The effectiveness of constraint-led training on skill development in interceptive sports: a systematic review (Clark, McEwan and Christie) – a commentary

Clark, McEwan and Christie's systematic review1 offers a timely examination of current literature assessing effects of a constraints-led approach (CLA) to training on ‘technical and cognitive skill in sport’, in comparison to traditional training methods. They concluded that, currently, there is strong evidence to advocate for the effects of training interventions that espouse benefits of constraints-led training on acquiring skill in interceptive actions. Clark, McEwan and Christie reported that 18 studies satisfied their proposed inclusion criteria and, of these studies, 77% provided evidence of the effectiveness of the CLA. Consequently, Clark, McEwan and Christie argued that a ‘the implementation of the constraints-led approach within interceptive sport can be advocated’ (p. 17). This is a revealing insight, which supports their claims that this finding ‘provides the opportunity for researchers to collect more compelling evidence to answer the question: “Does constraint-led training assist with the development of technical skills within interceptive sport?”’. While we endorse their call for more empirical evidence on the effectiveness of a CLA to practice and training design, we qualify it by highlighting some limitations of Clark, McEwan and Christie's systematic review

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

The inflammatory microenvironment in colorectal neoplasia

Peer reviewedPublisher PD

Monoubiquitination of syntaxin 3 leads to retrieval from the basolateral plasma membrane and facilitates cargo recruitment to exosomes

Syntaxin 3 (Stx3), a SNARE protein located and functioning at the apical plasma membrane of epithelial cells, is required for epithelial polarity. A fraction of Stx3 is localized to late endosomes/lysosomes, although how it traffics there and its function in these organelles is unknown. Here we report that Stx3 undergoes monoubiquitination in a conserved polybasic domain. Stx3 present at the basolateral—but not the apical—plasma membrane is rapidly endocytosed, targeted to endosomes, internalized into intraluminal vesicles (ILVs), and excreted in exosomes. A nonubiquitinatable mutant of Stx3 (Stx3-5R) fails to enter this pathway and leads to the inability of the apical exosomal cargo protein GPRC5B to enter the ILV/exosomal pathway. This suggests that ubiquitination of Stx3 leads to removal from the basolateral membrane to achieve apical polarity, that Stx3 plays a role in the recruitment of cargo to exosomes, and that the Stx3-5R mutant acts as a dominant-negative inhibitor. Human cytomegalovirus (HCMV) acquires its membrane in an intracellular compartment and we show that Stx3-5R strongly reduces the number of excreted infectious viral particles. Altogether these results suggest that Stx3 functions in the transport of specific proteins to apical exosomes and that HCMV exploits this pathway for virion excretion

Plasma lipid biomarker signatures in squamous carcinoma and adenocarcinoma lung cancer patients

There is a clinical need for reliable biomarkers for lung cancer that permit early diagnosis of the disease and provide prediction of histological phenotype. A prospective study design was used with a study population of patients with suspected lung cancer. Blood samples were collected from 17 patients with histologically confirmed squamous cell lung carcinoma, 17 individuals with adenocarcinoma, and 17 control individuals who did not subsequently have a diagnosis of lung cancer or any other cancer. Blood plasma samples were analysed for their lipid profiles using liquid chromatography coupled with high resolution mass spectrometry. Data were analysed using multivariate statistical methods. There was good separation between histological subtypes and control groups and also between individuals with a subsequent diagnosis of adenocarcinoma and squamous cell carcinoma (sensitivity 80 %, specificity 83 %, Q2 = 0.70). Alterations in the levels of different classes of lipids including triglycerides (TGs), phosphatidylinositols (PIs), phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), free fatty acids, lysophospholipids and sphingolipids were observed in squamous carcinoma and adenocarcinoma lung cancer patients when compared with control patients. In conclusion, this study has identified candidate lipid biomarkers of non-small cell lung cancer patients which may be helpful to indicate the tumour subtype and to differentiate them from patients who do not have lung cancer. Measuring these biomarkers has the potential to improve diagnosis in patients with suspected lung cancer and risk stratification in screening

Advanced optical imaging in living embryos

Developmental biology investigations have evolved from static studies of embryo anatomy and into dynamic studies of the genetic and cellular mechanisms responsible for shaping the embryo anatomy. With the advancement of fluorescent protein fusions, the ability to visualize and comprehend how thousands to millions of cells interact with one another to form tissues and organs in three dimensions (xyz) over time (t) is just beginning to be realized and exploited. In this review, we explore recent advances utilizing confocal and multi-photon time-lapse microscopy to capture gene expression, cell behavior, and embryo development. From choosing the appropriate fluorophore, to labeling strategy, to experimental set-up, and data pipeline handling, this review covers the various aspects related to acquiring and analyzing multi-dimensional data sets. These innovative techniques in multi-dimensional imaging and analysis can be applied across a number of fields in time and space including protein dynamics to cell biology to morphogenesis

Extensive telomere erosion is consistent with localised clonal expansions in Barrett’s metaplasia

Barrett’s oesophagus is a premalignant metaplastic condition that predisposes patients to the development of oesophageal adenocarcinoma. However, only a minor fraction of Barrett’s oesophagus patients progress to adenocarcinoma and it is thus essential to determine bio-molecular markers that can predict the progression of this condition. Telomere dysfunction is considered to drive clonal evolution in several tumour types and telomere length analysis provides clinically relevant prognostic and predictive information. The aim of this work was to use high-resolution telomere analysis to examine telomere dynamics in Barrett’s oesophagus. Telomere length analysis of XpYp, 17p, 11q and 9p, chromosome arms that contain key cancer related genes that are known to be subjected to copy number changes in Barrett’s metaplasia, revealed similar profiles at each chromosome end, indicating that no one specific telomere is likely to suffer preferential telomere erosion. Analysis of patient matched tissues (233 samples from 32 patients) sampled from normal squamous oesophagus, Z-line, and 2 cm intervals within Barrett’s metaplasia, plus oesophago-gastric junction, gastric body and antrum, revealed extensive telomere erosion in Barrett’s metaplasia to within the length ranges at which telomere fusion is detected in other tumour types. Telomere erosion was not uniform, with distinct zones displaying more extensive erosion and more homogenous telomere length profiles. These data are consistent with an extensive proliferative history of cells within Barrett’s metaplasia and are indicative of localised clonal growth. The extent of telomere erosion highlights the potential of telomere dysfunction to drive genome instability and clonal evolution in Barrett’s metaplasia

The many possible climates from the Paris Agreement’s aim of 1.5 °C warming

The United Nations’ Paris Agreement includes the aim of pursuing efforts to limit global warming to only 1.5 °C above pre-industrial levels. However, it is not clear what the resulting climate would look like across the globe and over time. Here we show that trajectories towards a ‘1.5 °C warmer world’ may result in vastly different outcomes at regional scales, owing to variations in the pace and location of climate change and their interactions with society’s mitigation, adaptation and vulnerabilities to climate change. Pursuing policies that are considered to be consistent with the 1.5 °C aim will not completely remove the risk of global temperatures being much higher or of some regional extremes reaching dangerous levels for ecosystems and societies over the coming decades

Assessing serious spinal pathology using Bayesian Network decision support: development and validation of a prototype tool (Preprint)

Background Identifying and managing serious spinal pathology (SSP) such as cauda equina syndrome or spinal infection in patients presenting with low back pain is challenging. Traditional red flag questioning is increasingly criticized, and previous studies show that many clinicians lack confidence in managing patients presenting with red flags. Improving decision-making and reducing the variability of care for these patients is a key priority for clinicians and researchers. Objective We aimed to improve SSP identification by constructing and validating a decision support tool using a Bayesian network (BN), which is an artificial intelligence technique that combines current evidence and expert knowledge. Methods A modified RAND appropriateness procedure was undertaken with 16 experts over 3 rounds, designed to elicit the variables, structure, and conditional probabilities necessary to build a causal BN. The BN predicts the likelihood of a patient with a particular presentation having an SSP. The second part of this study used an established framework to direct a 4-part validation that included comparison of the BN with consensus statements, practice guidelines, and recent research. Clinical cases were entered into the model and the results were compared with clinical judgment from spinal experts who were not involved in the elicitation. Receiver operating characteristic curves were plotted and area under the curve were calculated for accuracy statistics. Results The RAND appropriateness procedure elicited a model including 38 variables in 3 domains: risk factors (10 variables), signs and symptoms (17 variables), and judgment factors (11 variables). Clear consensus was found in the risk factors and signs and symptoms for SSP conditions. The 4-part BN validation demonstrated good performance overall and identified areas for further development. Comparison with available clinical literature showed good overall agreement but suggested certain improvements required to, for example, 2 of the 11 judgment factors. Case analysis showed that cauda equina syndrome, space-occupying lesion/cancer, and inflammatory condition identification performed well across the validation domains. Fracture identification performed less well, but the reasons for the erroneous results are well understood. A review of the content by independent spinal experts backed up the issues with the fracture node, but the BN was otherwise deemed acceptable. Conclusions The RAND appropriateness procedure and validation framework were successfully implemented to develop the BN for SSP. In comparison with other expert-elicited BN studies, this work goes a step further in validating the output before attempting implementation. Using a framework for model validation, the BN showed encouraging validity and has provided avenues for further developing the outputs that demonstrated poor accuracy. This study provides the vital first step of improving our ability to predict outcomes in low back pain by first considering the problem of SSP. International Registered Report Identifier (IRRID) RR2-10.2196/2180