive airway pressure (CPAP) to further stimulate SARs. ETIA was evoked in the diaphragm and in parasternal intercostal muscles by both stimuli (histamine and CNAP) in 8 out of 18 cats. After vagotomy, neither histamine nor CNAP evoked ETIA any more. At Tvg = 37 degrees C, CPAP suppressed histamine-induced ETIA; whereas, this suppression was diminished at Tvg between 14 and 8 degrees C. ETIA sharply declined for Tvg between 8 degrees and 4 degrees C, and at Tvg = 4 degrees C ETIA had virtually disappeared. At Tvg = 37 degrees and 22 degrees C values of ETIA during CNAP were larger than those in response to histamine; whereas, at Tvg = 10 degrees C comparable ETIA values were obtained. It was shown that ETIA is a vagal reflex activity in which C-fibre endings are not involved. Histamine-induced ETIA originates from stimulation of RARs, and is inhibited by stimulation of SARs. Mechanical stimulation of RARs is a forceful stimulus to induce ETIA. This suggests that hyperinflation in acute asthma might be due, at least in part, to ETIA resulting from an imbalance between SAR and RAR activity.
Phase II Study of the Oral MEK Inhibitor Selumetinib in Advanced Acute Myelogenous Leukemia: A University of Chicago Phase II Consortium Trial
Authors: Nitin Jain, Emily Curran, Neil M. Iyengar, Ernesto Diaz-Flores, Rangesh Kunnavakkam, Leslie Popplewell, Mark H. Kirschbaum, Theodore Karrison, Harry P. Erba, Margaret Green, Xavier Poire, Greg Koval, Kevin Shannon, Poluru L. Reddy, Loren Joseph, Ehab L. Atallah, Philip Dy, Sachdev P. Thomas, Scott E. Smith, L. Austin Doyle, Walter M. Stadler, Richard A. Larson, Wendy Stock, Olatoyosi Odenike
Journal: Clinical Cancer Research (2013)

Abstract Purpose: The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown. Experimental Design: Selumetinib is an oral small-molecule inhibitor of MAP–ERK kinase (MEK)-1/2. Forty-seven patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). Leukemia cells were analyzed for extracellular signal—regulated kinase (ERK) and mTOR phosphorylation. Results: Common drug-related toxicities were grade 1–2 diarrhea, fatigue, nausea, vomiting, and skin rash. In the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P = 0.027). Conclusions: Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials. Clin Cancer Res; 20(2); 490–8. ©2013 AACR.
Diabetes and Sepsis: Preclinical Findings and Clinical Relevance
Authors: Philipp Schuetz, Pedro Castro, Nathan I. Shapiro
Journal: Diabetes Care (2011)

Because of its high prevalence and potential to alter critical elements of sepsis pathophysiology, diabetes is likely an important comorbid condition in this disease; yet the exact influence of diabetes on infection and the development of sepsis remain undefined. The aim of this article is to review evidence from preclinical and clinical trials to discuss the influence of diabetes on sepsis pathophysiology, susceptibility, and clinical outcomes.

### Evidence from animal and in vitro studies

#### Diabetes has reduced bacterial clearance in animal models.

A series of studies investigated whether diabetic mice responded differently to sepsis compared with mice without diabetes. Thereby, 1–2 weeks prior to the experiment, diabetic conditions were induced with streptozotocin, a cytotoxic antibiotic substance isolated from Streptomyces achromogenes, which produces irreversible damage to pancreatic β-cells resulting in hyperglycemia. When mice were experimentally infected with group B streptococcal bacteria, diabetic mice had reduced clearance of bacteria and higher mortality rates (1). Remarkably, the increased mortality in diabetic animals occurred later in the course of the disease (after 72 h) and was associated with persistent bacteremia and prolonged sequestration of viable microorganisms in the hepatic and splenic reticuloendothelial system. Similar findings were reported after infecting diabetic mice with Pseudomonas aeruginosa , where there was a direct association between increased numbers of microorganisms in liver, kidney, and spleen, and mortality (2). A more recent study investigated the host defense against tuberculosis (3). Diabetic mice had a significantly higher bacterial burden and increased inflammation in the lung. Production of γ-interferon (IFN-γ) was reduced by the presence of fewer antigen–responsive T-cells. Interestingly, Yamashiro et al. (4) expanded upon these findings by demonstrating increased numbers of live mycobacteria in lung, liver, and spleen, and lower IFN-γ and interleukin (IL)-12 cytokine levels in diabetic mice. Importantly, the control of blood glucose levels by insulin therapy in this study resulted in improvement of the impaired host protection and T helper type 1-related …