Value of symptoms and additional diagnostic tests for colorectal cancer in primary care: systematic review and meta-analysis

Objective To summarise available evidence on diagnostic tests that might help primary care physicians to identify patients with an increased risk for colorectal cancer among those consulting for non-acute lower abdominal symptoms

Brief pain re-assessment provided more accurate prognosis than baseline information for low-back or shoulder pain

Background Research investigating prognosis in musculoskeletal pain conditions has only been moderately successful in predicting which patients are unlikely to recover. Clinical decision making could potentially be improved by combining information taken at baseline and re-consultation. Methods Data from four prospective clinical cohorts of adults presenting to UK and Dutch primary care with low-back or shoulder pain was analysed, assessing long-term disability at 6 or 12 months and including baseline and 4–6 week assessments of pain. Baseline versus short-term assessments of pain, and previously validated multivariable prediction models versus repeat assessment, were compared to assess predictive performance of long-term disability outcome. A hypothetical clinical scenario was explored which made efficient use of both baseline and repeated assessment to identify patients likely to have a poor prognosis and decide on further treatment. Results Short-term repeat assessment of pain was better than short-term change or baseline score at predicting long-term disability improvement across all cohorts. Short-term repeat assessment of pain was only slightly more predictive of long-term recovery (c-statistics 0.78, 95% CI 0.74 to 0.83 and 0.75, 95% CI 0.69 to 0.82) than a multivariable baseline prognostic model in the two cohorts presenting such a model (c-statistics 0.71, 95% CI 0.67 to 0.76 and 0.72, 95% CI 0.66 to 0.78). Combining optimal prediction at baseline using a multivariable prognostic model with short-term repeat assessment of pain in those with uncertain prognosis in a hypothetical clinical scenario resulted in reduction in the number of patients with an uncertain probability of recovery, thereby reducing the instances where patients may be inappropriately referred or reassured. Conclusions Incorporating short-term repeat assessment of pain into prognostic models could potentially optimise the clinical usefulness of prognostic information

CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability

A characteristic of memory T (TM) cells is their ability to mount faster and stronger responses to reinfection than naïve T (TN) cells do in response to an initial infection. However, the mechanisms that allow this rapid recall are not completely understood. We found that CD8 TM cells have more mitochondrial mass than CD8 TN cells and, that upon activation, the resulting secondary effector T (TE) cells proliferate more quickly, produce more cytokines, and maintain greater ATP levels than primary effector T cells. We also found that after activation, TM cells increase oxidative phosphorylation and aerobic glycolysis and sustain this increase to a greater extent than TN cells, suggesting that greater mitochondrial mass in TM cells not only promotes oxidative capacity, but also glycolytic capacity. We show that mitochondrial ATP is essential for the rapid induction of glycolysis in response to activation and the initiation of proliferation of both TN and TM cells. We also found that fatty acid oxidation is needed for TM cells to rapidly respond upon restimulation. Finally, we show that dissociation of the glycolysis enzyme hexokinase from mitochondria impairs proliferation and blocks the rapid induction of glycolysis upon T-cell receptor stimulation in TM cells. Our results demonstrate that greater mitochondrial mass endows TM cells with a bioenergetic advantage that underlies their ability to rapidly recall in response to reinfection

Manipulative therapy in addition to usual medical care accelerates recovery of shoulder complaints at higher costs: economic outcomes of a randomized trial

Background: Shoulder complaints are common in primary care and have unfavourable long term prognosis. Our objective was to evaluate the clinical effectiveness of manipulative therapy of the cervicothoracic spine and the adjacent ribs in addition to usual medical care (UMC) by the general practitioner in the treatment of shoulder complaints. Methods: This economic evaluation was conducted alongside a randomized trial in primary care. Included were 150 patients with shoulder complaints and a dysfunction of the cervicothoracic spine and adjacent ribs. Patients were treated with UMC (NSAID's, corticosteroid injection or referral to physical therapy) and were allocated at random (yes/no) to manipulative therapy (manipulation and mobilization). Patient perceived recovery, severity of main complaint, shoulder pain, disability and general health were outcome measures. Data about direct and indirect costs were collected by means of a cost diary. Results: Manipulative therapy as add-on to UMC accelerated recovery on all outcome measures included. At 26 weeks after randomization, both groups reported similar recovery rates (41% vs. 38%), but the difference between groups in improvement of severity of the main complaint, shoulder pain and disability sustained. Compared to the UMC group the total costs were higher in the manipulative group ((sic)1167 vs.(sic)555). This is explained mainly by the costs of the manipulative therapy itself and the higher costs due sick leave from work. The cost effectiveness ratio showed that additional manipulative treatment is more costly but also more effective than UMC alone. The cost-effectiveness acceptability curve shows that a 50%-probability of recovery with AMT within 6 months after initiation of treatment is achieved at (sic)2876. Conclusion: Manipulative therapy in addition to UMC accelerates recovery and is more effective than UMC alone on the long term, but is associated with higher costs

Transcutaneous electrical nerve stimulation as adjunct to primary care management for tennis elbow:

Can transcutaneous electrical nerve stimulation (TENS), as a patient controlled adjunct to primary care management for tennis elbow, provide superior pain relief to primary care management alone

Factors Influencing the Participation of Older People in Clinical Trials : Data Analysis from the MAVIS Trial

Peer reviewedPostprin

Posttranscriptional control of T cell effector function by aerobic glycolysis

A “switch” from oxidative phosphorylation (OXPHOS) to aerobic glycolysis is a hallmark of T cell activation and is thought to be required to meet the metabolic demands of proliferation. However, why proliferating cells adopt this less efficient metabolism, especially in an oxygen-replete environment, remains incompletely understood. We show here that aerobic glycolysis is specifically required for effector function in T cells but that this pathway is not necessary for proliferation or survival. When activated T cells are provided with costimulation and growth factors but are blocked from engaging glycolysis, their ability to produce IFN-γ is markedly compromised. This defect is translational and is regulated by the binding of the glycolysis enzyme GAPDH to AU-rich elements within the 3′ UTR of IFN-γ mRNA. GAPDH, by engaging/disengaging glycolysis and through fluctuations in its expression, controls effector cytokine production. Thus, aerobic glycolysis is a metabolically regulated signaling mechanism needed to control cellular function

Prognosis research strategy (PROGRESS) 1: a framework for researching clinical outcomes.

The PROGRESS series (www.progress-partnership.org) sets out a framework of four interlinked prognosis research themes and provides examples from several disease fields to show why evidence from prognosis research is crucial to inform all points in the translation of biomedical and health related research into better patient outcomes. Recommendations are made in each of the four papers to improve current research standards What is prognosis research? Prognosis research seeks to understand and improve future outcomes in people with a given disease or health condition. However, there is increasing evidence that prognosis research standards need to be improved Why is prognosis research important? More people now live with disease and conditions that impair health than at any other time in history; prognosis research provides crucial evidence for translating findings from the laboratory to humans, and from clinical research to clinical practice This first article introduces the framework of four interlinked prognosis research themes and then focuses on the first of the themes - fundamental prognosis research, studies that aim to describe and explain future outcomes in relation to current diagnostic and treatment practices, often in relation to quality of care Fundamental prognosis research provides evidence informing healthcare and public health policy, the design and interpretation of randomised trials, and the impact of diagnostic tests on future outcome. It can inform new definitions of disease, may identify unanticipated benefits or harms of interventions, and clarify where new interventions are required to improve prognosis

Work-related physical and psychosocial risk factors for sick leave in patients with neck or upper extremity complaints

Objectives: To study work-related physical and psychosocial risk factors for sick leave among patients who have visited their general practitioner for neck or upper extremity complaints. Methods: Three hundred and forty two patients with neck or upper extremity complaints completed self-report questionnaires at baseline and after 3 months. Cox regression models were used to investigate the association between work-related risk factors and sick leave (i.e., lost days from work due to neck or upper extremity complaints in 3 months). Effect modification by sick leave at baseline, sex, worrying and musculoskeletal co-morbidity was evaluated by adding product terms to the regression models. Results: In the subgroup of patients who scored high on the pain copying scale "worrying" the hazard ratio of sick leave was 1.32 (95% CI 1.07-1.62) per 10% increase in heavy physical work. The subgroup of patients who were sitting for long periods of time had a reduced risk of sick leave as compared to patients who did not spend a lot of time sitting, again only in patients who scored high on the pain coping scale "worrying" (adjusted HR = 0.17, 95%-CI 0.04-0.72). Other work-related risk factors were not significantly related to sick leave. Conclusions: Heavy physical work increased the risk of sick leave and prolonged sitting reduced the risk of sick leave in a subgroup of patients who worried much about their pain. Additional large longitudinal studies of sufficiently large size among employees with neck or upper extremity complaints are needed to confirm our results. © Springer-Verlag 2007

Study protocol for the development and internal validation of Schizophrenia Prediction of Resistance to Treatment (SPIRIT): a clinical tool for predicting risk of treatment resistance to antipsychotics in first-episode schizophrenia.

INTRODUCTION: Treatment-resistant schizophrenia (TRS) is associated with significant impairment of functioning and high treatment costs. Identification of patients at high risk of TRS at the time of their initial diagnosis may significantly improve clinical outcomes and minimise social and functional disability. We aim to develop a prognostic model for predicting the risk of developing TRS in patients with first-episode schizophrenia and to examine its potential utility and acceptability as a clinical decision tool. METHODS AND ANALYSIS: We will use two well-characterised longitudinal UK-based first-episode psychosis cohorts: Aetiology and Ethnicity in Schizophrenia and Other Psychoses and Genetics and Psychosis for which data have been collected on sociodemographic and clinical characteristics. We will identify candidate predictors for the model based on current literature and stakeholder consultation. Model development will use all data, with the number of candidate predictors restricted according to available sample size and event rate. A model for predicting risk of TRS will be developed based on penalised regression, with missing data handled using multiple imputation. Internal validation will be undertaken via bootstrapping, obtaining optimism-adjusted estimates of the model's performance. The clinical utility of the model in terms of clinically relevant risk thresholds will be evaluated using net benefit and decision curves (comparative to competing strategies). Consultation with patients and clinical stakeholders will determine potential thresholds of risk for treatment decision-making. The acceptability of embedding the model as a clinical tool will be explored using qualitative focus groups with up to 20 clinicians in total from early intervention services. Clinicians will be recruited from services in Stafford and London with the focus groups being held via an online platform. ETHICS AND DISSEMINATION: The development of the prognostic model will be based on anonymised data from existing cohorts, for which ethical approval is in place. Ethical approval has been obtained from Keele University for the qualitative focus groups within early intervention in psychosis services (ref: MH-210174). Suitable processes are in place to obtain informed consent for National Health Service staff taking part in interviews or focus groups. A study information sheet with cover letter and consent form have been prepared and approved by the local Research Ethics Committee. Findings will be shared through peer-reviewed publications, conference presentations and social media. A lay summary will be published on collaborator websites