Search

The strategy of outsourcing bioanalytical services at Janssen has been evolving over the last years and an update will be given on the recent changes in our processes. In 2016, all internal GLP-related activities were phased out and this decision lead to the re-orientation of the in-house bioanalytical activities. As a consequence, in-depth experience with the validated bioanalytical assays for new drug candidates is currently gained together with the external partner, since development and validation of the assay and execution of GLP preclinical studies are now transferred to the CRO. The evolution to externalize more bioanalytical support has created opportunities to build even stronger partnerships with the CROs and to refocus internal resources. Case studies are presented illustrating challenges encountered during method development and validation at preferred partners when limited internal experience is obtained or with introduction of new technology.

Computer-aided drug design encompasses a wide variety of tools and techniques, and can be implemented with a range of organisational structures and focus in different organisations. Here we outline the computational chemistry skills within Sygnature Discovery, along with the software and hardware at our disposal, and briefly discuss the methods that are not employed and why. The goal of the group is to provide support for design and analysis in order to improve the quality of compounds synthesised and reduce the timelines of drug discovery projects, and we reveal how this is achieved at Sygnature. Impact on medicinal chemistry is vital to demonstrating the value of computational chemistry, and we discuss the approaches taken to influence the list of compounds for synthesis, and how we recognise success. Finally we touch on some of the areas being developed within the team in order to provide further value to the projects and clients.

In recent years, the number and scope of outsourced activities in the pharmaceutical industry have increased heavily. In addition, also the type of outsourcing has changed significantly in that time. This raises the question of whether and how sponsors retain the capability to select and to control the contract research organizations (CROs) involved and what expertise still has to be present in the development department as well as other relevant departments to ensure adequate oversight, also in line with the expectations of regulators and health authorities. In order to answer these questions, a survey was conducted among the German vfa member companies. The survey describes the latest developments and experiences in outsourcing by 18 German vfa member companies. It concentrates on measures how to implement Quality Assurance (QA) when performing outsourced clinical studies. This study shows that the majority of companies apply a full-outsourcing, preferred-provider model of clinical trial services, with the clinical research department playing the major role in this process. A large amount of guiding documents, processes and tools are used to ensure an adequate oversight of the services performed by the CRO(s). Finally the guiding principles for all oversight processes should be transparent communication, a clearly established expectation for quality, a precise definition of accountability and responsibility while avoiding silo mentality, and a comprehensive documentation of the oversight's evidence. For globally acting and outsourcing sponsors, oversight processes need to be aligned with regards to local and global perspectives. This survey shows that the current implementation of oversight processes in the participating companies covers all relevant areas to ensure highest quality and integrity of the data produced by the outsourced clinical trial.

Phi11, a temperate bacteriophage of Staphylococcus aureus, has been found to harbor a cro repressor gene which facilitates Phi11 to adopt the lytic mode of development. The Cro protein has been found to bind very specifically to a 15-bp operator DNA, located in the Phi11 cI-cro intergenic region [1]. To investigate the effects exerted by different ions upon the interaction between Cro and its cognate operator DNA, we have employed gel shift assays as well as circular dichroism spectral analysis. In this communication, we have shown that NH 4 + ions better facilitated the binding of Cro with its cognate operator as compared to Na - ions better facilitated the binding of Cro with its cognate operator as compared to Na + , K + and Li + . Interestingly, Mg 2+ , carbonate 2- have an inhibitory effect upon the binding. The effect of the said ions upon the structure of Cro was also investigated by circular dichroism and it was found that other than Citrate 3- have an inhibitory effect upon the binding. The effect of the said ions upon the structure of Cro was also investigated by circular dichroism and it was found that other than Citrate 3- ions, none of the other ions destabilised the protein. On the other hand, Mg 2+ and carbonate 2- ions severely unfolded Cro and also inhibited its function. Considering all the data, NH 3- ions severely unfolded Cro and also inhibited its function. Considering all the data, NH 4 ions appeared to be more suitable in maintaining the biological activity of Cro.+ and acetate - ions appeared to be more suitable in maintaining the biological activity of Cro.

Purpose: The objective of this study was to develop and validate clinician and patient measures of satisfaction for pharmacologic stress agents (PSAs) used in single-photon emission computed tomography myocardial perfusion imaging procedures., Methods: Two questionnaires were developed: the Clinician Satisfaction and Preference Questionnaire (CSPQ) and the Patient Satisfaction and Preference Questionnaire (PSPQ). Items were developed, and the content validity of the questionnaires was ensured by participants' involvement in the item generation (5 clinician and 18 patient face-to-face concept elicitation interviews) and item modification phases (5 clinician and 10 patient face-to-face cognitive debriefing interviews). Psychometric validation of the satisfaction component of the questionnaires was conducted in a sample of 9 clinicians and 90 patients., Findings: After initial patient interviews and cognitive interviews, two 8-item instruments were developed with each containing an optional PSA preference question. The PSPQ assessed patients' receptiveness and satisfaction with the PSA that they received. The CSPQ assessed clinicians' satisfaction with the time and ease of PSA preparation, administration, and monitoring of the PSA. The optional preference question in both instruments assesses preference among PSAs. In a multicenter observational study of 88 patients and 9 clinicians, the PSPQ Preparation and Reaction to Agent scales elicited reliability coefficients of 0.90 and 0.87, respectively. In addition, the test-retest reliability was acceptable for all PSPQ scales (intraclass correlation coefficient range, 0.73-0.86). Concurrent validity with the Treatment Satisfaction Questionnaire for Medication (TSQM) indicates low-to-moderate correlations between the Effectiveness, Convenience, and Global Satisfaction scales of the TSQM with the PSPQ Satisfaction with Administration, Satisfaction with Effects, and Overall Satisfaction items (range, 0.46-0.78). Analysis of the CSPQ found that both the Preparation and Reaction to Agent subscales indicated strong internal consistency (α = 0.98 and 0.99, respectively)., Implications: The PSPQ and CSPQ were developed and validated with rigorous methods. The instruments and their domains found strong internal consistency and good test-retest reliability. These questionnaires, when used as measures of treatment satisfaction in clinical trials, real-world observational studies, or by clinicians in their own laboratories, may help patients and clinicians better understand the impact of single-photon emission computed tomography myocardial perfusion imaging pharmacologic stress testing., (Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.)

Chronic technology and business process disparities between High Income, Low Middle Income and Low Income (HIC, LMIC, LIC) research collaborators directly prevent the growth of sustainable Global Health innovation for infectious and rare diseases. There is a need for an Open Source-Open Science Architecture Framework to bridge this divide. We are proposing such a framework for consideration by the Global Health community, by utilizing a hybrid approach of integrating agnostic Open Source technology and healthcare interoperability standards and Total Quality Management principles. We will validate this architecture framework through our programme called Project Orchid. Project Orchid is a conceptual Clinical Intelligence Exchange and Virtual Innovation platform utilizing this approach to support clinical innovation efforts for multi-national collaboration that can be locally sustainable for LIC and LMIC research cohorts. The goal is to enable LIC and LMIC research organizations to accelerate their clinical trial process maturity in the field of drug discovery, population health innovation initiatives and public domain knowledge networks. When sponsored, this concept will be tested by 12 confirmed clinical research and public health organizations in six countries. The potential impact of this platform is reduced drug discovery and public health innovation lag time and improved clinical trial interventions, due to reliable clinical intelligence and bio-surveillance across all phases of the clinical innovation process.

Temperate bacteriophages possess a molecular switch, which regulates the lytic and lysogenic growth. The genomes of the temperate telomere phages N15, PY54 and ɸKO2 harbor a primary immunity region (immB) comprising genes for the prophage repressor, the lytic repressor and a putative antiterminator. The roles of these products are thought to be similar to those of the lambda proteins CI, Cro and Q, respectively. Moreover, the gene order and the location of several operator sites in the prototype telomere phage N15 and in ɸKO2 are also reminiscent of lambda-like phages. By contrast, in silico analyses revealed the presence of only one operator (O\(_{\rm{R}}\)3) in PY54. The purified PY54 Cro protein was used for EMSA studies demonstrating that it exclusively binds to a 16-bp palindromic site (O\(_{\rm{R}}\)3) upstream of the prophage repressor gene. The O\(_{\rm{R}}\)3 operator sequences of PY54 and ɸKO2/N15 only differ by their peripheral base pairs, which are responsible for Cro specificity. PY54 cI and cro transcription is regulated by highly active promoters initiating the synthesis of a homogenious species of leaderless mRNA. The location of the PY54 Cro binding site and of the identified promoters suggests that the lytic repressor suppresses cI transcription but not its own synthesis. The results indicate an unexpected diversity of the growth regulation mechanisms in lambda-related phages.

CI represses cro; Cro represses cI. This double negative feedback loop is the core of the classical CI Cro epigenetic switch of bacteriophage λ . Despite the classical status of this switch, the role in λ development of Cro repression of the PRM promoter for CI has remained unclear. To address this, we created binding site mutations that strongly impaired Cro repression of PRM with only minimal effects on CI regulation of PRM. These mutations had little impact on λ development after infection but strongly inhibited the transition from lysogeny to the lytic pathway. We demonstrate that following inactivation of CI by ultraviolet treatment of lysogens, repression of PRM by Cro is needed to prevent synthesis of new CI that would otherwise significantly impede lytic development. Thus a bistable CI Cro circuit reinforces the commitment to a developmental transition. [ABSTRACT FROM AUTHOR]

Objective: To assess the influence of symptom intensity, mood, and comorbidities on patient-clinician agreement and the consistency of responses to functional patient-reported outcomes (PROs)., Design: Two data sources were used. The first, a cross-sectional database of patients with breast cancer who completed functional PROs and were administered the FIM, was used to examine whether average pain intensity (as measured with an 11-point numeric rating scale [NRS]) and Rand Mental Health inventory scores differed among those rating their functional independence as different than clinicians. The second, a longitudinal database of 311 adults with late-stage lung cancer who completed the Activity Measure for Post Acute Care Computer Adaptive Test (AM PAC CAT) with differences between their expected and actual responses as reflected in their AM PAC CAT SEs., Setting: Two tertiary medical centers., Participants: Data source #1, 163 women with stage IV breast cancer; data source #2, 311 adults with late-stage lung cancer., Interventions: Not applicable., Main Outcome Measures: Data source #1, FIM, pain NRS, Older Americans Resource Study activities of daily living subscale, Physical Function-10, Mental Health Inventory-17. Data source #2, AM PAC CAT and NRS symptom ratings., Results: Pain intensity was significantly higher when clinicians and patients disagreed regarding a patient's independence in the ability to transfer (NRS pain severity, 3.78 vs 2.40; P=.014), groom (3.71 vs 2.36, P=.009), bathe (3.76 vs 2.40, P=.016), and dress (3.09 vs 2.44, P=.034). The magnitude of AM PAC CAT SEs was significantly associated with the severity of participants' pain, dyspnea, and fatigue, as well as the presence of musculoskeletal disorders and coronary artery disease. Neither mood nor emotional distress was associated with clinician-patient agreement or AM PAC CAT SE., Conclusions: Pain intensity is associated with disagreement between patients and clinicians about the patient's level of functioning. Moreover, physical symptoms (pain, dyspnea, fatigue) as well as specific medical comorbidities (musculoskeletal disorders, coronary artery disease), but not mood, are associated with inconsistency in patients' assessment of their functional abilities., (Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)