Showing papers by "John Radcliffe Hospital published in 2016"
TL;DR: Using multi-modal magnetic resonance images from the Human Connectome Project and an objective semi-automated neuroanatomical approach, 180 areas per hemisphere are delineated bounded by sharp changes in cortical architecture, function, connectivity, and/or topography in a precisely aligned group average of 210 healthy young adults.
Abstract: Understanding the amazingly complex human cerebral cortex requires a map (or parcellation) of its major subdivisions, known as cortical areas. Making an accurate areal map has been a century-old objective in neuroscience. Using multi-modal magnetic resonance images from the Human Connectome Project (HCP) and an objective semi-automated neuroanatomical approach, we delineated 180 areas per hemisphere bounded by sharp changes in cortical architecture, function, connectivity, and/or topography in a precisely aligned group average of 210 healthy young adults. We characterized 97 new areas and 83 areas previously reported using post-mortem microscopy or other specialized study-specific approaches. To enable automated delineation and identification of these areas in new HCP subjects and in future studies, we trained a machine-learning classifier to recognize the multi-modal 'fingerprint' of each cortical area. This classifier detected the presence of 96.6% of the cortical areas in new subjects, replicated the group parcellation, and could correctly locate areas in individuals with atypical parcellations. The freely available parcellation and classifier will enable substantially improved neuroanatomical precision for studies of the structural and functional organization of human cerebral cortex and its variation across individuals and in development, aging, and disease.
3,414 citations
Erasmus University Rotterdam1, University of Pennsylvania2, Bethel University3, McMaster Children's Hospital4, National Institutes of Health5, Children's Hospital at Westmead6, University of California, San Francisco7, Kaiser Permanente Oakland Medical Center8, Claude Bernard University Lyon 19, Medical University of Vienna10, Kitasato University11, John Radcliffe Hospital12, Charité13, Cleveland Clinic14, Innsbruck Medical University15, Witten/Herdecke University16, Johns Hopkins University School of Medicine17, Catalan Institution for Research and Advanced Studies18
TL;DR: Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.
Abstract: Summary Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.
2,391 citations
Wellcome Trust Sanger Institute1, National Institute for Health Research2, University of Cambridge3, NHS Blood and Transplant4, European Bioinformatics Institute5, Barts Health NHS Trust6, Radboud University Nijmegen7, University of Geneva8, Katholieke Universiteit Leuven9, University of Oxford10, Wellcome Trust Centre for Human Genetics11, British Heart Foundation12, University of Amsterdam13, Newcastle University14, McGill University15, Pompeu Fabra University16, University College London17, John Radcliffe Hospital18, Churchill Hospital19
TL;DR: A genome-wide association analysis in the UK Biobank and INTERVAL studies is performed, providing evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations betweenBlood cell indices and cardiovascular disease may be non-causal.
982 citations
TL;DR: An integrated approach to data acquisition, analysis and sharing that builds upon recent advances, particularly from the Human Connectome Project (HCP), and should accelerate progress in understanding the brain in health and disease.
Abstract: Noninvasive human neuroimaging has yielded many discoveries about the brain. Numerous methodological advances have also occurred, though inertia has slowed their adoption. This paper presents an integrated approach to data acquisition, analysis and sharing that builds upon recent advances, particularly from the Human Connectome Project (HCP). The 'HCP-style' paradigm has seven core tenets: (i) collect multimodal imaging data from many subjects; (ii) acquire data at high spatial and temporal resolution; (iii) preprocess data to minimize distortions, blurring and temporal artifacts; (iv) represent data using the natural geometry of cortical and subcortical structures; (v) accurately align corresponding brain areas across subjects and studies; (vi) analyze data using neurobiologically accurate brain parcellations; and (vii) share published data via user-friendly databases. We illustrate the HCP-style paradigm using existing HCP data sets and provide guidance for future research. Widespread adoption of this paradigm should accelerate progress in understanding the brain in health and disease.
793 citations
TL;DR: Brain activity in the “resting” state when subjects were not performing any explicit task predicted differences in fMRI activation across a range of cognitive paradigms, suggesting that individual differences in many cognitive tasks are a stable trait marker.
Abstract: When asked to perform the same task, different individuals exhibit markedly different patterns of brain activity. This variability is often attributed to volatile factors, such as task strategy or compliance. We propose that individual differences in brain responses are, to a large degree, inherent to the brain and can be predicted from task-independent measurements collected at rest. Using a large set of task conditions, spanning several behavioral domains, we train a simple model that relates task-independent measurements to task activity and evaluate the model by predicting task activation maps for unseen subjects using magnetic resonance imaging. Our model can accurately predict individual differences in brain activity and highlights a coupling between brain connectivity and function that can be captured at the level of individual subjects.
650 citations
TL;DR: These findings suggest that global relational codes may be used to organize nonspatial conceptual representations and that these codes may have a hexagonal gridlike pattern when conceptual knowledge is laid out in two continuous dimensions.
Abstract: It has been hypothesized that the brain organizes concepts into a mental map, allowing conceptual relationships to be navigated in a manner similar to that of space. Grid cells use a hexagonally symmetric code to organize spatial representations and are the likely source of a precise hexagonal symmetry in the functional magnetic resonance imaging signal. Humans navigating conceptual two-dimensional knowledge showed the same hexagonal signal in a set of brain regions markedly similar to those activated during spatial navigation. This gridlike signal is consistent across sessions acquired within an hour and more than a week apart. Our findings suggest that global relational codes may be used to organize nonspatial conceptual representations and that these codes may have a hexagonal gridlike pattern when conceptual knowledge is laid out in two continuous dimensions.
575 citations
Boston Children's Hospital1, Marmara University2, John Radcliffe Hospital3, Federal University of São Paulo4, Mount Sinai Hospital5, University of Texas Southwestern Medical Center6, Karolinska Institutet7, National Defense Medical College8, Sapienza University of Rome9, Children's Hospital of Wisconsin10, Royal Children's Hospital11, University Medical Center Freiburg12
TL;DR: The International Collaboration in Asthma, Allergy and Immunology initiated an international coalition among the American Academy of Allergy, Asthma & Immunology; the European Academy of allergy and Clinical Immunology, and the World Allergy Organization on common variable immunodeficiency.
552 citations
Harvard University1, Broad Institute2, University of Oslo3, Oslo University Hospital4, University of Helsinki5, Boston Children's Hospital6, University of Tartu7, Illumina8, Charité9, Brigham and Women's Hospital10, deCODE genetics11, Medical Research Council12, VU University Amsterdam13, Leiden University14, Helsinki University Central Hospital15, University of Tübingen16, Ludwig Maximilian University of Munich17, Karolinska Institutet18, QIMR Berghofer Medical Research Institute19, University of Ulm20, University of Oulu21, King's College London22, Erasmus University Medical Center23, University of Tampere24, University of Duisburg-Essen25, Washington University in St. Louis26, University Medical Center Groningen27, Wellcome Trust Sanger Institute28, University of Oxford29, John Radcliffe Hospital30, Max Planck Society31, University of Kiel32, Technische Universität München33, National Institutes of Health34, Norwegian Institute of Public Health35, University of Copenhagen36, Mental Health Services37, Lundbeck38, University of Turku39, Turku University Hospital40, University of Hamburg41, St George's, University of London42, University of Iceland43, Queensland University of Technology44
TL;DR: For example, the authors identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to date is the first to be identified on chromosome X.
Abstract: Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.
471 citations
Oslo University Hospital1, Imperial College London2, University of Amsterdam3, First Faculty of Medicine, Charles University in Prague4, Medical University of Vienna5, Gloucestershire Hospitals NHS Foundation Trust6, Eppendorf (Germany)7, Karolinska University Hospital8, Erasmus University Rotterdam9, John Radcliffe Hospital10, Coventry University11, Katholieke Universiteit Leuven12, University of Porto13, Instituto Português de Oncologia Francisco Gentil14, University Hospital of North Tees15, Durham University16
TL;DR: Endoscopy services across Europe are recommended to adopt the following seven key performance measures for lower gastrointestinal endoscopy for measurement and evaluation in daily practice at a center and endoscopist level.
Abstract: The European Society of Gastrointestinal Endoscopy and United European Gastroenterology present a short list of key performance measures for lower gastrointestinal endoscopy. We recommend that endoscopy services across Europe adopt the following seven key performance measures for lower gastrointestinal endoscopy for measurement and evaluation in daily practice at a center and endoscopist level: 1 Rate of adequate bowel preparation (minimum standard 90 %); 2 Cecal intubation rate (minimum standard 90 %); 3 Adenoma detection rate (minimum standard 25 %); 4 Appropriate polypectomy technique (minimum standard 80 %); 5 Complication rate (minimum standard not set); 6 Patient experience (minimum standard not set); 7 Appropriate post-polypectomy surveillance recommendations (minimum standard not set). Other identified performance measures have been listed as less relevant based on an assessment of their importance, scientific acceptability, feasibility, usability, and comparison to competing measures.
458 citations
TL;DR: The integrated genomics approach advances understanding of heterogeneity in sepsis by defining subgroups of patients with different immune response states and prognoses, as well as revealing the role of underlying genetic variation.
454 citations
TL;DR: Left atrial appendage closure with the WATCHMAN device has a high success rate in complete LAAC with low peri-procedural risk, even in a population with a higher risk of stroke and bleeding, and multiple co-morbidities.
Abstract: Aims Left atrial appendage closure is a non-pharmacological alternative for stroke prevention in high-risk patients with non-valvular atrial fibrillation. The objective of the multicentre EWOLUTION registry was to obtain clinical data on procedural success and complications, and long-term patient outcomes, including bleeding and incidence of stroke/transient ischaemic attack (TIA). Here, we report on the peri-procedural outcomes of up to 30 days.
Methods and results Baseline/implant data are available for 1021 subjects. Subjects in the study were at high risk of stroke (average CHADS2 score: 2.8 ± 1.3, CHA2DS2-VASc: 4.5 ± 1.6) and moderate-to-high risk of bleeding (average HAS-BLED score: 2.3 ± 1.2). Almost half of the subjects (45.4%) had a history of TIA, ischaemic stroke, or haemorrhagic stroke; 62% of patients were deemed unsuitable for novel oral anticoagulant by their physician. The device was successfully deployed in 98.5% of patients with no flow or minimal residual flow achieved in 99.3% of implanted patients. Twenty-eight subjects experienced 31 serious adverse events (SAEs) within 1 day of the procedure. The overall 30-day mortality rate was 0.7%. The most common SAE occurring within 30 days of the procedure was major bleeding requiring transfusion. Incidence of SAEs within 30 days was significantly lower for subjects deemed to be ineligible for oral anticoagulation therapy (OAT) compared with those eligible for OAT (6.5 vs. 10.2%, P = 0.042).
Conclusion Left atrial appendage closure with the WATCHMAN device has a high success rate in complete LAAC with low peri-procedural risk, even in a population with a higher risk of stroke and bleeding, and multiple co-morbidities. Improvement in implantation techniques has led to a reduction of peri-procedural complications previously limiting the net clinical benefit of the procedure.
TL;DR: Effect sizes were generally similar for CVD and T2DM, and suggested that the greatest gain in health is associated with moving from inactivity to small amounts of PA.
Abstract: Background The relationships between physical activity (PA) and both cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) have predominantly been estimated using categorical measures of PA, masking the shape of the dose‐response relationship. In this systematic review and meta‐analysis, for the very first time we are able to derive a single continuous PA metric to compare the association between PA and CVD/T2DM, both before and after adjustment for a measure of body weight.
Methods and Results The search was applied to MEDLINE and EMBASE electronic databases for all studies published from January 1981 to March 2014. A total of 36 studies (3 439 874 participants and 179 393 events, during an average follow‐up period of 12.3 years) were included in the analysis (33 pertaining to CVD and 3 to T2DM). An increase from being inactive to achieving recommended PA levels (150 minutes of moderate‐intensity aerobic activity per week) was associated with lower risk of CVD mortality by 23%, CVD incidence by 17%, and T2DM incidence by 26% (relative risk [RR], 0.77 [0.71–0.84]), (RR, 0.83 [0.77–0.89]), and (RR, 0.74 [0.72–0.77]), respectively, after adjustment for body weight.
Conclusions By using a single continuous metric for PA levels, we were able to make a comparison of the effect of PA on CVD incidence and mortality including myocardial infarct (MI), stroke, and heart failure, as well as T2DM. Effect sizes were generally similar for CVD and T2DM, and suggested that the greatest gain in health is associated with moving from inactivity to small amounts of PA.
TL;DR: It is demonstrated that MAIT cells are activated following viral infections, and a potential role in both host defence and immunopathology is suggested.
Abstract: Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize bacterial ligands. Here, we demonstrate that MAIT cells are also activated during human viral infections in vivo. MAIT cells activation was observed during infection with dengue virus, hepatitis C virus and influenza virus. This activation-driving cytokine release and Granzyme B upregulation-is TCR-independent but dependent on IL-18 in synergy with IL-12, IL-15 and/or interferon-α/β. IL-18 levels and MAIT cell activation correlate with disease severity in acute dengue infection. Furthermore, HCV treatment with interferon-α leads to specific MAIT cell activation in vivo in parallel with an enhanced therapeutic response. Moreover, TCR-independent activation of MAIT cells leads to a reduction of HCV replication in vitro mediated by IFN-γ. Together these data demonstrate MAIT cells are activated following viral infections, and suggest a potential role in both host defence and immunopathology.
TL;DR: How whole-genome sequencing studies have advanced understanding of the mechanisms and principles of within-host genome evolution is described, and the consequences of findings such as a potent adaptive potential for pathogenicity are considered.
Abstract: Whole-genome sequencing has opened the way for investigating the dynamics and genomic evolution of bacterial pathogens during the colonization and infection of humans. The application of this technology to the longitudinal study of adaptation in an infected host--in particular, the evolution of drug resistance and host adaptation in patients who are chronically infected with opportunistic pathogens--has revealed remarkable patterns of convergent evolution, suggestive of an inherent repeatability of evolution. In this Review, we describe how these studies have advanced our understanding of the mechanisms and principles of within-host genome evolution, and we consider the consequences of findings such as a potent adaptive potential for pathogenicity. Finally, we discuss the possibility that genomics may be used in the future to predict the clinical progression of bacterial infections and to suggest the best option for treatment.
TL;DR: Dorsal anterior cingulate cortex carries a wealth of value-related information necessary for regulating behavioral flexibility and persistence and may instigate attentionally demanding and difficult processes such as behavioral change via interactions with prefrontal cortex.
Abstract: Dorsal anterior cingulate cortex (dACC) carries a wealth of value-related information necessary for regulating behavioral flexibility and persistence. It signals error and reward events informing decisions about switching or staying with current behavior. During decision-making, it encodes the average value of exploring alternative choices (search value), even after controlling for response selection difficulty, and during learning, it encodes the degree to which internal models of the environment and current task must be updated. dACC value signals are derived in part from the history of recent reward integrated simultaneously over multiple time scales, thereby enabling comparison of experience over the recent and extended past. Such ACC signals may instigate attentionally demanding and difficult processes such as behavioral change via interactions with prefrontal cortex. However, the signal in dACC that instigates behavioral change need not itself be a conflict or difficulty signal.
TL;DR: The results suggest that RT‐QuiC analysis of cerebrospinal fluid is potentially useful for the early clinical assessment of patients with alpha‐synucleinopathies.
Abstract: We have developed a novel real-time quaking-induced conversion RT-QuIC-based assay to detect alpha-synuclein aggregation in brain and cerebrospinal fluid from dementia with Lewy bodies and Parkinson's disease patients. This assay can detect alpha-synuclein aggregation in Dementia with Lewy bodies and Parkinson's disease cerebrospinal fluid with sensitivities of 92% and 95%, respectively, and with an overall specificity of 100% when compared to Alzheimer and control cerebrospinal fluid. Patients with neuropathologically confirmed tauopathies (progressive supranuclear palsy; corticobasal degeneration) gave negative results. These results suggest that RT-QuiC analysis of cerebrospinal fluid is potentially useful for the early clinical assessment of patients with alpha-synucleinopathies.
TL;DR: The metabolic reprogramming of cancer is discussed, possible explanations for the high glucose consumption in cancer cells observed by Warburg, and key experimental practices should be considered when studying the metabolism of cancer.
Abstract: Influential research by Warburg and Cori in the 1920s ignited interest in how cancer cells' energy generation is different from that of normal cells. They observed high glucose consumption and large amounts of lactate excretion from cancer cells compared with normal cells, which oxidised glucose using mitochondria. It was therefore assumed that cancer cells were generating energy using glycolysis rather than mitochondrial oxidative phosphorylation, and that the mitochondria were dysfunctional. Advances in research techniques since then have shown the mitochondria in cancer cells to be functional across a range of tumour types. However, different tumour populations have different bioenergetic alterations in order to meet their high energy requirement; the Warburg effect is not consistent across all cancer types. This review will discuss the metabolic reprogramming of cancer, possible explanations for the high glucose consumption in cancer cells observed by Warburg, and suggest key experimental practices we should consider when studying the metabolism of cancer.
Wellcome Trust Sanger Institute1, University of Nottingham2, Katholieke Universiteit Leuven3, King Abdulaziz Medical City4, Harvard University5, Saarland University6, University of Manchester7, Central Manchester University Hospitals NHS Foundation Trust8, Charité9, University of Oxford10, Glenfield Hospital11, London North West Healthcare NHS Trust12, Leipzig University13, University of Cambridge14, Leeds Teaching Hospitals NHS Trust15, University of London16, Dresden University of Technology17, Salisbury NHS Foundation Trust18, Princess Anne Hospital19, University of Southampton20, Western General Hospital21, Hospital for Sick Children22, National Institutes of Health23, St. Michael's GAA, Sligo24, National Guard Health Affairs25, Cambridge University Hospitals NHS Foundation Trust26, Boston Children's Hospital27, Guy's and St Thomas' NHS Foundation Trust28, John Radcliffe Hospital29, NHS Blood and Transplant30, University of Freiburg31, University of Erlangen-Nuremberg32, Newcastle upon Tyne Hospitals NHS Foundation Trust33, Imperial College London34, Newcastle University35, King Saud bin Abdulaziz University for Health Sciences36, Medical Research Council37
TL;DR: Exome sequenced 1,891 probands and identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1, finding evidence for distinct genetic architectures underlying the low sibling recurrence risk in S- CHD and NS-CHd.
Abstract: Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.
TL;DR: Histological remission is a target distinct from endoscopic mucosal healing in UC and better predicts lower rates of corticosteroid use and acute severe colitis requiring hospitalisation, over a median of 6 years of follow-up.
Abstract: Background Endoscopic mucosal healing is an established treatment target for UC, yet the value of achieving histological remission remains unclear. Aims To evaluate histological remission compared to endoscopic mucosal healing for predicting patient outcomes in UC. Methods Blinded assessment of endoscopic and histological measures of disease activity was performed on patients with established UC at baseline. Concordance and prognostic values of endoscopic mucosal healing (defined by Baron score ≤1) and histological remission (defined by Truelove and Richards’ index) for predicting outcomes of corticosteroid use, hospitalisation and colectomy were determined over a median 6 years follow-up, including κ statistics and Cox regression multivariate analysis. Results 91 patients with UC were followed up for a median 72 months (IQR 54–75 months). Overall, concordance between endoscopic and histological remission was moderate (κ=0.56, 95% CI 0.36 to 0.77); 24% patients had persistent inflammation despite endoscopic remission. Histological remission predicted corticosteroid use and acute severe colitis requiring hospitalisation over the follow-up period (HR 0.42 (0.2 to 0.9), p=0.02; HR 0.21 (0.1 to 0.7), p=0.02; respectively), whereas endoscopic mucosal healing did not (HR 0.86, 95% CI 0.5 to 1.7, p0.65; HR 0.83 95% CI 0.3 to 2.4, p0.74; respectively). Conclusions Histological remission is a target distinct from endoscopic mucosal healing in UC and better predicts lower rates of corticosteroid use and acute severe colitis requiring hospitalisation, over a median of 6 years of follow-up. Our findings support the inclusion of histological indices in both UC clinical trials and practice, towards a target of ‘complete remission’.
TL;DR: Phenomena such as placebo analgesia or pain relief through distraction highlight the powerful influence cognitive processes and learning mechanisms have on the way the authors perceive pain.
Abstract: Phenomena such as placebo analgesia or pain relief through distraction highlight the powerful influence cognitive processes and learning mechanisms have on the way we perceive pain. Although contemporary models of pain acknowledge that pain is not a direct readout of nociceptive input, the neuronal processes underlying cognitive modulation are not yet fully understood. Modern concepts of perception—which include computational modeling to quantify the influence of cognitive processes—suggest that perception is critically determined by expectations and their modification through learning. Research on pain has just begun to embrace this view. Insights into these processes promise to open up new avenues to pain prevention and treatment by harnessing the power of the mind.
TL;DR: If ex-miRNA is to be employed in novel non-invasive diagnostic approaches and as a therapeutic target in cancer, two further advances are necessary: in methods to isolate and detect ex- miRNA, and a better understanding of their biogenesis and functions in tumour-cell communication.
Abstract: Intercommunication between cancer cells and with their surrounding and distant environments is key to the survival, progression and metastasis of the tumour. Exosomes play a role in this communication process. MicroRNA (miRNA) expression is frequently dysregulated in tumour cells and can be reflected by distinct exosomal miRNA (ex-miRNA) profiles isolated from the bodily fluids of cancer patients. Here, the potential of ex-miRNA as a cancer biomarker and therapeutic target is critically analysed. Exosomes are a stable source of miRNA in bodily fluids but, despite a number of methods for exosome extraction and miRNA quantification, their suitability for diagnostics in a clinical setting is questionable. Furthermore, exosomally transferred miRNAs can alter the behaviour of recipient tumour and stromal cells to promote oncogenesis, highlighting a role in cell communication in cancer. However, our incomplete understanding of exosome biogenesis and miRNA loading mechanisms means that strategies to target exosomes or their transferred miRNAs are limited and not specific to tumour cells. Therefore, if ex-miRNA is to be employed in novel non-invasive diagnostic approaches and as a therapeutic target in cancer, two further advances are necessary: in methods to isolate and detect ex-miRNA, and a better understanding of their biogenesis and functions in tumour-cell communication.
TL;DR: Bilateral aDBS can improve both axial and limb symptoms and can track the need for stimulation across drug states and in the face of concurrent medication.
Abstract: Introduction and objectives: Adaptive deep brain stimulation (aDBS) uses feedback from brain signals to guide stimulation. A recent acute trial of unilateral aDBS showed that aDBS can lead to substantial improvements in contralateral hemibody Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores and may be superior to conventional continuous DBS in Parkinson’s disease (PD). We test whether potential benefits are retained with bilateral aDBS and in the face of concurrent medication. Methods: We applied bilateral aDBS in 4 patients with PD undergoing DBS of the subthalamic nucleus. aDBS was delivered bilaterally with independent triggering of stimulation according to the amplitude of β activity at the corresponding electrode. Mean stimulation voltage was 3.0±0.1 volts. Motor assessments consisted of double-blinded video-taped motor UPDRS scores that included both limb and axial features. Results: UPDRS scores were 43% (p=0.04; Cohen’s d=1.62) better with aDBS than without stimulation. Motor improvement with aDBS occurred despite an average time on stimulation (ToS) of only 45%. Levodopa was well tolerated during aDBS and led to further reductions in ToS. Conclusion: Bilateral aDBS can improve both axial and limb symptoms and can track the need for stimulation across drug states.
TL;DR: It is shown that WGS has a scalable, rapid turnaround, and is a financially feasible method for full MTBC diagnostics, and Continued improvements to mycobacterial processing, bioinformatics, and analysis will improve the accuracy, speed, and scope of WGS-based diagnosis.
TL;DR: The current knowledge of the biology and function of EVs is examined, the evidence for their involvement in the pathogenesis of neurodegenerative diseases is discussed, and their potential as biomarkers of disease is considered.
Abstract: To develop effective disease-modifying therapies for neurodegenerative diseases, reliable markers of diagnosis, disease activity and progression are a research priority. The fact that neurodegenerative pathology is primarily associated with distinct subsets of cells in discrete areas of the CNS makes the identification of relevant biomarker molecules a challenge. The trafficking of macromolecules from the CNS to the cerebrospinal fluid and blood, mediated by extracellular vesicles (EVs), presents a promising source of CNS-specific biomarkers. EVs are released by almost all cell types and carry a cargo of protein and nucleic acid that varies according to the cell of origin. EV output changes with cell status and reflects intracellular events, so surface marker expression can be used to identify the cell type from which EVs originate. EVs could, therefore, provide an enriched pool of information about core neuropathogenic, cell-specific processes. This Review examines the current knowledge of the biology and function of EVs, discusses the evidence for their involvement in the pathogenesis of neurodegenerative diseases, and considers their potential as biomarkers of disease.
University College London1, Hebron University2, Aarhus University Hospital3, University of Padua4, University of South Alabama5, Copenhagen University Hospital6, Semmelweis University7, University of Duisburg-Essen8, Centro Nacional de Investigaciones Cardiovasculares9, National and Kapodistrian University of Athens10, Duke University11, University of Birmingham12, John Radcliffe Hospital13, South African Medical Research Council14, St Thomas' Hospital15, Sapporo Medical University16, University of Miami17, University of Oldenburg18, Wayne State University19, National University of Singapore20, Cincinnati Children's Hospital Medical Center21, Spanish National Research Council22, Emory University23
TL;DR: An overview of the major topics discussed at this special meeting of leading pioneers in the field of cardioprotection to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotsection is provided.
Abstract: To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research.
TL;DR: The prognosis of PBC patients can be accurately evaluated using the UK‐PBC risk scores, which may be used to identify high‐risk patients for closer monitoring and second‐line therapies, as well as low‐ risk patients who could potentially be followed up in primary care.
TL;DR: The primary aim was to determine how closely algorithms agreed with a gold standard RR measure when operating under ideal conditions, and to provide a toolbox of algorithms and data to allow future researchers to conduct reproducible comparisons of algorithms.
Abstract: Over 100 algorithms have been proposed to estimate respiratory rate (RR) from the electrocardiogram (ECG) and photoplethysmogram (PPG). As they have never been compared systematically it is unclear which algorithm performs the best. Our primary aim was to determine how closely algorithms agreed with a gold standard RR measure when operating under ideal conditions. Secondary aims were: (i) to compare algorithm performance with IP, the clinical standard for continuous respiratory rate measurement in spontaneously breathing patients; (ii) to compare algorithm performance when using ECG and PPG; and (iii) to provide a toolbox of algorithms and data to allow future researchers to conduct reproducible comparisons of algorithms. Algorithms were divided into three stages: extraction of respiratory signals, estimation of RR, and fusion of estimates. Several interchangeable techniques were implemented for each stage. Algorithms were assembled using all possible combinations of techniques, many of which were novel. After verification on simulated data, algorithms were tested on data from healthy participants. RRs derived from ECG, PPG and IP were compared to reference RRs obtained using a nasal-oral pressure sensor using the limits of agreement (LOA) technique. 314 algorithms were assessed. Of these, 270 could operate on either ECG or PPG, and 44 on only ECG. The best algorithm had 95% LOAs of -4.7 to 4.7 bpm and a bias of 0.0 bpm when using the ECG, and -5.1 to 7.2 bpm and 1.0 bpm when using PPG. IP had 95% LOAs of -5.6 to 5.2 bpm and a bias of -0.2 bpm. Four algorithms operating on ECG performed better than IP. All high-performing algorithms consisted of novel combinations of time domain RR estimation and modulation fusion techniques. Algorithms performed better when using ECG than PPG. The toolbox of algorithms and data used in this study are publicly available.
TL;DR: CEA TCB is a novel generation TCB displaying potent antitumor activity; it is efficacious in poorly infiltrated tumors where it increases T-cell infiltration and generates a highly inflamed tumor microenvironment.
Abstract: Purpose: CEA TCB is a novel IgG-based T-cell bispecific (TCB) antibody for the treatment of CEA-expressing solid tumors currently in phase I clinical trials (NCT02324257). Its format incorporates bivalent binding to CEA, a head-to-tail fusion of CEA- and CD3e-binding Fab domains and an engineered Fc region with completely abolished binding to FcγRs and C1q. The study provides novel mechanistic insights into the activity and mode of action of CEA TCB. Experimental Design: CEA TCB activity was characterized on 110 cell lines in vitro and in xenograft tumor models in vivo using NOG mice engrafted with human peripheral blood mononuclear cells. Results: Simultaneous binding of CEA TCB to tumor and T cells leads to formation of immunologic synapses, T-cell activation, secretion of cytotoxic granules, and tumor cell lysis. CEA TCB activity strongly correlates with CEA expression, with higher potency observed in highly CEA-expressing tumor cells and a threshold of approximately 10,000 CEA-binding sites/cell, which allows distinguishing between high- and low-CEA–expressing tumor and primary epithelial cells, respectively. Genetic factors do not affect CEA TCB activity confirming that CEA expression level is the strongest predictor of CEA TCB activity. In vivo, CEA TCB induces regression of CEA-expressing xenograft tumors with variable amounts of immune cell infiltrate, leads to increased frequency of activated T cells, and converts PD-L1 negative into PD-L1–positive tumors. Conclusions: CEA TCB is a novel generation TCB displaying potent antitumor activity; it is efficacious in poorly infiltrated tumors where it increases T-cell infiltration and generates a highly inflamed tumor microenvironment. Clin Cancer Res; 22(13); 3286–97. ©2016 AACR.
TL;DR: The present work summarizes the principles of cryoinjury and the relevance of permeating and nonpermeating cryoprotective agents and speculates with new research horizons on the preservation of boar sperm, such as vitrification and freeze-drying.
TL;DR: There is evidence that saline is beneficial in the treatment of the symptoms of chronic rhinosinusitis when used as the sole modality of treatment and some evidence suggests that hypertonic solutions improve objective measures but the impact on symptoms is less clear.
Abstract: BACKGROUND: The use of nasal irrigation for the treatment of nose and sinus complaints has its foundations in yogic and homeopathic traditions. There has been increasing use of saline irrigation, douches, sprays and rinsing as an adjunct to the medical management of chronic rhinosinusitis. Treatment strategies often include the use of topical saline from once to more than four times a day. Considerable patient effort is often involved. Any additional benefit has been difficult to discern from other treatments. OBJECTIVES: To evaluate the effectiveness and safety of topical saline in the management of chronic rhinosinusitis. SEARCH STRATEGY: Our search included the Cochrane Ear, Nose and Throat Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4 2006), MEDLINE (1950 to 2006) and EMBASE (1974 to 2006). The date of the last search was November 2006. SELECTION CRITERIA: Randomised controlled trials in which saline was evaluated in comparison with either no treatment, a placebo, as an adjunct to other treatments or against treatments. The comparison of hypertonic versus isotonic solutions was also compared. DATA COLLECTION AND ANALYSIS: Trials were graded for methodological quality using the Cochrane approach (modification of Chalmers 1990). Only symptom scores from saline versus no treatment and symptom and radiological scores from the hypertonic versus isotonic group could be pooled for statistical analysis. A narrative overview of the remaining results is presented. MAIN RESULTS: Eight trials were identified that satisfied the inclusion criteria. Three studies compared topical saline against no treatment, one against placebo, one as an adjunct to and one against an intranasal steroid spray. Two studies compared different hypertonic solutions against isotonic saline. There is evidence that saline is beneficial in the treatment of the symptoms of chronic rhinosinusitis when used as the sole modality of treatment. Evidence also exists in favour of saline as a treatment adjunct. No superiority was seen when saline was compared against a reflexology 'placebo'. Saline is not as effective as an intranasal steroid. Some evidence suggests that hypertonic solutions improve objective measures but the impact on symptoms is less clear. AUTHORS' CONCLUSIONS: Saline irrigations are well tolerated. Although minor side effects are common, the beneficial effect of saline appears to outweigh these drawbacks for the majority of patients. The use of topical saline could be included as a treatment adjunct for the symptoms of chronic rhinosinusitis.