Genetic and environmental factors shape the host response to Helicobacter hepaticus: insights into IBD pathogenesis.

Pathobionts are members of the gut microbiota with the capacity to cause disease when there is malfunctioning intestinal homeostasis. These organisms are thought to be major contributors to the pathogenesis of inflammatory bowel disease (IBD), a group of chronic inflammatory disorders driven by dysregulated responses towards the microbiota. Over two decades have passed since the discovery of Helicobacter hepaticus, a mouse pathobiont which causes colitis in the context of immune deficiency. During this time, we have developed a detailed understanding of the cellular players and cytokine networks which drive H. hepaticus immunopathology. However, we are just beginning to understand the microbial factors that enable H. hepaticus to interact with the host and influence colonic health and disease. Here we review key H. hepaticus-host interactions, their relevance to other exemplar pathobionts and how when maladapted they drive colitis. Further understanding of these pathways may offer new therapeutic approaches for IBD.

Mucosal immune responses in COVID19 - a living review.

COVID-19 was initially characterized as a disease primarily of the lungs, but it is becoming increasingly clear that the SARS-CoV2 virus is able to infect many organs and cause a broad pathological response. The primary infection site is likely to be a mucosal surface, mainly the lungs or the intestine, where epithelial cells can be infected with virus. Although it is clear that virus within the lungs can cause severe pathology, driven by an exaggerated immune response, infection within the intestine generally seems to cause minor or no symptoms. In this review, we compare the disease processes between the lungs and gastrointestinal tract, and what might drive these different responses. As the microbiome is a key part of mucosal barrier sites, we also consider the effect that microbial species may play on infection and the subsequent immune responses. Because of difficulties obtaining tissue samples, there are currently few studies focused on the local mucosal response rather than the systemic response, but understanding the local immune response will become increasingly important for understanding the mechanisms of disease in order to develop better treatments.

The Generation of an Engineered Interleukin-10 Protein With Improved Stability and Biological Function.

Interleukin-10 (IL-10) is an immunoregulatory cytokine that plays a pivotal role in modulating inflammation. IL-10 has inhibitory effects on proinflammatory cytokine production and function in vitro and in vivo; as such, IL-10 is viewed as a potential treatment for various inflammatory diseases. However, a significant drawback of using IL-10 in clinical application is the fact that the biologically active form of IL-10 is an unstable homodimer, which has a short half-life and is easily degraded in vivo. Consequently, IL-10 therapy using recombinant native IL-10 has had only limited success in the treatment of human disease. To improve the therapeutic potential of IL-10, we have generated a novel form of IL-10, which consists of two IL-10 monomer subunits linked in a head to tail fashion by a flexible linker. We show that the linker length per se did not affect the expression and biological activity of the stable IL-10 molecule, which was more active than natural IL-10, both in vitro and in vivo. We confirmed that the new form of IL-10 had a much-improved temperature- and pH-dependent biological stability compared to natural IL-10. The IL-10 dimer protein binds to the IL-10 receptor similarly to the natural IL-10 protein, as shown by antibody blocking and through the genetic modifications of one monomer in the IL-10 dimer specifically at the IL-10 receptor binding site. Finally, we showed that stable IL-10 is more effective at suppressing LPS-induced-inflammation in vivo compared to the natural IL-10. In conclusion, we have developed a new stable dimer version of the IL-10 protein with improved stability and efficacy to suppress inflammation. We propose that this novel stable IL-10 dimer could serve as the basis for the development of targeted anti-inflammatory drugs.

Interventions to improve adherence to cardiovascular disease guidelines: a systematic review.

BACKGROUND: Successful management of cardiovascular disease (CVD) is impaired by poor adherence to clinical practice guidelines. The objective of our review was to synthesize evidence about the effectiveness of interventions that target healthcare providers to improve adherence to CVD guidelines and patient outcomes. METHODS: We searched PubMed, EMBASE, Cochrane Library, PsycINFO, Web of Science and CINAHL databases from inception to June 2014, using search terms related to adherence and clinical practice guidelines. Studies were limited to randomized controlled trials testing an intervention to improve adherence to guidelines that measured both a patient and adherence outcome. Descriptive summary tables were created from data extractions. Meta-analyses were conducted on clinically homogeneous comparisons, and sensitivity analyses and subgroup analyses were carried out where possible. GRADE summary of findings tables were created for each comparison and outcome. RESULTS AND DISCUSSION: We included 38 RCTs in our review. Interventions included guideline dissemination, education, audit and feedback, and academic detailing. Meta-analyses were conducted for several outcomes by intervention type. Many comparisons favoured the intervention, though only the adherence outcome for the education intervention showed statistically significant improvement compared to usual care (standardized mean difference = 0.58 [95 % confidence interval 0.35 to 0.8]). CONCLUSIONS: Many interventions show promise to improve practitioner adherence to CVD guidelines. The quality of evidence and number of trials limited our ability to draw conclusions.

Interventions for enhancing medication adherence.

BACKGROUND: People who are prescribed self administered medications typically take only about half their prescribed doses. Efforts to assist patients with adherence to medications might improve the benefits of prescribed medications. OBJECTIVES: The primary objective of this review is to assess the effects of interventions intended to enhance patient adherence to prescribed medications for medical conditions, on both medication adherence and clinical outcomes. SEARCH METHODS: We updated searches of The Cochrane Library, including CENTRAL (via http://onlinelibrary.wiley.com/cochranelibrary/search/), MEDLINE, EMBASE, PsycINFO (all via Ovid), CINAHL (via EBSCO), and Sociological Abstracts (via ProQuest) on 11 January 2013 with no language restriction. We also reviewed bibliographies in articles on patient adherence, and contacted authors of relevant original and review articles. SELECTION CRITERIA: We included unconfounded RCTs of interventions to improve adherence with prescribed medications, measuring both medication adherence and clinical outcome, with at least 80% follow-up of each group studied and, for long-term treatments, at least six months follow-up for studies with positive findings at earlier time points. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data and a third author resolved disagreements. The studies differed widely according to medical condition, patient population, intervention, measures of adherence, and clinical outcomes. Pooling results according to one of these characteristics still leaves highly heterogeneous groups, and we could not justify meta-analysis. Instead, we conducted a qualitative analysis with a focus on the RCTs with the lowest risk of bias for study design and the primary clinical outcome. MAIN RESULTS: The present update included 109 new RCTs published since the previous update in January 2007, bringing the total number of RCTs to 182; we found five RCTs from the previous update to be ineligible and excluded them. Studies were heterogeneous for patients, medical problems, treatment regimens, adherence interventions, and adherence and clinical outcome measurements, and most had high risk of bias. The main changes in comparison with the previous update include that we now: 1) report a lack of convincing evidence also specifically among the studies with the lowest risk of bias; 2) do not try to classify studies according to intervention type any more, due to the large heterogeneity; 3) make our database available for collaboration on sub-analyses, in acknowledgement of the need to make collective advancement in this difficult field of research. Of all 182 RCTs, 17 had the lowest risk of bias for study design features and their primary clinical outcome, 11 from the present update and six from the previous update. The RCTs at lowest risk of bias generally involved complex interventions with multiple components, trying to overcome barriers to adherence by means of tailored ongoing support from allied health professionals such as pharmacists, who often delivered intense education, counseling (including motivational interviewing or cognitive behavioral therapy by professionals) or daily treatment support (or both), and sometimes additional support from family or peers. Only five of these RCTs reported improvements in both adherence and clinical outcomes, and no common intervention characteristics were apparent. Even the most effective interventions did not lead to large improvements in adherence or clinical outcomes. AUTHORS' CONCLUSIONS: Across the body of evidence, effects were inconsistent from study to study, and only a minority of lowest risk of bias RCTs improved both adherence and clinical outcomes. Current methods of improving medication adherence for chronic health problems are mostly complex and not very effective, so that the full benefits of treatment cannot be realized. The research in this field needs advances, including improved design of feasible long-term interventions, objective adherence measures, and sufficient study power to detect improvements in patient-important clinical outcomes. By making our comprehensive database available for sharing we hope to contribute to achieving these advances.

Activity-based funding of hospitals and its impact on mortality, readmission, discharge destination, severity of illness, and volume of care: a systematic review and meta-analysis.

BACKGROUND: Activity-based funding (ABF) of hospitals is a policy intervention intended to re-shape incentives across health systems through the use of diagnosis-related groups. Many countries are adopting or actively promoting ABF. We assessed the effect of ABF on key measures potentially affecting patients and health care systems: mortality (acute and post-acute care); readmission rates; discharge rate to post-acute care following hospitalization; severity of illness; volume of care. METHODS: We undertook a systematic review and meta-analysis of the worldwide evidence produced since 1980. We included all studies reporting original quantitative data comparing the impact of ABF versus alternative funding systems in acute care settings, regardless of language. We searched 9 electronic databases (OVID MEDLINE, EMBASE, OVID Healthstar, CINAHL, Cochrane CENTRAL, Health Technology Assessment, NHS Economic Evaluation Database, Cochrane Database of Systematic Reviews, and Business Source), hand-searched reference lists, and consulted with experts. Paired reviewers independently screened for eligibility, abstracted data, and assessed study credibility according to a pre-defined scoring system, resolving conflicts by discussion or adjudication. RESULTS: Of 16,565 unique citations, 50 US studies and 15 studies from 9 other countries proved eligible (i.e. Australia, Austria, England, Germany, Israel, Italy, Scotland, Sweden, Switzerland). We found consistent and robust differences between ABF and no-ABF in discharge to post-acute care, showing a 24% increase with ABF (pooled relative risk  = 1.24, 95% CI 1.18-1.31). Results also suggested a possible increase in readmission with ABF, and an apparent increase in severity of illness, perhaps reflecting differences in diagnostic coding. Although we found no consistent, systematic differences in mortality rates and volume of care, results varied widely across studies, some suggesting appreciable benefits from ABF, and others suggesting deleterious consequences. CONCLUSIONS: Transitioning to ABF is associated with important policy- and clinically-relevant changes. Evidence suggests substantial increases in admissions to post-acute care following hospitalization, with implications for system capacity and equitable access to care. High variability in results of other outcomes leaves the impact in particular settings uncertain, and may not allow a jurisdiction to predict if ABF would be harmless. Decision-makers considering ABF should plan for likely increases in post-acute care admissions, and be aware of the large uncertainty around impacts on other critical outcomes.

Adherence measurement and patient recruitment methods are poor in intervention trials to improve patient adherence.

OBJECTIVES: To develop a scale and survey the measurement of patient adherence and patient recruitment, and to explore how these methods impact the results in randomized controlled trials of interventions to improve patient adherence to medications. STUDY DESIGN: Analytic survey of a purposively selected sample of patient adherence intervention trials from a systematic review, assessing the quality of adherence measurement and patient recruitment methods. RESULTS: We identified 44 different measures of adherence, with qualities ranging from valid and objective to unreliable and subjective. The median overall quality of measures of adherence was 5 (interquartile range [IQR], 3; range, 0-9, 9 is high quality). The quality of the measures was associated with variation in the estimate of adherence (Spearman r = 0.66; 95% confidence interval: 0.39, 0.83). The median overall quality of patient recruitment methods was 2 (IQR, 1; maximum score 6, higher is better). There was no significant correlation between the power of the trial to detect an effect and the quality of the patient recruitment methods. CONCLUSION: Measurement and recruitment methods in adherence trials varied considerably, and most methods were of low quality. Adherence research could be advanced by using higher quality measures of adherence and better selection and baseline assessment of study participants.

Measuring trade-offs that matter: assessing the impact of a new electronic cross-match policy on the turnaround time and the cross-match workload efficiency.

BACKGROUND: Our traditional cross-match (XM) policy generated a significant number of XM units that were never issued. To minimize the unnecessary XM workload, we proposed a new policy where orders eligible for the electronic XM (EXM) are pended until orders to issue red blood cells (RBCs) are received. To address concerns that this new policy might unduly delay blood availability, we conducted a study to assess whether the new policy was noninferior to the traditional policy with regard to the turnaround time (TAT). STUDY DESIGN AND METHODS: We monitored the TAT and XM workload efficiency (XM-to-issue [C : I] ratio) for a total of 8 weeks split between the two policies' periods. The primary outcome was the proportion of RBC issue requests that was turned around in less than 12 minutes. RESULTS: Fifty percent (1133 of 2265) of issue requests were turned around in 12 minutes or less under the traditional policy compared to 43.9% (975 of 2223) under the new policy (absolute difference of 6.1%; 95% confidence interval [CI], 3.2%-9.1%; p < 0.001). The adjusted overall median TAT was slower by 1 minute (13 min vs. 14 min, p < 0.001) but the adjusted C : I ratio was better (1.00 vs. 1.15; p < 0.001) under the new policy. CONCLUSION: Our study showed that the impact of the new policy on the TAT was not inferior to the traditional policy. Since the median TAT of 14 minutes under the new policy met the published benchmarks, the trade-off between delays in the TAT and efficiency gains in the XM workload remained acceptable for patient care.

A demographic survey of unwanted horses in Ireland in 2011 and totals for 2012 and a comparison with 2010.

This report compiles the available information on unwanted horses in Ireland for 2011 and 2012 and builds upon the previous report for the period 2005 to 2010. Similar trends are present in the high value responsible ownership category and the practicing veterinary profession although extensively involved in horse welfare, euthanises a small proportion of Ireland's unwanted horses. Welfare groups have limited resources and a limited ability to deal with such an extensive problem, which has involved very large numbers of horses. Local authorities continue to have to devote significant efforts and calls on public finances to deal with unwanted horses. Those that they have to deal with are, in the main, not identifiable by either passports or microchips. Category 2 plants and abattoirs continue to provide the principal means of disposal of unwanted horses. The need for abattoirs continues to increase and it is essential that these facilities remain in operation. They processed more than 49,000 horses between 2010 and 2012. The samples they have to submit for Trichinella testing are the most sensitive indicator of the extent of the unwanted horse problem and the most immediate source of information on when it may begin to abate. Trichinella sample numbers and this by inference, horses ponies and donkeys sent to slaughter have fallen by some 35% from 2012 numbers, in the year to date (2013). This may reflect the commercial decision to cease horse slaughter by two slaughterhouses that had hitherto provided this service. Their commercial decision was not in any way related to the identification of fraudulent mislabeled beef in other plants.

How current are leading evidence-based medical textbooks? An analytic survey of four online textbooks.

BACKGROUND: The consistency of treatment recommendations of evidence-based medical textbooks with more recently published evidence has not been investigated to date. Inconsistencies could affect the quality of medical care. OBJECTIVE: To determine the frequency with which topics in leading online evidence-based medical textbooks report treatment recommendations consistent with more recently published research evidence. METHODS: Summarized treatment recommendations in 200 clinical topics (ie, disease states) covered in four evidence-based textbooks--UpToDate, Physicians' Information Education Resource (PIER), DynaMed, and Best Practice--were compared with articles identified in an evidence rating service (McMaster Premium Literature Service, PLUS) since the date of the most recent topic updates in each textbook. Textbook treatment recommendations were compared with article results to determine if the articles provided different, new conclusions. From these findings, the proportion of topics which potentially require updating in each textbook was calculated. RESULTS: 478 clinical topics were assessed for inclusion to find 200 topics that were addressed by all four textbooks. The proportion of topics for which there was 1 or more recently published articles found in PLUS with evidence that differed from the textbooks' treatment recommendations was 23% (95% CI 17-29%) for DynaMed, 52% (95% CI 45-59%) for UpToDate, 55% (95% CI 48-61%) for PIER, and 60% (95% CI 53-66%) for Best Practice (χ(2) (3)=65.3, P<.001). The time since the last update for each textbook averaged from 170 days (range 131-209) for DynaMed, to 488 days (range 423-554) for PIER (P<.001 across all textbooks). CONCLUSIONS: In online evidence-based textbooks, the proportion of topics with potentially outdated treatment recommendations varies substantially.

An investigation of stride interval stationarity while listening to music or viewing television.

In recent years, there has been considerable interest in the effects of auditory and visual distractions on pedestrian ambulation. A fundamental temporal characteristic of ambulation is the temporal fluctuation of the stride interval. In this paper, we investigate the stationarity of stride interval time series when people are exposed to different forms of auditory and visual distractions. An increase in nonstationary behavior may be suggestive of divided attention and more frequent central modulation of locomotion, both of which may have ramifications on pedestrian vigilance and responsiveness to environmental perturbations. One group of fifteen able-bodied (6 females) young adult participants completed a music protocol (overground walking with and without music). A second group of fifteen (7 females) did a television protocol (treadmill walking while watching TV with and without sound). Three walking trials, each 15min in duration, were performed at each participant's comfortable walking speed, with force sensitive resistors under the heel of each foot. Using the reverse arrangements test, the vast majority of time series were nonstationary, with a time-varying mean as the principal source of nonstationarity. Furthermore, the television trial with sound had the greatest number of nonstationarities followed by overground walking while listening to music. We discuss the possibility that these conditions measurably affect gait dynamics through a subconscious synchronization to external rhythms or a cyclic distraction followed by a period of increased conscious correction of gait timing. Our findings suggest that the regulation of stride timing is particularly susceptible to constant, time-evolving auditory stimuli, but that normal pacing can be restored quickly upon stimulus withdrawal. These kinds of sensory distractions should thus be carefully considered in studies of pedestrian ambulation.

Accurate assessment of breast volume: a study comparing the volumetric gold standard (direct water displacement measurement of mastectomy specimen) with a 3D laser scanning technique.

Preoperative assessment of breast volume could contribute significantly to the planning of breast-related procedures. The availability of 3D scanning technology provides us with an innovative method for doing this. We performed this study to compare measurements by this technology with breast volume measurement by water displacement. A total of 30 patients undergoing 39 mastectomies were recruited from our center. The volume of each patient's breast(s) was determined with a preoperative 3D laser scan. The volume of the mastectomy specimen was then measured in the operating theater by water displacement. There was a strong linear association between breast volumes measured using the 2 different methods when using a Pearson correlation (r = 0.95, P < 0.001). The mastectomy mean volume was defined by the equation: mastectomy mean volume = (scan mean volume × 1.03) -70.6. This close correlation validates the Cyberware WBX Scanner as a tool for assessment of breast volume.