How to promote knowledge sharing in cross-functional NPD teams

This paper investigates the common issues that may arise in cross-functional new product development (NPD) teams from a Knowledge Management perspective. The study has been built around a contextualized trigger, where several factors were preventing a new-born NPD team from performing effectively. The purpose of this paper is to give insights of the main dynamics involved in the knowledge sharing process throughout the application of a systematic problem-solving approach to the case investigated by the authors. Due to the impossibility of building a universal recipe suitable for every team in every situation, this work represents a compromise trying to exemplify how to prioritise interventions in a given context, in order to provide a benchmark for similar circumstances. This paper, using an action research method within a single case context, takes shape around the advises and suggestions made by authors to Electronic Connected Ltd (disguised name), a small-medium enterprise (SME) in a situation of NPD paralysis. In particular, the paper emphasizes the importance of effective leadership and supporting environment in facilitating communication, enhancing cohesiveness, fostering joint commitment and giving direction in order to enable knowledge sharing and to leverage capabilities to conclusively deliver new products

Leading Wrist Injuries in a Golfing Population. Golf Swing Biomechanics a Significant Cause of Pathology

Golf participation has increased significantly over the past 50 years. Injury rates have mirrored this increase with amateur and elite golfers suffering a similar injury incidence to rugby players. The upper limb is the second most common anatomical site of injury in this population. Wrist injury and specifically the ulnar side of the leading wrist is the most prevalent. Leading wrist injuries affect the tendons, fibrocartilage, bones and neural structures that are located on the ulnar side of the wrist and hand as well as the soft tissue aponeurosis and bony and ligamentous canals that traverse the wrist joint. The most commonly injured lateral wrist structure is the Extensor Carpi Ulnaris tendon. This is particularly liable to injury due to the forces placed on it during the golf swing. Other structures on the medial side of the leading wrist associated with golf related injury and pathology include Triangular Fibro-cartilage, the hamate bone, the bony canals through which the nerves travel, as well as the flexor aponeurosis and Flexor Carpi Ulnaris tendon. Risk injury to the medial aspect of the leading wrist is increased by the newer golfing theories and techniques which endeavour to create increase golf club head speeds by storing greater energy by a phenomenon called “lag”. Lag results in greater speed as the club head releases at impact but results in injury to the medial wrist anatomical structures. Swing biomechanics, and their alteration and augmentation are a major factor in medial wrist injury. Diagnosis of these pathologies requires careful history and examination, as well as the use of radiology and electrodiagnostic medicine to confirm the pathology and degree. Treatment is targeted to the specific disability. Classical treatments are mostly employed and usually involve rest and anti-inflammatory treatments. Newer therapies such as Platelet Rich Plasma injection and Deep Oscillation therapy have proven beneficial. Splinting is often employed on return to play. Early diagnosis and cessation of the offending activity often allays the need for surgery. The rhyme that “minutes to diagnosis means weeks to recovery” is particularly apt for medial wrist golf injuries. Surgery will be required in long standing or chronic cases. Return to play, unlike many sports injuries, will require careful golf biomechanical assessment and alteration in swing dynamics. The objective of this chapter is to identify how the new biomechanical manipulation of the wrist and specifically the leading wrist has resulted in increased injuries to this anatomical structure. The type of injury, diagnosis and treatment is discussed in detail. Club head speed is generated through a combination of improved golf club equipment, golf payer fitness and manipulation of the golf club by the left wrist resulting in increased golf club lag and torque which all contribute to wrist injuries

Integrated analysis of genomic and epigenomic instability for CHO cell line engineering

Stability is an important factor in the development of cell lines for therapeutic protein production. In culture, the chromosome number and structure of Chinese Hamster Ovary (CHO) cells undergo rapid change. Over the course of cultivation, selection, and adaptation, chromosomal aberrations such as mutations, deletions, duplications, and other structural variants can accumulate. Some genomic regions may be more prone to such instability than others. When introducing exogenous genes for product formation or for engineering cell characteristics, it is critical to integrate into a stable region. A deeper understanding of the relationship between structure and stability is important for cell culture engineering. We investigated the genome stability of CHO cell lines at the macroscopic and microscopic levels, as well as from the epigenetic and genetic perspective. At the macroscopic level, we examined chromosomal and karyotypic variation, observing that the progenies of single cell clones quickly developed widely distributed variants with different numbers and types of chromosomes. However, at the population level the karyotype and chromosomal number distribution remained in a similar range. Stability at the microscopic level was analyzed using a gene-coding region focused comparative genomic hybridization (CGH) microarray, allowing us to determine genomic variations in gene copy number. With CGH data for many parent-daughter relationships, including subclones and relationships between host and producing cell lines, we identified genome segment changes that happen commonly during cell line development and subcloning. To further examine variation at the microscopic and genetic level, whole genome sequencing data of multiple CHO cell lines was used to identify structural variants, such as deletions, inversions, and duplications using the tools DELLY2 and LUMPY. Heterogeneity was present within each cell line and visible in the form of genome mosaicism. The effect of epigenetic modifications on the CHO genome was explored using the Assay for Transposase Accessible Chromatin Sequencing (ATAC-seq), which examines chromatin accessibility. ATAC-seq information was incorporated with transcriptional activity data using RNA-seq from multiple cell lines to identify inaccessible regions of the genome. This integrated systems approach combining chromosome number, karyotyping, CGH, genome sequencing, ATAC-seq, and RNA-seq gives us insight into the heterogeneity and instability of CHO cells, allowing us to identify desirable and undesirable regions for gene integration. With this data, we can select sites ideal for targeted integration of transgenes as well as screen out potentially unstable cell lines developed using random integration

A synthetic biology based cell line engineering pipeline

An ideal host cell line for deriving cell lines of high recombinant protein production should be stable, predictable, and amenable to rapid cell engineering or other forms of phenotypical manipulation. In the past few years we have employed genomic information to identify “safe harbors” for exogenous gene integration in CHO cells, deployed systems modeling and optimization to design pathways and control strategies to modify important aspects of recombinant protein productivity, and established a synthetic biology approach to implement genetic changes, all with the goal of creating a pipeline to produce “designer” cell lines. Chinese hamster ovary (CHO) cells are the preferred platform for protein production. However, the Chinese hamster genome is unstable in its ploidy, is subject to long and short deletions, duplications, and translocations. In addition, gene expression is subject to epigenetic changes including DNA methylation, histone modification and heterochromatin invasion, thus further complicating transgene expression for protein production in cell lines. With these issues in mind, we set out to engineer a CHO cell line highly amenable to stable protein production using a synthetic biology approach. We compiled karyotyping and chromosome number data of several CHO cell lines and sublines, identified genomic regions with high a frequency of gain and loss of copy number using comparative genome hybridization (CGH), and verified structural variants using sequencing data. We further used ATAC (Assay for Transposase-Accessible Chromatin) sequencing to study chromatin accessibility and epigenetic stability within the CHO genome. RNA-seq data from multiple cell lines were also used to identify regions with high transcriptional activity. Analysis of these data allowed the identification of several “safe harbor” loci that could be used for cell engineering. Based on results of the data analysis and identification of “safe harbors”, we engineered an IgG producing cell line with a single copy of the product transgene as a template cell line. This product gene site is flanked by sequences for recombinase mediated cassette exchange, therefore allowing easy substitution of the IgG producing gene for an alternative product gene. Furthermore, a “landing pad” for multi-gene cassette insertion was integrated into the genome at an additional site. Together, these sites allowed engineering of new cell lines producing a fusion protein and Erythropoietin to be generated from the template cell line. To enable rapid assembly of product transgenes and genetic elements for engineering cell attributes into multi-gene cassettes, we adopted a golden-gate based synthetic biology approach. The assembly of genetic parts into multi-gene cassettes in a LEGO-like fashion allowed different combinations of genes under the control of various promoters to be generated quickly for introduction into the template cell line. Using this engineered CHO cell line, we set out to study metabolism and product protein glycosylation for cell engineering. To guide the selection of genetic elements for cell engineering, we developed a multi-compartment kinetic model, as well as a flux model of energy metabolism and glycosylation. The transcriptome meta-data was used extensively to identify genes and isoforms expressed in the cell line and to estimate the enzyme levels in the model. The flux model was used to identify and the LEGO-like platform was used to implement the genetic changes that can alter the glycosylation pattern of the IgG produced by the template cell line. Concurrently we employed a systems optimization approach to identify the genetic alterations in the metabolic pathway to guide cell metabolism toward a favorable state. The model prediction is being implemented experimentally using the synthetic biology approach. In conclusion, we have illustrated a pipeline of rational cell line engineering that integrates genomic science, systems engineering and synthetic biology approaches. The promise, the technical challenges and possible limitations will be discussed in this presentation

Effectiveness of the internet-based Unified Protocol transdiagnostic intervention for the treatment of depression, anxiety and related disorders in a primary care setting: a randomized controlled trial

Background Research has shown that internet-based cognitive behavioural therapy (iCBT) can be a very promising solution to increase access to and the dissemination of evidence-based treatments to all of the population in need. However, iCBT is still underutilized in clinical contexts, such as primary care. In order to achieve the effective implementation of these protocols, more studies in ecological settings are needed. The Unified Protocol (UP) is a transdiagnostic CBT protocol for the treatment of emotional disorders, which includes depression, anxiety and related disorders, that has shown its efficacy across different contexts and populations. An internet-based UP (iUP) programme has recently been developed as an emerging internet-based treatment for emotional disorders. However, the internet-delivered version of the UP (iUP) has not yet been examined empirically. The current project seeks to analyse the effectiveness of the iUP as a treatment for depression, anxiety and related emotional disorders in a primary care public health setting. Methods The current study will employ a parallel-group, randomized controlled trial design. Participants will be randomly assigned to (a) the internet-based Unified Protocol (iUP), or (b) enhanced waiting list control (eWLC). Randomization will follow a 2:1 allocation ratio, with sample size calculations suggesting a required sample of 120 (iUP=80; eWLC=40). The Mini-International Neuropsychiatric Interview (M.I.N.I.) will be used for assessing potential participants. The Overall Anxiety Severity and Impairment Scale (OASIS) and the Overall Depression Severity and Impairment Scale (ODSIS) as well as other standardized questionnaires will be used for assessments at baseline, 4 weeks, 8 weeks and 12 weeks from baseline and for the iUP condition during the follow-up. Discussion Combining the advantages of a transdiagnostic treatment with an online delivery format may have the potential to significantly lower the burden of emotional disorders in public health primary care setting. Anxiety and depression, often comorbid, are the most prevalent psychological disorders in primary care. Because the iUP allows for the treatment of different disorders and comorbidity, this treatment could represent an adequate choice for patients that demand mental health care in a primary care setting

Computable phenotype for real-world, data-driven retrospective identification of relapse in ANCA-associated vasculitis

Objective: ANCA-associated vasculitis (AAV) is a relapsing-remitting disease, resulting in incremental tissue injury. The gold-standard relapse definition (Birmingham Vasculitis Activity Score, BVAS>0) is often missing or inaccurate in registry settings, leading to errors in ascertainment of this key outcome. We sought to create a computable phenotype (CP) to automate retrospective identification of relapse using real-world data in the research setting. Methods: We studied 536 patients with AAV and >6 months follow-up recruited to the Rare Kidney Disease registry (a national longitudinal, multicentre cohort study). We followed five steps: (1) independent encounter adjudication using primary medical records to assign the ground truth, (2) selection of data elements (DEs), (3) CP development using multilevel regression modelling, (4) internal validation and (5) development of additional models to handle missingness. Cut-points were determined by maximising the F1-score. We developed a web application for CP implementation, which outputs an individualised probability of relapse. Results: Development and validation datasets comprised 1209 and 377 encounters, respectively. After classifying encounters with diagnostic histopathology as relapse, we identified five key DEs; DE1: change in ANCA level, DE2: suggestive blood/urine tests, DE3: suggestive imaging, DE4: immunosuppression status, DE5: immunosuppression change. F1-score, sensitivity and specificity were 0.85 (95% CI 0.77 to 0.92), 0.89 (95% CI 0.80 to 0.99) and 0.96 (95% CI 0.93 to 0.99), respectively. Where DE5 was missing, DE2 plus either DE1/DE3 were required to match the accuracy of BVAS. Conclusions: This CP accurately quantifies the individualised probability of relapse in AAV retrospectively, using objective, readily accessible registry data. This framework could be leveraged for other outcomes and relapsing diseases

Computable phenotype for real-world, data-driven retrospective identification of relapse in ANCA-associated vasculitis

Objective: ANCA-associated vasculitis (AAV) is a relapsing-remitting disease, resulting in incremental tissue injury. The gold-standard relapse definition (Birmingham Vasculitis Activity Score, BVAS>0) is often missing or inaccurate in registry settings, leading to errors in ascertainment of this key outcome. We sought to create a computable phenotype (CP) to automate retrospective identification of relapse using real-world data in the research setting.Methods: We studied 536 patients with AAV and >6 months follow-up recruited to the Rare Kidney Disease registry (a national longitudinal, multicentre cohort study). We followed five steps: (1) independent encounter adjudication using primary medical records to assign the ground truth, (2) selection of data elements (DEs), (3) CP development using multilevel regression modelling, (4) internal validation and (5) development of additional models to handle missingness. Cut-points were determined by maximising the F1-score. We developed a web application for CP implementation, which outputs an individualised probability of relapse.Results: Development and validation datasets comprised 1209 and 377 encounters, respectively. After classifying encounters with diagnostic histopathology as relapse, we identified five key DEs; DE1: change in ANCA level, DE2: suggestive blood/urine tests, DE3: suggestive imaging, DE4: immunosuppression status, DE5: immunosuppression change. F1-score, sensitivity and specificity were 0.85 (95% CI 0.77 to 0.92), 0.89 (95% CI 0.80 to 0.99) and 0.96 (95% CI 0.93 to 0.99), respectively. Where DE5 was missing, DE2 plus either DE1/DE3 were required to match the accuracy of BVAS.Conclusions: This CP accurately quantifies the individualised probability of relapse in AAV retrospectively, using objective, readily accessible registry data. This framework could be leveraged for other outcomes and relapsing diseases.Keywords: Classification; Epidemiology; Outcome Assessment, Health Care; Vasculitis

Implementing a Sleep Health Education and Sleep Disorders Screening Program in Fire Departments: A Comparison of Methodology

Objective: The objective of this study is to compare three methods of administering a sleep health program (SHP) in fire departments. Methods: An SHP, comprising sleep health education and screening for common sleep disorders, was implemented in eight fire departments using three approaches: expert-led, train-the-trainer, and online. Participation rates, knowledge assessments, surveys, and focus group interviews were analyzed to assess the reach and effectiveness of the methodologies. Results: The Expert-led SHP had the highest participation rate, greatest improvement in knowledge scores, and prompted more firefighters to seek clinical sleep disorder evaluations (41%) than the other approaches (20 to 25%). Forty-two percent of focus group participants reported changing their sleep behaviors. Conclusion: All approaches yielded reasonable participation rates, but expert-led programs had the greatest reach and effectiveness in educating and screening firefighters for sleep disorders

Scalable production of large quantities of defect-free few-layer graphene by shear exfoliation in liquids

To progress from the laboratory to commercial applications, it will be necessary to develop industrially scalable methods to produce large quantities of defect-free graphene. Here we show that high-shear mixing of graphite in suitable stabilizing liquids results in large-scale exfoliation to give dispersions of graphene nanosheets. X-ray photoelectron spectroscopy and Raman spectroscopy show the exfoliated flakes to be unoxidized and free of basal-plane defects. We have developed a simple model that shows exfoliation to occur once the local shear rate exceeds 10(4) s(-1). By fully characterizing the scaling behaviour of the graphene production rate, we show that exfoliation can be achieved in liquid volumes from hundreds of millilitres up to hundreds of litres and beyond. The graphene produced by this method performs well in applications from composites to conductive coatings. This method can be applied to exfoliate BN, MoS2 and a range of other layered crystals