Historic landmarks in clinical transplantation: Conclusions from the consensus conference at the University of California, Los Angeles

The transplantation of organs, cells, and tissues has burgeoned during the last quarter century, with the development of multiple new specialty fields. However, the basic principles that made this possible were established over a three-decade period, beginning during World War II and ending in 1974. At the historical consensus conference held at UCLA in March 1999, 11 early workers in the basic science or clinical practice of transplantation (or both) reached agreement on the most significant contribution of this era that ultimately made transplantation the robust clinical discipline it is today. These discoveries and achievements are summarized here is six tables and annotated with references

Pruning of genetic programming trees using permutation tests

We present a novel approach based on statistical permutation tests for pruning redundant subtrees from genetic programming (GP) trees that allows us to explore the extent of effective redundancy . We observe that over a range of regression problems, median tree sizes are reduced by around 20% largely independent of test function, and that while some large subtrees are removed, the median pruned subtree comprises just three nodes; most take the form of an exact algebraic simplification. Our statistically-based pruning technique has allowed us to explore the hypothesis that a given subtree can be replaced with a constant if this substitution results in no statistical change to the behavior of the parent tree – what we term approximate simplification. In the eventuality, we infer that more than 95% of the accepted pruning proposals are the result of algebraic simplifications, which provides some practical insight into the scope of removing redundancies in GP trees

"Summary Page": a novel tool that reduces omitted data in research databases

<p>Abstract</p> <p>Background</p> <p>Data entry errors are common in clinical research databases. Omitted data are of particular concern because they are more common than erroneously inserted data and therefore could potentially affect research findings. However, few affordable strategies for their prevention are available.</p> <p>Methods</p> <p>We have conducted a prospective observational study of the effect of a novel tool called "<it>Summary Page</it>" on the frequency of correction of omitted data errors in a radiation oncology research database between July 2008 and March 2009. "<it>Summary Page</it>" was implemented as an optionally accessed screen in the database that visually integrates key fields in the record. We assessed the frequency of omitted data on the example of the <it>Date of Relapse </it>field. We considered the data in this field to be omitted for all records that had empty <it>Date of Relapse </it>field and evidence of relapse elsewhere in the record.</p> <p>Results</p> <p>A total of 1,156 records were updated and 200 new records were entered in the database over the study period. "<it>Summary Page</it>" was accessed for 44% of all updated records and for 69% of newly entered records. Frequency of correction of the omitted date of cancer relapse was six-fold higher in records for which "<it>Summary Page</it>" was accessed (p = 0.0003).</p> <p>Conclusions</p> <p>"<it>Summary Page</it>" was strongly associated with an increased frequency of correction of omitted data errors. Further, controlled, studies are needed to confirm this finding and elucidate its mechanism of action.</p

'Linkage' pharmaceutical evergreening in Canada and Australia

'Evergreening' is not a formal concept of patent law. It is best understood as a social idea used to refer to the myriad ways in which pharmaceutical patent owners utilise the law and related regulatory processes to extend their high rent-earning intellectual monopoly privileges, particularly over highly profitable (either in total sales volume or price per unit) 'blockbuster' drugs. Thus, while the courts are an instrument frequently used by pharmaceutical brand name manufacturers to prolong their patent royalties, 'evergreening' is rarely mentioned explicitly by judges in patent protection cases. The term usually refers to threats made to competitors about a brand-name manufacturer's tactical use of pharmaceutical patents (including over uses, delivery systems and even packaging), not to extension of any particular patent over an active product ingredient. This article focuses in particular on the 'evergreening' potential of so-called 'linkage' provisions, imposed on the regulatory (safety, quality and efficacy) approval systems for generic pharmaceuticals of Canada and Australia, by specific articles in trade agreements with the US. These 'linkage' provisions have also recently appeared in the Korea-US Free Trade Agreement (KORUSFTA). They require such drug regulators to facilitate notification of, or even prevent, any potential patent infringement by a generic pharmaceutical manufacturer. This article explores the regulatory lessons to be learnt from Canada's and Australia's shared experience in terms of minimizing potential adverse impacts of such 'linkage evergreening' provisions on drug costs and thereby potentially on citizen's access to affordable, essential medicines

Neural Correlates of Threat Perception: Neural Equivalence of Conspecific and Heterospecific Mobbing Calls Is Learned

Songbird auditory areas (i.e., CMM and NCM) are preferentially activated to playback of conspecific vocalizations relative to heterospecific and arbitrary noise [1]–[2]. Here, we asked if the neural response to auditory stimulation is not simply preferential for conspecific vocalizations but also for the information conveyed by the vocalization. Black-capped chickadees use their chick-a-dee mobbing call to recruit conspecifics and other avian species to mob perched predators [3]. Mobbing calls produced in response to smaller, higher-threat predators contain more “D” notes compared to those produced in response to larger, lower-threat predators and thus convey the degree of threat of predators [4]. We specifically asked whether the neural response varies with the degree of threat conveyed by the mobbing calls of chickadees and whether the neural response is the same for actual predator calls that correspond to the degree of threat of the chickadee mobbing calls. Our results demonstrate that, as degree of threat increases in conspecific chickadee mobbing calls, there is a corresponding increase in immediate early gene (IEG) expression in telencephalic auditory areas. We also demonstrate that as the degree of threat increases for the heterospecific predator, there is a corresponding increase in IEG expression in the auditory areas. Furthermore, there was no significant difference in the amount IEG expression between conspecific mobbing calls or heterospecific predator calls that were the same degree of threat. In a second experiment, using hand-reared chickadees without predator experience, we found more IEG expression in response to mobbing calls than corresponding predator calls, indicating that degree of threat is learned. Our results demonstrate that degree of threat corresponds to neural activity in the auditory areas and that threat can be conveyed by different species signals and that these signals must be learned

The Influence of Personality Traits on Reported Adherence to Medication in Individuals with Chronic Disease: An Epidemiological Study in West Sweden

BACKGROUND: Limited research exists exploring the influence of personality on adherence behaviour. Since non-adherence is a major obstacle in treating prevalent chronic diseases the aim was to determine whether personality traits are related to reported adherence to medication in individuals with chronic disease. METHODOLOGY/PRINCIPAL FINDINGS: Individuals with chronic disease (n = 749) were identified in a random population sample of 5000 inhabitants aged 30-70 in two municipalities in West Sweden. Data on five personality traits, Neuroticism, Extraversion, Openness to experiences, Agreeableness, and Conscientiousness, and medication adherence behaviour was collected by questionnaires. Statistical analyses resulted in a negative relationship between Neuroticism and medication adherence (P < 0.001), while both Agreeableness (P < 0.001) and Conscientiousness (P < 0.001) were positively related to adherence. At high levels of Conscientiousness, low adherence was related to higher scores in Neuroticism. At high levels of Agreeableness, low adherence was related to low scores in Conscientiousness and high scores in Openness to experiences. CONCLUSIONS: This study demonstrated that multiple personality traits are of significant importance for adherence behaviour in individuals with chronic disease. The findings suggest that several personality traits may interact in influencing adherence behaviour. Personality traits could putatively be used to focus efforts to educate and support patients with high risk of low medical adherence

Bacterial community development in experimental gingivitis.

Current knowledge of the microbial composition of dental plaque in early gingivitis is based largely on microscopy and cultural methods, which do not provide a comprehensive description of oral microbial communities. This study used 454-pyrosequencing of the V1-V3 region of 16S rRNA genes (approximately 500 bp), and bacterial culture, to characterize the composition of plaque during the transition from periodontal health to gingivitis. A total of 20 healthy volunteers abstained from oral hygiene for two weeks, allowing plaque to accumulate and gingivitis to develop. Plaque samples were analyzed at baseline, and after one and two weeks. In addition, plaque samples from 20 chronic periodontitis patients were analyzed for cross-sectional comparison to the experimental gingivitis cohort. All of the healthy volunteers developed gingivitis after two weeks. Pyrosequencing yielded a final total of 344,267 sequences after filtering, with a mean length of 354 bases, that were clustered into an average of 299 species-level Operational Taxonomic Units (OTUs) per sample. Principal coordinates analysis (PCoA) plots revealed significant shifts in the bacterial community structure of plaque as gingivitis was induced, and community diversity increased significantly after two weeks. Changes in the relative abundance of OTUs during the transition from health to gingivitis were correlated to bleeding on probing (BoP) scores and resulted in the identification of new health- and gingivitis-associated taxa. Comparison of the healthy volunteers to the periodontitis patients also confirmed the association of a number of putative periodontal pathogens with chronic periodontitis. Taxa associated with gingivitis included Fusobacterium nucleatum subsp. polymorphum, Lachnospiraceae [G-2] sp. HOT100, Lautropia sp. HOTA94, and Prevotella oulorum, whilst Rothia dentocariosa was associated with periodontal health. Further study of these taxa is warranted and may lead to new therapeutic approaches to prevent periodontal disease.BBSRC Industrial Case Studentship ref no. BB/G01714X/1 in collaboration with GlaxoSmithKline

Leukocytes Are Recruited through the Bronchial Circulation to the Lung in a Spontaneously Hypertensive Rat Model of COPD

Chronic obstructive pulmonary disease (COPD) kills approximately 2.8 million people each year, and more than 80% of COPD cases can be attributed to smoking. Leukocytes recruited to the lung contribute to COPD pathology by releasing reactive oxygen metabolites and proteolytic enzymes. In this work, we investigated where leukocytes enter the lung in the early stages of COPD in order to better understand their effect as a contributor to the development of COPD. We simultaneously evaluated the parenchyma and airways for neutrophil accumulation, as well as increases in the adhesion molecules and chemokines that cause leukocyte recruitment in the early stages of tobacco smoke induced lung disease. We found neutrophil accumulation and increased expression of adhesion molecules and chemokines in the bronchial blood vessels that correlated with the accumulation of leukocytes recovered from the lung. The expression of adhesion molecules and chemokines in other vascular beds did not correlate with leukocytes recovered in bronchoalveolar lavage fluid (BALF). These data strongly suggest leukocytes are recruited in large measure through the bronchial circulation in response to tobacco smoke. Our findings have important implications for understanding the etiology of COPD and suggest that pharmaceuticals designed to reduce leukocyte recruitment through the bronchial circulation may be a potential therapy to treat COPD

Left atrial mechanics and aortic stiffness following high intensity interval training: a randomised controlled study

Purpose: High intensity interval training (HIIT) has been shown to improve important health parameters, including aerobic capacity, blood pressure, cardiac autonomic modulation and left ventricular (LV) mechanics. However, adaptations in left atrial (LA) mechanics and aortic stiffness remain unclear. Methods: Forty-one physically inactive males and females were recruited. Participants were randomised to either a 4-week HIIT intervention (n=21) or 4-week control period (n=20). The HIIT protocol consisted of 3x30-second maximal cycle ergometer sprints with a resistance of 7.5% body weight, interspersed with 2-minutes of active unloaded recovery, 3 times per week. Speckle tracking imaging of the LA and M-Mode tracing of the aorta was performed pre and post HIIT and control period. Results: Following HIIT, there was significant improvement in LA mechanics, including LA reservoir (13.9±13.4%, p=0.033), LA conduit (8.9±11.2%, p=0.023) and LA contractile (5±4.5%, p=0.044) mechanics compared to the control condition. In addition, aortic distensibility (2.1±2.7cm2dyn-1103, p=0.031) and aortic stiffness index (-2.6±4.6, p=0.041) were improved compared to the control condition. In stepwise linear regression analysis, aortic distensibility change was significantly associated with LA stiffness change R2 of 0.613 (p=0.002). Conclusion: A short-term programme of HIIT was associated with a significant improvement in LA mechanics and aortic stiffness. These adaptations may have important health implications and contribute to the improved LV diastolic and systolic mechanics, aerobic capacity and blood pressure previously documented following HIIT