A multivariable prediction model to select colorectal surgical patients for co-management

Funding: The work of A.L. Papoila and C. Geraldes is partially sponsored by national funds through Fundação Nacional para a Ciência e Tecnologia, Portugal—FCT under the project PEst-OE/MAT/UI0006/2014. The work of Cátia Salgado was supported by the PhD Scholarship SFRH/BD/121875/2016 from Portuguese Foundation for Science & Technology. S. M. Vieira acknowledges the support by Program Investigador FCT (IF/00833/2014) from FCT, co-funded by the European Social Fund (ESF) through the Operational Program Human Potential (POPH).Introduction: Increased life expectancy leads to older and frailer surgical patients. Co-management between medical and surgical specialities has proven favourable in complex situations. Selection of patients for co-management is full of difficulties. The aim of this study was to develop a clinical decision support tool to select surgical patients for co-management. Material and Methods: Clinical data was collected from patient electronic health records with an ICD-9 code for colorectal surgery from January 2012 to December 2015 at a hospital in Lisbon. The outcome variable consists in co-management signalling. A dataset from 344 patients was used to develop the prediction model and a second data set from 168 patients was used for external validation. Results: Using logistic regression modelling the authors built a five variable (age, burden of comorbidities, ASA-PS status, surgical risk and recovery time) predictive referral model for co-management. This model has an area under the curve (AUC) of 0.86 (95% CI: 0.81 - 0.90), a predictive Brier score of 0.11, a sensitivity of 0.80, a specificity of 0.82 and an accuracy of 81.3%. Discussion: Early referral of high-risk patients may be valuable to guide the decision on the best level of post-operative clinical care. We developed a simple bedside decision tool with a good discriminatory and predictive performance in order to select patients for comanagement. Conclusion: A simple bed-side clinical decision support tool of patients for co-management is viable, leading to potential improvement in early recognition and management of postoperative complications and reducing the ‘failure to rescue’. Generalizability to other clinical settings requires adequate customization and validation.publishersversionpublishe

Biomarker-Drug and Liquid Biopsy Co-development for Disease Staging and Targeted Therapy: Cornerstones for Alzheimer's Precision Medicine and Pharmacology.

Systems biology studies have demonstrated that different (epi)genetic and pathophysiological alterations may be mapped onto a single tumor's clinical phenotype thereby revealing commonalities shared by cancers with divergent phenotypes. The success of this approach in cancer based on analyses of traditional and emerging body fluid-based biomarkers has given rise to the concept of liquid biopsy enabling a non-invasive and widely accessible precision medicine approach and a significant paradigm shift in the management of cancer. Serial liquid biopsies offer clues about the evolution of cancer in individual patients across disease stages enabling the application of individualized genetically and biologically guided therapies. Moreover, liquid biopsy is contributing to the transformation of drug research and development strategies as well as supporting clinical practice allowing identification of subsets of patients who may enter pathway-based targeted therapies not dictated by clinical phenotypes alone. A similar liquid biopsy concept is emerging for Alzheimer's disease, in which blood-based biomarkers adaptable to each patient and stage of disease, may be used for positive and negative patient selection to facilitate establishment of high-value drug targets and counter-measures for drug resistance. Going beyond the "one marker, one drug" model, integrated applications of genomics, transcriptomics, proteomics, receptor expression and receptor cell biology and conformational status assessments during biomarker-drug co-development may lead to a new successful era for Alzheimer's disease therapeutics. We argue that the time is now for implementing a liquid biopsy-guided strategy for the development of drugs that precisely target Alzheimer's disease pathophysiology in individual patients

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

Conservative interventions for urinary incontinence in women: an overview of Cochrane systematic reviews

This is the protocol for a review and there is no abstract. The objectives are as follows:  To synthesise Cochrane reviews of conservative interventions, as described above, for the prevention or treatment of female urinary incontinence.Output Type: Protoco

Description and Experience of the Clinical Testbeds

This deliverable describes the up-to-date technical environment at three clinical testbed demonstrator sites of the 6WINIT Project, including the adapted clinical applications, project components and network transition technologies in use at these sites after 18 months of the Project. It also provides an interim description of early experiences with deployment and usage of these applications, components and technologies, and their clinical service impact

Toward a process theory of entrepreneurship: revisiting opportunity identification and entrepreneurial actions

This dissertation studies the early development of new ventures and small business and the entrepreneurship process from initial ideas to viable ventures. I unpack the micro-foundations of entrepreneurial actions and new ventures’ investor communications through quality signals to finance their growth path. This dissertation includes two qualitative papers and one quantitative study. The qualitative papers employ an inductive multiple-case approach and include seven medical equipment manufacturers (new ventures) in a nascent market context (the mobile health industry) across six U.S. states and a secondary data analysis to understand the emergence of opportunities and the early development of new ventures. The quantitative research chapter includes 770 IPOs in the manufacturing industries in the U.S. and investigates the legitimation strategies of young ventures to gain resources from targeted resource-holders.Open Acces

PD-L1 testing for lung cancer in the UK: recognizing the challenges for implementation.

A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available

Developing a distributed electronic health-record store for India

The DIGHT project is addressing the problem of building a scalable and highly available information store for the Electronic Health Records (EHRs) of the over one billion citizens of India

The miR-139-5p regulates proliferation of supratentorial paediatric low-grade gliomas by targeting the PI3K/AKT/mTORC1 signalling

Paediatric low-grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs