Education Interventions to Improve Knowledge, Beliefs, Intentions and Practices with Respect to Dietary Supplements and Doping Substances: A Narrative Review.

The misuse of dietary supplements and doping substances is commonly associated with toxicity, nutritional imbalances, and health and psychological consequences. This is alarming especially in light of the increasing prevalence of the use of dietary supplements and doping, particularly among young adults including athletes. There is evidence that education interventions can lead to improved knowledge, intentions, and practices. However, no review has summarized and evaluated the effectiveness of such interventions. The aim of this article is to review the characteristics, contents and effects of education interventions that were designed and implemented to improve knowledge, attitudes, beliefs and intentions with respect to the use of dietary supplements and doping agents in different populations. PubMed, Scopus, CINAHL, PsycInfo and Google Scholar were searched for English-language education interventions targeting dietary supplements and doping substances. A total of 20 articles were identified and have generally provided consistent findings. Most interventions reported a significant improvement in knowledge on dietary supplements and doping agents. Unfortunately, the heavy reliance on self-reported assessment tools limits the validity of these interventions, with almost all articles targeting athletes and adolescents.

Genetically-encoded discovery of proteolytically stable bicyclic inhibitors for morphogen NODAL.

In this manuscript, we developed a two-fold symmetric linchpin (TSL) that converts readily available phage-displayed peptides libraries made of 20 common amino acids to genetically-encoded libraries of bicyclic peptides displayed on phage. TSL combines an aldehyde-reactive group and two thiol-reactive groups; it bridges two side chains of cysteine [C] with an N-terminal aldehyde group derived from the N-terminal serine [S], yielding a novel bicyclic topology that lacks a free N-terminus. Phage display libraries of SX1CX2X3X4X5X6X7C sequences, where X is any amino acid but Cys, were converted to a library of bicyclic TSL-[S]X1[C]X2X3X4X5X6X7[C] peptides in 45 ± 15% yield. Using this library and protein morphogen NODAL as a target, we discovered bicyclic macrocycles that specifically antagonize NODAL-induced signaling in cancer cells. At a 10 µM concentration, two discovered bicyclic peptides completely suppressed NODAL-induced phosphorylation of SMAD2 in P19 embryonic carcinoma cells. The TSL-[S]Y[C]KRAHKN[C] bicycle inhibited NODAL-induced proliferation of NODAL-TYK-nu ovarian carcinoma cells with apparent IC50 of 1 µM. The same bicycle at 10 µM concentration did not affect the growth of the control TYK-nu cells. TSL-bicycles remained stable over the course of the 72 hour-long assays in a serum-rich cell-culture medium. We further observed general stability in mouse serum and in a mixture of proteases (Pronase™) for 21 diverse bicyclic macrocycles of different ring sizes, amino acid sequences, and cross-linker geometries. TSL-constrained peptides to expand the previously reported repertoire of phage-displayed bicyclic architectures formed by cross-linking Cys side chains. We anticipate that it will aid the discovery of proteolytically stable bicyclic inhibitors for a variety of protein targets.

Registered Dietitians' Knowledge, Attitudes, and Behaviour Related to Physical Activity and Sedentariness.

Purpose: To explore knowledge, attitudes, and behaviour related to physical activity (PA) and sedentariness among registered dietitians (RDs) in family health teams in Ontario.Methods: This cross-sectional, descriptive study utilized a semi-structured interview guide to conduct qualitative interviews with 20 RDs. Self-administered questionnaires were used to assess personal PA (short version of the International Physical Activity Questionnaire) and sedentary behaviour (Sedentary Behavior Questionnaire).Results: Thematic analysis indicated that, in general, participants had good knowledge of PA and sedentariness. They were knowledgeable about the PA guidelines. They had positive attitudes toward PA and nonsedentariness, stating that both are important in the prevention and treatment of chronic conditions. Quantitative analysis indicated they had moderate-to-high PA levels and were fairly sedentary.Conclusions: This study supports the position that RDs can serve as excellent role models for PA. Though participants had basic knowledge, RDs may benefit from additional education regarding PA and sedentariness when counselling.

Registered dietitians' beliefs and behaviours related to counselling patients on physical activity and sedentary behaviour from a theory of planned behaviour perspective.

BACKGROUND: Registered dietitians working in team-based primary care settings (e.g., family health teams [FHTs]) are positioned to counsel on physical activity and sedentary behaviour when providing nutrition-related services to promote health and prevent disease. This qualitative study explored FHT registered dietitians' beliefs and behaviours related to counselling patients on physical activity and sedentary behaviour. METHODS: Twenty registered dietitians in FHTs in Ontario, Canada were interviewed in person. Theory of planned behaviour guided the development of this cross-sectional, descriptive study. Thematic analysis was used to identify themes within each of the following theoretical constructs (topics): registered dietitians' behaviour (practice), behavioural intention, attitude, subjective norm, and perceived behavioural control related to physical activity and sedentary behaviour counselling. RESULTS: All participants counselled patients on physical activity, using some motivational interviewing strategies, and most counselled on sedentary behaviour. Many participants intended to continue their current physical activity counselling practices and increase sedentary behaviour counselling. Some participants had a positive attitude about the effectiveness of counselling on physical activity and sedentary behaviour, but their belief about effectiveness was dependent on factors such as time frame for behaviour change. Many participants felt that other health care professionals expected them to counsel on physical activity and they believed that other registered dietitians counsel on physical activity and sedentary behaviour. Facilitators to counselling included FHT dynamics and time with patients. In terms of barriers, almost all participants were confident in basic PA counselling only and contended that only this is within their scope of practice. Many participants posited that exercise prescription is outside their scope of practice. Other barriers included registered dietitians' lack of knowledge and not having a physical activity expert on the team. CONCLUSIONS: The results suggest that strategies are warranted to improve FHT registered dietitians' knowledge, attitude, and counselling skills related to physical activity and sedentary behaviour. This study provides a strong foundation to develop a theory-based, quantitative measure to assess physical activity and sedentary behaviour counselling practices and determinants among registered dietitians.

Generating high-quality data abstractions from scanned clinical records: text-mining-assisted extraction of endometrial carcinoma pathology features as proof of principle.

OBJECTIVE: Medical research studies often rely on the manual collection of data from scanned typewritten clinical records, which can be laborious, time consuming and error prone because of the need to review individual clinical records. We aimed to use text mining to assist with the extraction of clinical features from complex text-based scanned pathology records for medical research studies. DESIGN: Text mining performance was measured by extracting and annotating three distinct pathological features from scanned photocopies of endometrial carcinoma clinical pathology reports, and comparing results to manually abstracted terms. Inclusion and exclusion keyword trigger terms to capture leiomyomas, endometriosis and adenomyosis were provided based on expert knowledge. Terms were expanded with character variations based on common optical character recognition (OCR) error patterns as well as negation phrases found in sample reports. The approach was evaluated on an unseen test set of 1293 scanned pathology reports originating from laboratories across Australia. SETTING: Scanned typewritten pathology reports for women aged 18-79 years with newly diagnosed endometrial cancer (2005-2007) in Australia. RESULTS: High concordance with final abstracted codes was observed for identifying the presence of three pathology features (94%-98% F-measure). The approach was more consistent and reliable than manual abstractions, identifying 3%-14% additional feature instances. CONCLUSION: Keyword trigger-based automation with OCR error correction and negation handling proved not only to be rapid and convenient, but also providing consistent and reliable data abstractions from scanned clinical records. In conjunction with manual review, it can assist in the generation of high-quality data abstractions for medical research studies.

Co-existence of leiomyomas, adenomyosis and endometriosis in women with endometrial cancer.

Leiomyomas, adenomyosis, and endometriosis are reported to be risk factors for endometrial carcinoma (EC), and adenomyosis and endometriosis also for ovarian carcinoma (OC). We aimed to describe the prevalence of these conditions in EC patients with or without an OC diagnosis, and to investigate their relationship with EC risk and prognostic factors in these patients. We evaluated the co-existence of these three conditions in 1399 EC patients, and compared the prevalence of epidemiological risk factors and tumor prognostic features in patients with each condition versus not. Prevalence of conditions was also assessed in the subset of patients with prior/concurrent OC. The observed coexistence of leiomyomas, adenomyosis and endometriosis significantly deviated from that expected (P = 1.2 × 10-8). Patients were more likely to: report a younger age at menarche (PTrend = 0.004) if they had leiomyomas; have used oral contraceptives (P = 6.6 × 10-5) or had ≥2 full-term pregnancies (PTrend = 2.0 × 10-9) if they had adenomyosis; be diagnosed with EC at younger age (P = 5.0 × 10-11) if they had endometriosis. Patients with prior/concurrent OC were more likely to be diagnosed at younger age (P = 5.0 × 10-5), have endometriosis (P = 9.9 × 10-7), and present with higher stage EC (PTrend = 6.6 × 10-5). These findings justify further consideration of these gynecologic conditions as independent risk and prognostic factors for EC.

Cost-Effectiveness of Pain Management Strategies in Advanced Cancer.

OBJECTIVES: Uncontrolled pain in advanced cancer is a common problem and has significant impact on individuals' quality of life and use of healthcare resources. Interventions to help manage pain at the end of life are available, but there is limited economic evidence to support their wider implementation. We conducted a case study economic evaluation of two pain self-management interventions (PainCheck and Tackling Cancer Pain Toolkit [TCPT]) compared with usual care. METHODS: We generated a decision-analytic model to facilitate the evaluation. This modelled the survival of individuals at the end of life as they moved through pain severity categories. Intervention effectiveness was based on published meta-analyses results. The evaluation was conducted from the perspective of the U.K. health service provider and reported cost per quality-adjusted life-year (QALY). RESULTS: PainCheck and TCPT were cheaper (respective incremental costs -GBP148 [-EUR168.53] and -GBP474 [-EUR539.74]) and more effective (respective incremental QALYs of 0.010 and 0.013) than usual care. There was a 65 percent and 99.5 percent chance of cost-effectiveness for PainCheck and TCPT, respectively. Results were relatively robust to sensitivity analyses. The most important driver of cost-effectiveness was level of pain reduction (intervention effectiveness). Although cost savings were modest per patient, these were considerable when accounting for the number of potential intervention beneficiaries. CONCLUSIONS: Educational and monitoring/feedback interventions have the potential to be cost-effective. Economic evaluations based on estimates of effectiveness from published meta-analyses and using a decision modeling approach can support commissioning decisions and implementation of pain management strategies.

Extracting tumour prognostic factors from a diverse electronic record dataset in genito-urinary oncology.

OBJECTIVES: To implement a system for unsupervised extraction of tumor stage and prognostic data in patients with genitourinary cancers using clinicopathological and radiology text. METHODS: A corpus of 1054 electronic notes (clinician notes, radiology reports and pathology reports) was annotated for tumor stage, prostate specific antigen (PSA) and Gleason grade. Annotations from five clinicians were reconciled to form a gold standard dataset. A training dataset of 386 documents was sequestered. The Medtex algorithm was adapted using the training dataset. RESULTS: Adapted Medtex equaled or exceeded human performance in most annotations, except for implicit M stage (F-measure of 0.69 vs 0.84) and PSA (0.92 vs 0.96). Overall Medtex performed with an F-measure of 0.86 compared to human annotations of 0.92. There was significant inter-observer variability when comparing human annotators to the gold standard. CONCLUSIONS: The Medtex algorithm performed similarly to human annotators for extracting stage and prognostic data from varied clinical texts.

Improving the management of pain from advanced cancer in the community: study protocol for a pragmatic multicentre randomised controlled trial.

INTRODUCTION: For patients with advanced cancer, research shows that pain is frequent, burdensome and undertreated. Evidence-based approaches to support cancer pain management have been developed but have not been implemented within the context of the UK National Health Service. This protocol is for a pragmatic multicentre randomised controlled trial (RCT) to assess feasibility, acceptability, effectiveness and cost-effectiveness for a multicomponent intervention for pain management in patients with advanced cancer. METHODS AND ANALYSIS: This trial will assess the feasibility of implementation and uptake of evidence-based interventions, developed and piloted as part of the Improving the Management of Pain from Advanced Cancer in the Community Programme grant, into routine clinical practice and determine whether there are potential differences with respect to patient-rated pain, patient pain knowledge and experience, healthcare use, quality of life and cost-effectiveness. 160 patients will receive either the intervention (usual care plus supported self-management) delivered within the oncology clinic and palliative care services by locally assigned community palliative care nurses, consisting of a self-management educational intervention and eHealth intervention for routine pain assessment and monitoring; or usual care. The primary outcomes are to assess implementation and uptake of the interventions, and differences in terms of pain severity. Secondary outcomes include pain interference, participant pain knowledge and experience, and cost-effectiveness. Outcome assessment will be blinded and patient-reported outcome measures collected via post at 6 and 12 weeks following randomisation. ETHICS AND DISSEMINATION: This RCT has the potential to significantly influence National Health Service delivery to community-based patients with pain from advanced cancer. We aim to provide definitive evidence of whether two simple interventions delivered by community palliative care nurse in palliative care that support-self-management are clinically effective and cost-effective additions to standard community palliative care. TRIAL REGISTRATION NUMBER: ISRCTN18281271; Pre-results.

Feasibility of a multicentre, randomised controlled trial of laparoscopic versus open colorectal surgery in the acute setting: the LaCeS feasibility trial protocol.

INTRODUCTION: Acute colorectal surgery forms a significant proportion of emergency admissions within the National Health Service. There is limited evidence to suggest minimally invasive surgery may be associated with improved clinical outcomes in this cohort of patients. Consequently, there is a need to assess the clinical effectiveness and cost-effectiveness of laparoscopic surgery in the acute colorectal setting. However,emergency colorectal surgical trials have previously been difficult to conduct due to issues surrounding recruitment and equipoise. The LaCeS (randomised controlled trial of Laparoscopic versus open Colorectal Surgery in the acute setting) feasibility trial will determine the feasibility of conducting a definitive, phase III trial of laparoscopic versus open acute colorectal resection. METHODS AND ANALYSIS: The LaCeS feasibility trial is a prospective, multicentre, single-blinded, parallel group, pragmatic randomised controlled feasibility trial. Patients will be randomised on a 1:1 basis to receive eitherlaparoscopic or open surgery. The trial aims to recruit at least 66 patients from five acute general surgical units across the UK. Patients over the age of 18 with a diagnosis of acute colorectal pathology requiring resection on clinical and radiological/endoscopic investigations, with a National Confidential Enquiry into Patient Outcome and Death classification of urgent will be considered eligible for participation. The primary outcome is recruitment. Secondary outcomes include assessing the safety profile of laparoscopic surgery using intraoperative and postoperative complication rates, conversion rates and patient-safety indicators as surrogate markers. Clinical and patient-reported outcomes will also be reported. The trial will contain an embedded qualitative study to assess clinician and patient acceptability of trial processes. ETHICS AND DISSEMINATION: The LaCeS feasibility trial is approved by the Yorkshire and The Humber, Bradford Leeds Research Ethics Committee (REC reference: 15/ YH/0542). The results from the trial will be presented at national and international colorectal conferences and will be submitted for publication to peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN15681041; Pre-results.

Aciclovir-induced acute kidney injury in patients with 'suspected viral encephalitis' encountered on a liaison neurology service.

BACKGROUND: Patients with 'suspected viral encephalitis' are frequently empirically treated with intravenous aciclovir. Increasing urea and creatinine are 'common', but rapidly progressive renal failure is reported to be 'very rare'. AIMS: To describe the clinical course and outcome of cases of aciclovir-induced acute kidney injury (AKI) encountered by the Liaison Neurology Service at AMNCH and to highlight the importance of surveillance and urgent treatment of this iatrogenic complication. METHODS: Retrospectively and prospectively collected data from the Liaison Neurology Service at AMNCH on patients who received IV aciclovir for suspected viral encephalitis and developed AKI were analysed. Aciclovir-induced AKI was defined by a consultant nephrologist in all cases as a rise in serum creatinine of > 26 µmol/L in 48 h or by ≥ 1.5 times the baseline value. Renal function, haematocrit, and fluid balance were monitored following AKI onset. RESULTS: Data from 10 patients were analysed. Median time to AKI onset was 3.5 days (range: 1-6 days). Aciclovir was stopped or the dose adjusted. All patients recovered with IV normal saline, aiming for a urine output > 100-150 ml/h. The interval between first rise in creatinine and return to normal levels varied between 5 and 19 days. CONCLUSIONS: Liaison neurologists and general physicians need to be aware that aciclovir may cause AKI attributed to distal intra-tubular crystal nephropathy. Daily fluid balance and renal function monitoring are essential because AKI may arise even with intensive pre-hydration. Prognosis is good if identified early and actively treated.

Cost-Effectiveness of Tight Control of Inflammation in Early Psoriatic Arthritis: Economic Analysis of a Multicenter Randomized Controlled Trial.

OBJECTIVE: Treat-to-target approaches have proved to be effective in rheumatoid arthritis, but have not been studied in psoriatic arthritis (PsA). This study was undertaken to examine the cost-effectiveness of tight control (TC) of inflammation in early PsA compared to standard care. METHODS: Cost-effectiveness analyses were undertaken alongside a UK-based, open-label, multicenter, randomized controlled trial. Taking the perspective of the health care sector, effectiveness was measured using the 3-level EuroQol 5-domain, which allows for the calculation of quality-adjusted life-years (QALYs). Incremental cost-effectiveness ratios (ICERs) are presented, which represent the additional cost per QALY gained over a 48-week time horizon. Sensitivity analyses are presented assessing the impact of variations in the analytical approach and assumptions on the cost-effectiveness estimates. RESULTS: The mean cost and QALYs were higher in the TC group: £4,198 versus £2,000 and 0.602 versus 0.561. These values yielded an ICER of £53,948 per QALY. Bootstrapped uncertainty analysis suggests that the TC has a 0.07 probability of being cost-effective at a £20,000 threshold. Stratified analysis suggests that with certain costs being controlled, an ICER of £24,639 can be calculated for patients with a higher degree of disease severity. CONCLUSION: A tight control strategy to treat PsA is an effective intervention in the treatment pathway; however, this study does not find tight control to be cost-effective in most analyses. Lower drug prices, targeting polyarthritis patients, or reducing the frequency of rheumatology visits may improve value for money metrics in future studies.

Clinical effectiveness and cost-effectiveness results from the randomised, Phase IIB trial in previously untreated patients with chronic lymphocytic leukaemia to compare fludarabine, cyclophosphamide and rituximab with fludarabine, cyclophosphamide, mitoxantrone and low-dose rituximab: the Attenuated dose Rituximab with ChemoTherapy In Chronic lymphocytic leukaemia (ARCTIC) trial.

BACKGROUND: The conventional frontline therapy for fit patients with chronic lymphocytic leukaemia (CLL) is fludarabine, cyclophosphamide and rituximab (FCR). Rituximab (Mabthera®, Roche Products Ltd) targets the CD20 antigen, which is expressed at low levels in CLL. The standard dose of rituximab in CLL (375 mg/m2 in cycle 1 and 500 mg/m2 in cycles 2-6) was selected based on toxicity data only. Small doses of rituximab (as low as 20 mg) have biological activity in CLL, with an immediate reduction in circulating CLL cells and down-regulation of CD20. Phase II trials had suggested improved efficacy with the addition of mitoxantrone to FCR. The key assumption for the Attenuated dose Rituximab with ChemoTherapy In CLL (ARCTIC) trial was that the addition of mitoxantrone to fludarabine, cyclophosphamide and low-dose rituximab would be more effective than conventional FCR. OBJECTIVES: To assess whether fludarabine, cyclophosphamide, mitoxantrone and low-dose rituximab (FCM-miniR) (100 mg of rituximab per cycle) was non-inferior to FCR in frontline CLL. Complete response (CR) rate was the primary end point, with the secondary end points being progression-free survival (PFS), overall survival (OS), overall response rate, eradication of minimal residual disease (MRD), safety and cost-effectiveness. DESIGN: ARCTIC was a UK multicentre, randomised, controlled, open, Phase IIB non-inferiority trial in previously untreated CLL. A total of 206 patients with previously untreated CLL who required treatment, according to the International Workshop on Chronic Lymphocytic Leukaemia criteria, were to be randomised to FCR or FCM-miniR. There was an independent Data Monitoring and Ethics Committee (DMEC) with a pre-planned interim efficacy assessment on 103 participants. RESULTS: The DMEC's interim analysis led to early trial closure. Although the response rates in both arms were higher than anticipated, FCM-miniR had a lower CR rate than FCR. This was partly attributable to the higher toxicity associated with mitoxantrone. A total of 100 participants completed FCR, 79 completed FCM-miniR and 21 commenced FCM-miniR but switched to FCR following DMEC recommendations. The CR rate for participants receiving FCR was 76%, compared with 55% for FCM-miniR (adjusted odds ratio 0.37; 95% confidence interval 0.19 to 0.73). Key secondary end points also showed that FCR was superior, with more participants achieving MRD negativity (57% for FCR vs. 46% for FCM-miniR). More participants experienced a serious adverse reaction with FCM-miniR compared with FCR (50% vs. 41%). At a median of 37.3 months' follow-up, the PFS and OS rates are good compared with previous studies, with no significant difference between the treatment arms. The economic analysis indicates that because FCM-miniR is less effective than FCR, FCM-miniR is not expected to be cost-effective over a lifetime horizon, producing a mean cost-saving of -£7723, a quality-adjusted life-year loss of -0.73 and a resulting incremental net monetary loss of -£6780. CONCLUSIONS: FCM-miniR is less well tolerated, with poorer response rates, than FCR, partly owing to the additional toxicity associated with mitoxantrone. In view of this, FCM-miniR will not be taken forward into a larger definitive Phase III trial. The trial demonstrated that oral FCR yields extremely high response rates compared with historical series with intravenous chemotherapy. FUTURE WORK: We shall compare the results of ARCTIC with those of the ADMIRE (Does the ADdition of Mitoxantrone Improve Response to FCR chemotherapy in patients with CLL?) trial, which compared FCR with FCM-R to assess the efficacy of low- versus standard-dose rituximab, allowing for the toxicity associated with mitoxantrone. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16544962. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 28. See the NIHR Journals Library website for further project information.

Patient Preferences for Pain Management in Advanced Cancer: Results from a Discrete Choice Experiment.

BACKGROUND: Pain from advanced cancer remains prevalent, severe and often under-treated. AIM: The aim of this study was to conduct a discrete choice experiment with patients to understand their preferences for pain management services and inform service development. METHODS: Focus groups were used to develop the attributes and levels of the discrete choice experiment. The attributes were: waiting time, type of healthcare professional, out-of-pocket costs, side-effect control, quality of communication, quality of information and pain control. Patients completed the discrete choice experiment along with clinical and health-related quality of life questions. Conditional and mixed logit models were used to analyse the data. RESULTS: Patients with cancer pain (n = 221) and within palliative care services completed the survey (45% were female, mean age 64.6 years; age range 21-92 years). The most important aspects of pain management were: good pain control, zero out-of-pocket costs and good side-effect control. Poor or moderate pain control and £30 costs drew the highest negative preferences. Respondents preferred control of side effects and provision of better information and communication, over access to certain healthcare professionals. Those with lower health-related quality of life were less willing to wait for treatment and willing to incur higher costs. The presence of a carer influenced preferences. CONCLUSIONS: Outcome attributes were more important than process attributes but the latter were still valued. Thus, supporting self-management, for example by providing better information on pain may be a worthwhile endeavour. However, service provision may need to account for individual characteristics given the heterogeneity in preferences.

The experience of parental cancer among emerging adult university students.

Cancer is a disease that can have negative as well as some positive outcomes for the survivor, caregiver, and offspring. To date, there has been little research on the experiences of emerging adult offspring. When these offspring are also university students, they can experience unique challenges. In this phenomenological study, we explored the lived experience of parental cancer among emerging adult university students by interviewing 17 university students and using thematic analysis. The overarching themes were perceptions and beliefs about cancer, the outcomes of having a parent with cancer, influence of parental cancer on life as a university student, coping with having a parent with cancer, and attitudes and experiences around health and personal lifestyle. These results will be particularly useful to practitioners who provide services to university students experiencing parental cancer.

Synthesis and Pharmacological Characterization of Novel Glucagon-like Peptide-2 (GLP-2) Analogues with Low Systemic Clearance.

Glucagon-like peptide-2 receptor agonists have therapeutic potential for the treatment of intestinal diseases. The native hGLP-2, a 33 amino acid gastrointestinal peptide, is not a suitable clinical candidate, due to its very short half-life in humans. In search of GLP-2 receptor agonists with better pharmacokinetic characteristics, a series of GLP-2 analogues containing Gly substitution at position 2, norleucine in position 10, and hydrophobic substitutions in positions 11 and/or 16 was designed and synthesized. In vitro receptor potency at the human GLP-2, selectivity vs the human GLP-1 and GCG receptors, and PK profile in rats were determined for the new analogues. A number of compounds more potent at the hGLP-2R than the native hormone, showing excellent receptor selectivity and very low systemic clearance (CL) were discovered. Analogues 69 ([Gly(2),Nle(10),D-Thi(11),Phe(16)]hGLP-2-(1-30)-NH2), 72 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-OH), 73 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NH2), 81 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NHEt), and 85 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NH-((CH2)2O)4-(CH2)2-CONH2) displayed the desired profiles (EC50 (hGLP-2R) < 100 pM, CL in rat <0.3 mL/min/kg, selective vs hGLP-1R and hGCGR). Compound 73 (FE 203799) was selected as a candidate for clinical development.

Automated Cancer Registry Notifications: Validation of a Medical Text Analytics System for Identifying Patients with Cancer from a State-Wide Pathology Repository.

The paper assesses the utility of Medtex on automating Cancer Registry notifications from narrative histology and cytology reports from the Queensland state-wide pathology information system. A corpus of 45.3 million pathology HL7 messages (including 119,581 histology and cytology reports) from a Queensland pathology repository for the year of 2009 was analysed by Medtex for cancer notification. Reports analysed by Medtex were consolidated at a patient level and compared against patients with notifiable cancers from the Queensland Oncology Repository (QOR). A stratified random sample of 1,000 patients was manually reviewed by a cancer clinical coder to analyse agreements and discrepancies. Sensitivity of 96.5% (95% confidence interval: 94.5-97.8%), specificity of 96.5% (95.3-97.4%) and positive predictive value of 83.7% (79.6-86.8%) were achieved for identifying cancer notifiable patients. Medtex achieved high sensitivity and specificity across the breadth of cancers, report types, pathology laboratories and pathologists throughout the State of Queensland. The high sensitivity also resulted in the identification of cancer patients that were not found in the QOR. High sensitivity was at the expense of positive predictive value; however, these cases may be considered as lower priority to Cancer Registries as they can be quickly reviewed. Error analysis revealed that system errors tended to be tumour stream dependent. Medtex is proving to be a promising medical text analytic system. High value cancer information can be generated through intelligent data classification and extraction on large volumes of unstructured pathology reports.

Assessing the Utility of Automatic Cancer Registry Notifications Data Extraction from Free-Text Pathology Reports.

Cancer Registries record cancer data by reading and interpreting pathology cancer specimen reports. For some Registries this can be a manual process, which is labour and time intensive and subject to errors. A system for automatic extraction of cancer data from HL7 electronic free-text pathology reports has been proposed to improve the workflow efficiency of the Cancer Registry. The system is currently processing an incoming trickle feed of HL7 electronic pathology reports from across the state of Queensland in Australia to produce an electronic cancer notification. Natural language processing and symbolic reasoning using SNOMED CT were adopted in the system; Queensland Cancer Registry business rules were also incorporated. A set of 220 unseen pathology reports selected from patients with a range of cancers was used to evaluate the performance of the system. The system achieved overall recall of 0.78, precision of 0.83 and F-measure of 0.80 over seven categories, namely, basis of diagnosis (3 classes), primary site (66 classes), laterality (5 classes), histological type (94 classes), histological grade (7 classes), metastasis site (19 classes) and metastatic status (2 classes). These results are encouraging given the large cross-section of cancers. The system allows for the provision of clinical coding support as well as indicative statistics on the current state of cancer, which is not otherwise available.

Lead discovery and optimization strategies for peptide macrocycles.

Peptide macrocycles represent a chemical space where the best of biological tools can synergize with the best of chemical approaches in the quest for leads against undruggable targets. Peptide macrocycles offer some key advantages in both lead discovery and lead optimization phases of drug discovery when compared to natural product and synthetic macrocycles. In addition, they are uniquely positioned to capitalize on the therapeutic potential of peptides because cyclization can help drive selectivity, potency and overcome the common limitations of metabolic instability of peptides.

Paraneoplastic dentate ganglionopathy: clinical and neuroimmunologic studies.

We describe the clinical and neuropathological features of two cases of cerebellar degeneration with selective involvement of the dentate nucleus. Both cases were associated with malignancy, however known paraneoplastic antibodies were absent. Pathological studies at autopsy confirmed T-cell-mediated neuronal destruction in the cerebellum which was strikingly limited to the dentate nucleus in both patients. The occurrence of these pathological features has not been previously described in antibodynegative paraneoplastic disease, but bears similarities to Rasmussen’s encephalitis.