Clinical proteomics for precision medicine: the bladder cancer case

Precision medicine can improve patient management by guiding therapeutic decision based on molecular characteristics. The concept has been extensively addressed through the application of –omics based approaches. Proteomics attract high interest, as proteins reflect a “real-time” dynamic molecular phenotype. Focusing on proteomics applications for personalized medicine, a literature search was conducted to cover: a) disease prevention, b) monitoring/ prediction of treatment response, c) stratification to guide intervention and d) identification of drug targets. The review indicates the potential of proteomics for personalized medicine by also highlighting multiple challenges to be addressed prior to actual implementation. In oncology, particularly bladder cancer, application of precision medicine appears especially promising. The high heterogeneity and recurrence rates together with the limited treatment options, suggests that earlier and more efficient intervention, continuous monitoring and the development of alternative therapies could be accomplished by applying proteomics-guided personalized approaches. This notion is backed by studies presenting biomarkers that are of value in patient stratification and prognosis, and by recent studies demonstrating the identification of promising therapeutic targets. Herein, we aim to present an approach whereby combining the knowledge on biomarkers and therapeutic targets in bladder cancer could serve as basis towards proteomics- guided personalized patient management

Point of care testing for urinary tract infection in primary care (POETIC): protocol for a randomised controlled trial of the clinical and cost effectiveness of FLEXICULT (TM) informed management of uncomplicated UTI in primary care

BACKGROUND: Urinary tract infections (UTI) are the most frequent bacterial infection affecting women and account for about 15% of antibiotics prescribed in primary care. However, some women with a UTI are not prescribed antibiotics or are prescribed the wrong antibiotics, while many women who do not have a microbiologically confirmed UTI are prescribed antibiotics. Inappropriate antibiotic prescribing unnecessarily increases the risk of side effects and the development of antibiotic resistance, and wastes resources. POETIC is a randomised controlled trial of a Point Of Care Test (POCT) (Flexicult™) guided UTI management strategy for use in primary care, which may help General Practitioners more effectively decide both whether or not to prescribe antibiotics, and if so, to select the most appropriate antibiotic. METHODS/DESIGN: 614 adult female patients will be recruited from four primary care research networks (Wales, England, Spain, the Netherlands) and individually randomised to either POCT guided care or the guideline-informed ‘standard care’ arm. Urine and stool samples (where possible) will be obtained at presentation (day 1) and two weeks later for microbiological analysis. All participants will be followed up on the course of their illness and their quality of life, using a 2 week self-completed symptom diary. At 3 months, a primary care notes review will be conducted for evidence of further evidence of treatment failures, recurrence, complications, hospitalisations and health service costs. The primary objective is to compare appropriate antibiotic use on day 3 between the POCT and standard care arms using multi-level logistic regression to produce an odds ratio and associated 95% confidence interval. Costs of the two management approaches will be assessed in terms of the primary outcome. DISCUSSION: Although the Flexicult™ POCT is used in some countries in routine primary care, it’s clinical and cost effectiveness has never been evaluated in a randomised clinical trial. If shown to be effective, the use of this POCT could benefit individual sufferers and provide evidence for health care authorities to develop evidence based policies to combat the spread and impact of the unprecedented rise of infections caused by antibiotic resistant bacteria in Europe. TRIAL REGISTRATION NUMBER: ISRCTN65200697 (Registered 10 September 2013)

Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance.

IntroductionMucopolysaccharidosis (MPS) IVA or Morquio A syndrome is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme, which impairs lysosomal degradation of keratan sulphate and chondroitin-6-sulphate. The multiple clinical manifestations of MPS IVA present numerous challenges for management and necessitate the need for individualised treatment. Although treatment guidelines are available, the methodology used to develop this guidance has come under increased scrutiny. This programme was conducted to provide evidence-based, expert-agreed recommendations to optimise management of MPS IVA.MethodsTwenty six international healthcare professionals across multiple disciplines, with expertise in managing MPS IVA, and three patient advocates formed the Steering Committee (SC) and contributed to the development of this guidance. Representatives from six Patient Advocacy Groups (PAGs) were interviewed to gain insights on patient perspectives. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with experience managing patients with MPS IVA and the manuscript was evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers.ResultsA total of 87 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) disease-modifying interventions (enzyme replacement therapy [ERT] and haematopoietic stem cell transplantation [HSCT]); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions (including spinal, limb, ophthalmic, cardio-thoracic and ear-nose-throat [ENT] surgeries). Consensus was reached on all statements after two rounds of voting. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance).ConclusionThis manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS IVA and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps

Point-of-Care Ultrasound Assessment of Tropical Infectious Diseases—A Review of Applications and Perspectives

The development of good quality and affordable ultrasound machines has led to the establishment and implementation of numerous point-of-care ultrasound (POCUS) protocols in various medical disciplines. POCUS for major infectious diseases endemic in tropical regions has received less attention, despite its likely even more pronounced benefit for populations with limited access to imaging infrastructure. Focused assessment with sonography for HIV-associated TB (FASH) and echinococcosis (FASE) are the only two POCUS protocols for tropical infectious diseases, which have been formally investigated and which have been implemented in routine patient care today. This review collates the available evidence for FASH and FASE, and discusses sonographic experiences reported for urinary and intestinal schistosomiasis, lymphatic filariasis, viral hemorrhagic fevers, amebic liver abscess, and visceral leishmaniasis. Potential POCUS protocols are suggested and technical as well as training aspects in the context of resource-limited settings are reviewed. Using the focused approach for tropical infectious diseases will make ultrasound diagnosis available to patients who would otherwise have very limited or no access to medical imaging

Verifying a medical protocol with temporal graphs: The case of a nosocomial disease

Objective: Our contribution focuses on the implementation of a formal verification approach for medical protocols with graphical temporal reasoning paths to facilitate the understanding of verification steps. Materials and methods: Formal medical guideline specifications and background knowledge are represented through conceptual graphs, and reasoning is based on graph homomorphism. These materials explain the underlying principles or rationale that guide the functioning of verifications. Results: An illustration of this proposal is made using a medical protocol defining guidelines for the monitoring and prevention of nosocomial infections. Such infections, which are acquired in the hospital, increasemorbidity andmortality and add noticeably to economic burden. An evaluation of the use of the graphical verification found that this method aids in the improvement of both clinical knowledge and the quality of actions made. Discussion: As conceptual graphs, representations based on diagrams can be translated into computational tree logic. However, diagrams are much more natural and explicitly human, emphasizing a theoretical and practical consistency. Conclusion: The proposed approach allows for the visualmodeling of temporal reasoning and a formalization of knowledge that can assist in the diagnosis and treatment of nosocomial infections and some clinical problems. This is the first time that one emphasizes the temporal situation modeling in conceptual graphs. It will also deliver a formal verification method for clinical guideline analyses

Treatment of infections caused by multidrug-resistant Gram-negative bacteria:Report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party

The Working Party makes more than 100 tabulated recommendations in antimicrobial prescribing for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) and suggest further research, and algorithms for hospital and community antimicrobial usage in urinary infection. The international definition of MDR is complex, unsatisfactory and hinders the setting and monitoring of improvement programmes. We give a new definition of multiresistance. The background information on the mechanisms, global spread and UK prevalence of antibiotic prescribing and resistance has been systematically reviewed. The treatment options available in hospitals using intravenous antibiotics and in primary care using oral agents have been reviewed, ending with a consideration of antibiotic stewardship and recommendations. The guidance has been derived from current peer-reviewed publications and expert opinion with open consultation. Methods for systematic review were NICE compliant and in accordance with the SIGN 50 Handbook; critical appraisal was applied using AGREE II. Published guidelines were used as part of the evidence base and to support expert consensus. The guidance includes recommendations for stakeholders (including prescribers) and antibiotic-specific recommendations. The clinical efficacy of different agents is critically reviewed. We found there are very few good-quality comparative randomized clinical trials to support treatment regimens, particularly for licensed older agents. Susceptibility testing of MDR GNB causing infection to guide treatment needs critical enhancements. Meropenem- or imipenem-resistant Enterobacteriaceae should have their carbapenem MICs tested urgently, and any carbapenemase class should be identified: mandatory reporting of these isolates from all anatomical sites and specimens would improve risk assessments. Broth microdilution methods should be adopted for colistin susceptibility testing. Antimicrobial stewardship programmes should be instituted in all care settings, based on resistance rates and audit of compliance with guidelines, but should be augmented by improved surveillance of outcome in Gram-negative bacteraemia, and feedback to prescribers. Local and national surveillance of antibiotic use, resistance and outcomes should be supported and antibiotic prescribing guidelines should be informed by these data. The diagnosis and treatment of both presumptive and confirmed cases of infection by GNB should be improved. This guidance, with infection control to arrest increases in MDR, should be used to improve the outcome of infections with such strains. Anticipated users include medical, scientific, nursing, antimicrobial pharmacy and paramedical staff where they can be adapted for local use

The Diagnosis of Urinary Tract infection in Young children (DUTY): a diagnostic prospective observational study to derive and validate a clinical algorithm for the diagnosis of urinary tract infection in children presenting to primary care with an acute illness

Background: It is not clear which young children presenting acutely unwell to primary care should be investigated for urinary tract infection (UTI) and whether or not dipstick testing should be used to inform antibiotic treatment.Objectives: To develop algorithms to accurately identify pre-school children in whom urine should be obtained; assess whether or not dipstick urinalysis provides additional diagnostic information; and model algorithm cost-effectiveness.Design: Multicentre, prospective diagnostic cohort study.Setting and participants: Children &lt; 5 years old presenting to primary care with an acute illness and/or new urinary symptoms.Methods: One hundred and seven clinical characteristics (index tests) were recorded from the child’s past medical history, symptoms, physical examination signs and urine dipstick test. Prior to dipstick results clinician opinion of UTI likelihood (‘clinical diagnosis’) and urine sampling and treatment intentions (‘clinical judgement’) were recorded. All index tests were measured blind to the reference standard, defined as a pure or predominant uropathogen cultured at ? 105 colony-forming units (CFU)/ml in a single research laboratory. Urine was collected by clean catch (preferred) or nappy pad. Index tests were sequentially evaluated in two groups, stratified by urine collection method: parent-reported symptoms with clinician-reported signs, and urine dipstick results. Diagnostic accuracy was quantified using area under receiver operating characteristic curve (AUROC) with 95% confidence interval (CI) and bootstrap-validated AUROC, and compared with the ‘clinician diagnosis’ AUROC. Decision-analytic models were used toidentify optimal urine sampling strategy compared with ‘clinical judgement’.Results: A total of 7163 children were recruited, of whom 50% were female and 49% were &lt; 2 years old. Culture results were available for 5017 (70%); 2740 children provided clean-catch samples, 94% of whom were ? 2 years old, with 2.2% meeting the UTI definition. Among these, ‘clinical diagnosis’ correctly identified 46.6% of positive cultures, with 94.7% specificity and an AUROC of 0.77 (95% CI 0.71 to 0.83). Four symptoms, three signs and three dipstick results were independently associated with UTI with an AUROC (95% CI; bootstrap-validated AUROC) of 0.89 (0.85 to 0.95; validated 0.88) for symptoms and signs, increasing to 0.93 (0.90 to 0.97; validated 0.90) with dipstick results. Nappy pad samples were provided from the other 2277 children, of whom 82% were &lt; 2 years old and 1.3% met the UTI definition.‘Clinical diagnosis’ correctly identified 13.3% positive cultures, with 98.5% specificity and an AUROC of 0.63 (95% CI 0.53 to 0.72). Four symptoms and two dipstick results were independently associated with UTI, with an AUROC of 0.81 (0.72 to 0.90; validated 0.78) for symptoms, increasing to 0.87 (0.80 to 0.94; validated 0.82) with the dipstick findings. A high specificity threshold for the clean-catch model was more accurate and less costly than, and as effective as, clinical judgement. The additional diagnostic utility of dipstick testing was offset by its costs. The cost-effectiveness of the nappy pad model was not clear-cut.Conclusions: Clinicians should prioritise the use of clean-catch sampling as symptoms and signs can cost-effectively improve the identification of UTI in young children where clean catch is possible. Dipstick testing can improve targeting of antibiotic treatment, but at a higher cost than waiting for a laboratory result. Future research is needed to distinguish pathogens from contaminants, assess the impact of the clean-catch algorithm on patient outcomes, and the cost-effectiveness of presumptive versus dipstick versus laboratory-guided antibiotic treatment.Funding: The National Institute for Health Research Health Technology Assessment programme.<br/

Aid decision algorithms to estimate the risk in congenital heart surgery

Background and objective: In this paper, we have tested the suitability of using different artificial intelligence-based algorithms for decision support when classifying the risk of congenital heart surgery. In this sense, classification of those surgical risks provides enormous benefits as the a priori estimation of surgical outcomes depending on either the type of disease or the type of repair, and other elements that influence the final result. This preventive estimation may help to avoid future complications, or even death. Methods: We have evaluated four machine learning algorithms to achieve our objective: multilayer perceptron, self-organizing map, radial basis function networks and decision trees. The architectures implemented have the aim of classifying among three types of surgical risk: low complexity, medium complexity and high complexity. Results: Accuracy outcomes achieved range between 80% and 99%, being the multilayer perceptron method the one that offered a higher hit ratio. Conclusions: According to the results, it is feasible to develop a clinical decision support system using the evaluated algorithms. Such system would help cardiology specialists, paediatricians and surgeons to forecast the level of risk related to a congenital heart disease surgery

Intestinal and urinary schistosomiasis dynamics in sub-Saharan Africa

Schistosomiasis is a chronic infection by a digean trematode of the genus Schistosoma. More than 207 million people are infected with this parasite, of which 120 million are symptomatic. There are two main species infecting humans in sub-Saharan Africa: Schistosoma haematobium and S. mansoni, both occur in areas with similar socio-economic and environmental conditions and often have matching distribution patterns. The principle aims of the research presented in this thesis were to further our understanding of schistosome population genetics, associated human host morbidity and chemotherapeutic treatment of schistosomes in relation to mixed species infections. Structured sampling of parasites and/or host traits from school-aged children at baseline and post Mass Drug Administration (MDA) in Niger and Kenya were performed. The results presented provided evidence for S. haematobium - S. mansoni interactions and their impact on the human host and on the parasite population. In Kenya coinfections had lower S. haematobium related morbidity relative to single S. haematobium infections pre and post MDA. Additionally parasite infra-populations from coinfected children had higher genetic diversity levels compared to single infected children in mixed infection foci. In Niger, an impact of MDA on the population genetics of S. mansoni was detected in one mixed infection village, characterised as a noticeable bottleneck effect, but not in the other. There was no apparent impact of MDA on the population genetics of S. haematobium. Conversely, in Kenya, a significant impact of MDA on both species was detected, with a bottleneck effect occurring on the S. haematobium population and conversely, an increase in genetic diversity in the S. mansoni population. The results of this thesis are discussed in terms of their implications on schistosome epidemiology and evolution, and in relation to the control of schistosomiasis in sub-Saharan Africa