Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews . Main outcome measure: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. Results: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. Conclusions: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. Key messages Systematic reviews of randomised trials are the best strategy for appraising evidence; however, the findings of some meta-analyses were later contradicted by large trials Funnel plots, plots of the trials9 effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials Funnel plot asymmetry was found in 38% of meta-analyses published in leading general medicine journals and in 13% of reviews from the Cochrane Database of Systematic Reviews Critical examination of systematic reviews for publication and related biases should be considered a routine procedure

/pdf/bias-in-meta-analysis-detected-by-a-simple-graphical-test-5erh428s5c.pdf

Bias in meta-analysis detected by a simple, graphical test

OBJECTIVE: To test the feasibility of creating a valid and reliable checklist with the following features: appropriate for assessing both randomised and non-randomised studies; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting, internal validity (bias and confounding) and power, but also for external validity. DESIGN: A pilot version was first developed, based on epidemiological principles, reviews, and existing checklists for randomised studies. Face and content validity were assessed by three experienced reviewers and reliability was determined using two raters assessing 10 randomised and 10 non-randomised studies. Using different raters, the checklist was revised and tested for internal consistency (Kuder-Richardson 20), test-retest and inter-rater reliability (Spearman correlation coefficient and sign rank test; kappa statistics), criterion validity, and respondent burden. MAIN RESULTS: The performance of the checklist improved considerably after revision of a pilot version. The Quality Index had high internal consistency (KR-20: 0.89) as did the subscales apart from external validity (KR-20: 0.54). Test-retest (r 0.88) and inter-rater (r 0.75) reliability of the Quality Index were good. Reliability of the subscales varied from good (bias) to poor (external validity). The Quality Index correlated highly with an existing, established instrument for assessing randomised studies (r 0.90). There was little difference between its performance with non-randomised and with randomised studies. Raters took about 20 minutes to assess each paper (range 10 to 45 minutes). CONCLUSIONS: This study has shown that it is feasible to develop a checklist that can be used to assess the methodological quality not only of randomised controlled trials but also non-randomised studies. It has also shown that it is possible to produce a checklist that provides a profile of the paper, alerting reviewers to its particular methodological strengths and weaknesses. Further work is required to improve the checklist and the training of raters in the assessment of external validity.

https://jech.bmj.com/content/jech/52/6/377.full.pdf

The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions.

Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

Antibiotics have always been considered one of the wonder discoveries of the 20th century. This is true, but the real wonder is the rise of antibiotic resistance in hospitals, communities, and the environment concomitant with their use. The extraordinary genetic capacities of microbes have benefitted from man's overuse of antibiotics to exploit every source of resistance genes and every means of horizontal gene transmission to develop multiple mechanisms of resistance for each and every antibiotic introduced into practice clinically, agriculturally, or otherwise. This review presents the salient aspects of antibiotic resistance development over the past half-century, with the oft-restated conclusion that it is time to act. To achieve complete restitution of therapeutic applications of antibiotics, there is a need for more information on the role of environmental microbiomes in the rise of antibiotic resistance. In particular, creative approaches to the discovery of novel antibiotics and their expedited and controlled introduction to therapy are obligatory.

Origins and Evolution of Antibiotic Resistance

### A. Overview

Extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface receptors termed purine receptors. In this review particular emphasis is placed on the discrepancy between the

/pdf/receptors-for-purines-and-pyrimidines-56f78tnpew.pdf

Receptors for Purines and Pyrimidines

To the Editor—We thank Dr Ito for thoughtful observations about our research and we appreciate the opportunity to respond [1]. In a matched retrospective observational cohort of 1842 patients, we found that patients receiving outpatient parenteral antimicrobial therapy (OPAT) had a similar number of adverse events and lower direct healthcare costs than patients receiving inpatient parenteral antimicrobial therapy (IPAT) [2]. Dr Ito highlights that unobserved differences in treatment adherence might have influenced our findings [1]. We believe that this raises two related but distinct issues. First, hospitalized patients receiving IPAT have intravenous antimicrobials directly administered by nurses. In contrast, community-based patients receiving OPAT plausibly face more logistical barriers (eg, missed appointments and homecare visits, undelivered drugs, or venous access malfunction) that result in delayed, incomplete, or omitted antimicrobial doses. In a randomized trial, these factors might reduce antimicrobial adherence and produce less favorable outcomes among these patients. Second, physicians in clinical practice do not randomly allocate patients to OPAT or IPAT. Real-world outcomes might appear better with OPAT because physicians selecting patients for outpatient care probably “cherry-pick” the healthiest and most treatment-adherent patients who already have a better-than-average prognosis [3]. We used matching and adjustment to account for prognostically important baseline differences between OPAT and IPAT patient groups in our study, but our adjusted effect estimates are still subject to bias from residual confounding [2]. This remains a previously acknowledged limitation of our study. Our results nonetheless suggest that OPAT is a safe and effective choice for appropriately selected patients. The substantial cost savings arising from the transition from IPAT to OPAT should be reallocated to support adherence and expand delivery of OPAT in the community [4]. 

Reply to Ito.

1 diarrhea and prevention of disease recurrence in hamsters 2 Rifaximin for Clostridium difficile-associated diarrhea 3 4 Efi Kokkotou, Alan C Moss, Athanasios Michos, Daniel Espinoza, Jeffrey W Cloud, 5 Nasima Mustafa, Michael O’Brien, Charalabos Pothoulakis, Ciarán P. Kelly 6 7 Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA. 8 Mallory Institute and Department of Pathology, Boston University Medical Center, 9 Boston, MA 10 11 12 Corresponding Author: 13 Ciarán P Kelly MD 14 Division of Gastroenterology 15 Dana 601 / East Campus 16 Beth Israel Deaconess Medical Center 17 Boston MA 02215 18 T: (617) 667-1264 19 F: (617) 975-5071 20 ckelly2@bidmc.harvard.edu 21 22 AC CE PT ED Copyright © 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved. Antimicrob. Agents Chemother. doi:10.1128/AAC.01143-07 AAC Accepts, published online ahead of print on 14 January 2008

Efficacy of rifaximin vs. vancomycin for treatment of Clostridium difficile-associated 1 diarrhea and prevention of disease recurrence in hamsters 2 Rifaximin for Clostridium difficile-associated diarrhea 3 4

Why does the stomach not digest itself? The food we put in our stomach is efficiently broken down in this harsh acidic environment and yet somehow the acid does not damage the stomach itself. The answer is that the mucus gel layer lining the inside of the stomach serves as a protective barrier. For the past several years we have been engaged in a collaborative research program (with the groups of Drs Thomas Lamont and Nezam Afdhal of Beth Israel Deaconess Medical Center, Harvard Medical School) examining the biophysical mechanism that causes the mucus to form a gel. We have unlocked many clues toward obtaining a detailed molecular picture. Our research is now at the stage where we can meaningfully address the biophysics of a gastric mucus related disease, i.e. ulcers.

/pdf/impact-of-helicobacter-pylori-on-mucus-rheology-2ilgklj80r.pdf

Impact of Helicobacter Pylori on Mucus Rheology

Response to Rettally and Husby and Murray.

Venous Thromboembolic Disease and Pregnancy

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