Translational Medicine Guide transforms drug development processes: the recent Merck experience.

Merck is implementing a question-based Translational Medicine Guide (TxM Guide) beginning as early as lead optimization into its stage-gate drug development process. Initial experiences with the TxM Guide, which is embedded into an integrated development plan tailored to each development program, demonstrated opportunities to improve target understanding, dose setting (i.e., therapeutic index), and patient subpopulation selection with more robust and relevant early human-based evidence, and increased use of biomarkers and simulations. The TxM Guide is also helping improve organizational learning, costs, and governance. It has also shown the need for stronger external resources for validating biomarkers, demonstrating clinical utility, tracking natural disease history, and biobanking

The theophylline‐enoxacin interaction: I. Effect of enoxacin dose size on theophylline disposition

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110004/1/cptclpt1988197.pd

Association of endocrine active environmental compounds with body mass index and weight loss following bariatric surgery

IntroductionThe objective of this study was to study associations of a wide range of halogenated biphenyls, dibenzo‐p‐dioxins, dibenzofurans, and diphenylethers with body mass index (BMI) and evaluate changes in their concentration following bariatric surgery.MethodsSubcutaneous fat, visceral fat, and liver tissue samples were collected from 106 patients undergoing Roux‐en‐Y gastric bypass surgery for weight loss or patients who were undergoing abdominal surgery for non‐bariatric reasons. We measured concentrations of an extensive panel of chlorinated and brominated biphenyls, dioxins, and furans, and brominated diphenylethers in the samples. We conducted linear regression to examine associations with BMI, adjusting for age and gender. Changes in concentration for indicator chemicals were evaluated in samples collected following bariatric surgery in a small sub‐population.ResultsAfter adjustments for age and gender and correction for multiple testing, seven ortho‐chlorinated biphenyls, one non‐ortho‐chlorinated biphenyl, four PCDD/F’s and one ortho‐brominated biphenyl were associated with BMI. The strongest associations between BMI and lipid‐adjusted concentrations were seen with PCB‐105 in subcutaneous fat (beta=16.838 P‐val=1.45E‐06) PCB‐126 in visceral fat (beta=15.067 P‐val=7.72E‐06) and PCB‐118 (beta=14.101 P‐val=2.66E‐05) in liver. The concentrations of sum PCBs, chlorinated toxic equivalent quantity (TEQ's) and brominated compounds increased significantly with weight loss in subcutaneous fat in a group of ten individuals resampled up to five years after bariatric surgery and substantial weight loss.ConclusionWe show that selected polychlorinated biphenyls PCBs and structurally related polychlorinated dibenzo‐p‐dioxins dibenzofurans (PCDD/Fs) were associated with BMI. Concentrations of these lipophilic compounds in subcutaneous fat increased following bariatric surgery

Improved physiology and metabolic flux after Roux-en-Y gastric bypass is associated with temporal changes in the circulating microRNAome: A longitudinal study in humans

BackgroundThe global pandemic of obesity and the metabolic syndrome are leading causes of mortality and morbidity. Bariatric surgery leads to sustained weight loss and improves obesity-associated morbidity including remission of type 2 diabetes. MicroRNAs are small, endogenous RNAs that regulate gene expression post-transcriptionally, controlling most of the human transcriptome and contributing to the regulation of systemic metabolism. This preliminary, longitudinal, repeat sampling study, in which subjects acted as their own control, aimed to assess the temporal effect of bariatric surgery on circulating microRNA expression profiles.MethodsWe used Exiqon’s optimized circulating microRNA panel (comprising 179 validated miRNAs) and miRCURY locked nucleic acid plasma/serum Polymerase Chain Reaction (PCR) to assess circulating microRNA expression. The microRNAome was determined for Roux-en-Y gastric bypass (RYGB) patients examined preoperatively and at 1 month, 3 months, 6 months, 9 months and 12 months postoperatively. Data was analysed using multivariate and univariate statistics.ResultsCompared to the preoperative circulating microRNA expression profile, RYGB altered the circulating microRNAome in a time dependent manner and the expression of 48 circulating microRNAs were significantly different. Importantly, these latter microRNAs are associated with pathways involved in regulation and rescue from metabolic dysfunction and correlated with BMI, the percentage of excess weight loss and fasting blood glucose levels.ConclusionsThe results of this pilot study show that RYGB fundamentally alters microRNA expression in circulation with a time-dependent progressive departure in profile from the preoperative baseline and indicate that microRNAs are potentially novel biomarkers for the benefits of bariatric surgery

The impact of EAES Fellowship Programme:a five-year review and evaluation

Background: The European Association of Endoscopic Surgery (EAES) fellowship programme was established in 2014, allowing nine surgeons annually to obtain experience and skills in minimally invasive surgery (MIS) from specialist centres across the Europe and United States. It aligns with the strategic focus of EAES Education and Training Committee on enabling Learning Mobility opportunities. To assess the impact of the programme, a survey was conducted aiming to evaluate the experience and impact of the programme and receive feedback for improvements.Methods: A survey using a 5-point Likert scale was used to evaluate clinical, education and research experience. The impact on acquisition of new technical skills, change in clinical practice and ongoing collaboration with the host institute was assessed. The fellows selected between 2014 and 2018 were included. Ratings were analysed in percentage; thematic analysis was applied to the free-text feedbacks using qualitative analysis.Results: All the fellows had good access to observing in operating theatres and 70.6% were able to assist. 91.2% participated in educational activities and 23.5% were able to contribute through teaching. 44.1% participated in research activities and 41.2% became an author/co-author of a publication from the host. 97.1% of fellows stated that their operative competency had increased, 94.3% gained new surgical skills and 85.7% was able to introduce new techniques in their hospitals. 74.29% agreed that the clinical experience led to a change in their practices. The most commonly suggested improvements were setting realistic target in clinical and research areas, increasing fellowship duration, and maximising theatre assisting opportunities. Nevertheless, 100% of fellows would recommend the fellowship to their peers.Conclusion: EAES fellowship programme has shown a positive impact on acquiring and adopting new MIS techniques. To further refine the programme, an individualised approach should be adopted to set achievable learning objectives in clinical skills, education and research.</p

Up All Night: The Shifting Roles of Home Media Formats as Transmedia Storytelling

In this age of convergence, where media platforms and industries are becoming increasingly connected and intertwined, ‘transmedia’ has become a buzzword that scholars and industry alike have come to perceive as the media production strategy of the future. When scholars theorise transmedia storytelling, they typically prioritise film, TV, videogames and websites. DVDs and Blu-Rays—physical formats that occupy a vital role in extending and repurposing media content across new terrains—are often overlooked. This chapter will question what specific roles they play in extending stories across media platforms. This chapter explores the specific case studies of Doctor Who and the Marvel Cinematic Universe

The theophylline‐enoxacin interaction: II. Changes in the disposition of theophylline and its metabolites during intermittent administration of enoxacin

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109958/1/cptclpt1989160.pd

Fundoplication in chronic intractable cough

BACKGROUND: Airway reflux is a common cause of chronic cough and this is often refractory to medical therapy. Surgery in the form of Nissen fundoplication has been highly successful in the treatment of the classic reflux symptoms of heartburn and dyspepsia. There is a paucity of data regarding response to fundoplication in patients presenting with chronic cough. METHODS: We retrospectively reviewed the case notes of patients from the Hull Cough Clinic who had undergone Nissen fundoplication over the past 6 years. Demographic details, duration of symptoms, presence of other symptoms, results of oesophageal studies, outcome and complications were recorded. Patients were contacted by post and asked to complete a questionnaire detailing current symptoms. In a subgroup with continued troublesome cough 24 hour pharyngeal pH measurements were undertaken. RESULTS: Forty seven patients underwent fundoplication. The average duration of pre-operative cough was 8 years. Gastro intestinal symptoms were present in the majority. In 30 (64%) patients a positive response to treatment was recorded. Mild dysphagia or bloating was seen in 18 patients following surgery. Four patients needed repeat surgical intervention for modification of fundoplication. One patient developed aspiration pneumonia eight weeks following surgery and died of a myocardial infarction. Two thirds of patients with persisting cough had evidence of airway reflux on pharyngeal pH monitoring. CONCLUSION: In these patients with intractable cough a long term response rate of 63% represents a useful therapeutic option. Treatment failure is more frequent than for classic peptic symptoms and may be related to persistent gaseous reflux