MicroRNAs as Novel Biomarkers for Breast Cancer

Breast cancer is a complex phenotypically diverse genetic disease, involving a variety of changes in gene expression and structure. Recent advances in molecular profiling technology have made great progress in unravelling the molecular taxonomy of breast cancer, which has shed new light on the aetiology of the disease and also heralded great potential for the development of novel biomarkers and therapeutic targets. Mi(cro)RNAs are a contemporary class of small noncoding endogenous RNA molecules, generating great excitement in the clinical and scientific communities. The recent discovery that miRNA expression is frequently dysregulated in cancer has uncovered an entirely new repertoire of molecular factors upstream of gene expression, which warrants extensive investigation to further elucidate their precise role in malignancy. We present a comprehensive and timely review of the role of miRNAs in cancer: addressing miRNA function, their putative role as oncogenes or tumor suppressors, with a particular emphasis on breast cancer throughout. We discuss the recent discovery of quantifiable circulating cancer-associated miRNAs, which heralds immense potential for their use as novel minimally invasive biomarkers for breast and other cancers. Finally, we comment on the potential role of miRNAs in breast cancer management, particularly in improving current prognostic tools and achieving the goal of individualized cancer treatment

Definition and classification for adverse events following spinal and peripheral joint manipulation and mobilization: A scoping review

INTRODUCTION Spinal and peripheral joint manipulation and mobilization are interventions used by many healthcare providers to manage musculoskeletal conditions. Although there are many reports of adverse events (or undesirable outcomes) following such interventions, there is no common definition for an adverse event or clarity on any severity classification. This impedes advances of patient safety initiatives and practice. This scoping review mapped the evidence of adverse event definitions and classification systems following spinal and peripheral joint manipulation and mobilization for musculoskeletal conditions in adults. METHODS An electronic search of the following databases was performed from inception to February 2021: MEDLINE, EMBASE, CINAHL, Scopus, AMED, ICL, PEDro, Cochrane Library, Open Grey and Open Theses and Dissertations. Studies including adults (18 to 65 years old) with a musculoskeletal condition receiving spinal or peripheral joint manipulation or mobilization and providing an adverse event definition and/or classification were included. All study designs of peer-reviewed publications were considered. Data from included studies were charted using a standardized data extraction form and synthesised using narrative analysis. RESULTS From 8248 identified studies, 98 were included in the final synthesis. A direct definition for an adverse event and/or classification system was provided in 69 studies, while 29 provided an indirect definition and/or classification system. The most common descriptors to define an adverse event were causality, symptom severity, onset and duration. Twenty-three studies that provided a classification system described only the end anchors (e.g., mild/minor and/or serious) of the classification while 26 described multiple categories (e.g., moderate, severe). CONCLUSION A vast array of terms, definition and classification systems were identified. There is no one common definition or classification for adverse events following spinal and peripheral joint manipulation and mobilization. Findings support the urgent need for consensus on the terms, definition and classification system for adverse events related to these interventions

Patient journey following lumbar spinal fusion surgery (LSFS): protocol for a multicentre qualitative analysis of the patient rehabilitation experience (FuJourn)

INTRODUCTION: There has been a 65% increase in lumbar spinal fusion surgery (LSFS) worldwide over the last 13 years, with costs of £26 million to the UK National Health Service annually. Patient dissatisfaction with outcome and persistent pain and disability incurs further costs. Three trials provide low-quality evidence for the role of physiotherapy. Our UK surveys investigating physiotherapy/surgeon practice concluded rehabilitation should be tailored to the individual patient owing to considerable clinical heterogeneity. This study will explore the perceptions of patients who undergo LSFS to inform precision rehabilitation. METHODS AND ANALYSIS: A qualitative study, using interpretive phenomenological analysis, will recruit a purposive sample (n=40) to ensure patterns of similarity and difference in their journeys can be explored. In-depth semistructured interviews will be undertaken following discharge from hospital and at 12 months postsurgery. Patients' preoperative and postoperative experiences, underlying attitudes and beliefs towards the surgical intervention, facilitators and barriers to recovery, adherence to advice and physiotherapy, experiences of rehabilitation and return to normal function/activity/work will be explored. A 12-month patient diary will provide real time access to patient data, capturing a weekly record of life as lived, including symptoms, medication, experiences of stages of recovery, rehabilitation adherence, healthcare professional appointments, attitudes, their feelings and experiences throughout their journey. Data will be analysed in a number of stages in accordance with interpretive phenomenological analysis, supported using NVivo software. Analysis of the first interviews and patient diaries will afford a rich density of data to build an overall understanding of the patients' lived experiences, informing the 12-month interview. Strategies (eg, reflexivity) will ensure trustworthiness. ETHICS AND DISSEMINATION: The study has ethical approval (IRAS 223283). Findings will ensure that patient-driven data inform precision rehabilitation by understanding the patient journey. Findings will be disseminated through peer-reviewed journals and conferences

Primary care management for optimized antithrombotic treatment [PICANT]: study protocol for a cluster-randomized controlled trial

Background: Antithrombotic treatment is a continuous therapy that is often performed in general practice and requires careful safety management. The aim of this study is to investigate whether a best practice model that applies major elements of case management, including patient education, can improve antithrombotic management in primary health care in terms of reducing major thromboembolic and bleeding events. Methods: This 24-month cluster-randomized trial will be performed in 690 adult patients from 46 practices. The trial intervention will be a complex intervention involving general practitioners, health care assistants and patients with an indication for oral anticoagulation. To assess adherence to medication and symptoms in patients, as well as to detect complications early, health care assistants will be trained in case management and will use the Coagulation-Monitoring-List (Co-MoL) to regularly monitor patients. Patients will receive information (leaflets and a video), treatment monitoring via the Co-MoL and be motivated to perform self-management. Patients in the control group will continue to receive treatment-as-usual from their general practitioners. The primary endpoint is the combined endpoint of all thromboembolic events requiring hospitalization, and all major bleeding complications. Secondary endpoints are mortality, hospitalization, strokes, major bleeding and thromboembolic complications, severe treatment interactions, the number of adverse events, quality of anticoagulation, health-related quality of life and costs. Further secondary objectives will be investigated to explain the mechanism by which the intervention is effective: patients' assessment of chronic illness care, self-reported adherence to medication, general practitioners' and health care assistants' knowledge, patients' knowledge and satisfaction with shared decision making. Practice recruitment is expected to take place between July and December 2012. Recruitment of eligible patients will start in July 2012. Assessment will occur at three time points: baseline (T0), follow-up after 12 (T1) and after 24 months (T2). Discussion: The efficacy and effectiveness of individual elements of the intervention, such as antithrombotic interventions, self-management concepts in orally anticoagulated patients and the methodological tool, case-management, have already been extensively demonstrated. This project foresees the combination of several proven instruments, as a result of which we expect to profit from a reduction in the major complications associated with antithrombotic treatment

Possibility between earthquake and explosion seismogram differentiation by discrete stochastic non-Markov processes and local Hurst exponent analysis

The basic purpose of the paper is to draw the attention of researchers to new possibilities of differentiation of similar signals having different nature. One of examples of such kind of signals is presented by seismograms containing recordings of earthquakes (EQ's) and technogenic explosions (TE's). We propose here a discrete stochastic model for possible solution of a problem of strong EQ's forecasting and differentiation of TE's from the weak EQ's. Theoretical analysis is performed by two independent methods: with the use of statistical theory of discrete non-Markov stochastic processes (Phys. Rev. E62,6178 (2000)) and the local Hurst exponent. Time recordings of seismic signals of the first four dynamic orthogonal collective variables, six various plane of phase portrait of four dimensional phase space of orthogonal variables and the local Hurst exponent have been calculated for the dynamic analysis of the earth states. The approaches, permitting to obtain an algorithm of strong EQ's forecasting and to differentiate TE's from weak EQ's, have been developed.Comment: REVTEX +12 ps and jpg figures. Accepted for publication in Phys. Rev. E, December 200

The biopsychosocial factors associated with development of chronic musculoskeletal pain. An umbrella review and meta-analysis of observational systematic reviews.

AIM: The aim of this umbrella review was to establish which biopsychosocial factors are associated with development of chronic musculoskeletal pain. METHODS: Ovid Medline, Embase, Web of Science Core Collection, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, PsycINFO, CINAHL, PEDro, PROSPERO, Google Scholar and grey literature were searched from database inception to 4th April 2023. Systematic reviews of observational prospective longitudinal studies, including populations with 3 months) musculoskeletal pain. Two reviewers searched the literature, assessed risk of bias (Assessing the Methodological Quality of Systematic Reviews-2), and evaluated quality (Grading of Recommendations, Assessment, Development and Evaluation) to provide an overall statement on the certainty of evidence for each biopsychosocial factor. Data analysis was performed through random effects meta-analysis (including meta-analysis of meta-analyses where possible) and descriptive synthesis. RESULTS: 13 systematic reviews were included comprising 185 original research studies (n = 489,644 participants). Thirty-four biopsychosocial factors are associated with development of chronic musculoskeletal pain. Meta-analyses of odds and/or likelihood ratios were possible for 25 biopsychosocial factors. There is moderate certainty evidence that smoking (OR 1.24 [95%CI, 1.14-1.34), fear avoidance (LR+ 2.11 [95%CI, 1.59-2.8]; LR- 0.5 [95%CI, 0.35-0.71]) poorer support networks (OR 1.21 [95%CI, 1.14-1.29]), lower socioeconomic status (OR 2.0 [95%CI, 1.64-2.42]), and high levels of pain (OR 5.61 [95%CI, 3.74-8.43]) are associated with development of chronic musculoskeletal pain (all P<0.001). Remaining factors are of low or very low certainty evidence. CONCLUSIONS AND RELEVANCE: There is moderate certainty evidence that smoking, fear avoidance, poorer support networks, lower socioeconomic status, and high levels of pain are associated with development of chronic musculoskeletal pain. High risk of bias was evident in most included reviews; this highlights the need for higher quality systematic reviews

Development and validation of a novel non-contact monitor of nocturnal respiration for identifying sleep-disordered breathing in patients with heart failure

© 2016 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology. Aims: At least 50% of patients with heart failure (HF) may have sleep-disordered breathing (SDB). Overnight in-hospital polysomnography (PSG) is considered the gold standard for diagnosis, but a lack of access to such testing contributes to under-diagnosis of SDB. Therefore, there is a need for simple and reliable validated methods to aid diagnosis in patients with HF. The aim of this study was to investigate the accuracy of a non-contact type IV screening device, SleepMinderTM (SM), compared with in-hospital PSG for detecting SDB in patients with HF. Methods and results: The study included 75 adult patients with systolic HF and suspected SDB who underwent simultaneous PSG and SM recordings. An algorithm was developed from the SM signals, using digital signal processing and pattern recognition techniques to calculate the SM apnoea-hypopnoea index (AHI). This was then compared with expert-scored PSGAHI. The SM algorithm had 70% sensitivity and 89% specificity for identifying patients with clinically significant SDB (AHI ≥ 15/h). At this threshold, it had a positive likelihood ratio of 6.3 and a negative likelihood ratio of 0.16. The overall accuracy of the SMAHI algorithm was 85.8% as shown by the area under a receiver operator characteristic curve. The mean AHI with SM was 3.8/h (95% confidence interval 0.5–7.1) lower than that with PSG. Conclusions: The accuracy of the non-contact type IV screening device SM is good for clinically significant SDB in patients with systolic HF and could be considered as a simple first step in the diagnostic pathway

Development and validation of two clinical prediction models to inform clinical decision-making for lumbar spinal fusion surgery for degenerative disorders and rehabilitation following surgery: protocol for a prospective observational study

INTRODUCTION: Potential predictors of poor outcome will be measured at baseline: (1) preoperatively to develop a clinical prediction model to predict which patients are likely to have favourable outcome following lumbar spinal fusion surgery (LSFS) and (2) postoperatively to predict which patients are likely to have favourable long-term outcomes (to inform rehabilitation). METHODS AND ANALYSIS: Prospective observational study with a defined episode inception of the point of surgery. Electronic data will be collected through the British Spine Registry and will include patient-reported outcome measures (eg, Fear-Avoidance Beliefs Questionnaire) and data items (eg, smoking status). Consecutive patients (≥18 years) undergoing LSFS for back and/or leg pain of degenerative cause will be recruited. EXCLUSION CRITERIA: LSFS for spinal fracture, inflammatory disease, malignancy, infection, deformity and revision surgery. 1000 participants will be recruited (n=600 prediction model development, n=400 internal validation derived model; planning 10 events per candidate prognostic factor). The outcome being predicted is an individual's absolute risk of poor outcome (disability and pain) at 6 weeks (objective 1) and 12 months postsurgery (objective 2). Disability and pain will be measured using the Oswestry Disability Index (ODI), and severity of pain in the previous week with a Numerical Rating Scale (NRS 0-10), respectively. Good outcome is defined as a change of 1.7 on the NRS for pain, and a change of 14.3 on the ODI. Both linear and logistic (to dichotomise outcome into low and high risk) multivariable regression models will be fitted and mean differences or ORs for each candidate predictive factor reported. Internal validation of the derived model will use a further set of British Spine Registry data. External validation will be geographical using two spinal registries in The Netherlands and Switzerland. ETHICS AND DISSEMINATION: Ethical approval (University of Birmingham ERN_17-0446A). Dissemination through peer-reviewed journals and conferences

Descriptive analysis of a 1:1 physiotherapy outpatient intervention post primary lumbar discectomy: One arm of a small-scale parallel randomised controlled trial across two UK sites

Objective: There is a lack of high-quality evidence for physiotherapy post lumbar discectomy. Substantial heterogeneity in treatment effects may be explained by variation in quality, administration and components of interventions. An optimised physiotherapy intervention may reduce heterogeneity and improve patient benefit. The objective was to describe, analyse and evaluate an optimised 1:1 physiotherapy outpatient intervention for patients following primary lumbar discectomy, to provide preliminary insights. Design: A descriptive analysis of the intervention embedded within an external pilot and feasibility trial. Setting: Two UK spinal centres. Participants: Participants aged .18; post primary, single level, lumbar discectomy were recruited. Intervention: The intervention encompassed education, advice, mobility and core stability exercises, progressive exercise, and encouragement of early return to work/activity. Patients received .8 sessions for .8 weeks, starting 4 weeks post surgery (baseline). Outcomes: Blinded outcome assessment at baseline and 12 weeks ( post intervention) included the Roland Morris Disability Questionnaire. STarT Back data were collected at baseline. Statistical analyses summarised participant characteristics and preplanned descriptive analyses. Thematic analysis grouped related data. Findings: Twenty-two of 29 allocated participants received the intervention. STarT Back categorised n=16 (55%) participants 'enot at low risk'f. Physiotherapists identified reasons for caution for 8 (36%) participants, commonly risk of overdoing activity (n=4, 18%). There was no relationship between STarT Back and physiotherapists'f evaluation of caution. Physiotherapists identified 154 problems (mean (SD) 5.36 (2.63)). Those 'enot at low risk'f, and/or requiring caution presented with more problems, and required more sessions (mean (SD) 3.14 (1.16)). Conclusions: Patients present differently and therefore require tailored interventions. These differences may be identified using clinical reasoning and outcome data. Trial registration number: ISRCTN33808269; post results