South West London and St George's Mental Health NHS Trust

Over the last decade, there have been numerous developments and changes in treatment practices for the management of patients with immune thrombocytopenia (ITP). This article is an update of the International Consensus Report published in 2010. A critical review was performed to identify all relevant articles published between 2009 and 2018. An expert panel screened, reviewed, and graded the studies and formulated the updated consensus recommendations based on the new data. The final document provides consensus recommendations on the diagnosis and management of ITP in adults, during pregnancy, and in children, as well as quality-of-life considerations.

RATIONALE: Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. OBJECTIVES: Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. METHODS: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. RESULTS: Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen's d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. CONCLUSIONS: Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.

BACKGROUND: Complications from major surgery are undesirable, common, and potentially avoidable. The long-term consequences of short-term surgical complications have recently been recognized to have a profound influence on longevity and quality of life in survivors. In the past 30 years, there have been a number of studies conducted attempting to reduce surgical mortality and morbidity by deliberately and preemptively manipulating perioperative hemodynamics. Early studies had a high control-group mortality rate and were criticized for this as being unrepresentative of current practice and raised opposition to its implementation as routine care. We performed this review to update this body of literature and to examine the effect of changes in current practice and quality of care to see whether the conclusions from previous quantitative analyses of this field remain valid. METHODS: Randomized clinical trials evaluating the use of preemptive hemodynamic intervention to improve surgical outcome were identified using multiple methods. Electronic databases (MEDLINE, EMBASE, and the Cochrane Controlled Clinical Trials register) were screened for potential trials, reference lists of identified trials were examined, and additional sources were sought from experts and industry representatives. Identified studies that fulfilled the entry criteria were examined in full and subjected to quantifiable analysis, subgroup analysis, and sensitivity analysis where possible. RESULTS: There were 29 studies identified, 23 of which reported surgical complications. In total, the 29 trials involved 4805 patients with an overall mortality of 7.6%. The use of preemptive hemodynamic intervention significantly reduced mortality (pooled odds ratio [95% confidence interval] of 0.48 [0.33-0.78]; P = 0.0002) and surgical complications (odds ratio 0.43 [0.34-0.53]; P < 0.0001). Subgroup analysis showed significant reductions in mortality for studies using a pulmonary artery catheter, supranormal resuscitation targets, studies using cardiac index or oxygen delivery as goals, and the use of fluids and inotropes as opposed to fluids alone. By contrast, there was a significant reduction in morbidity for each of the 4 subgroups analyzed. CONCLUSION: The use of a preemptive strategy of hemodynamic monitoring and coupled therapy reduces surgical mortality and morbidity.

The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.

OBJECTIVE: Although postoperative cognitive dysfunction (POCD) often complicates recovery from major surgery, the pathogenic mechanisms remain unknown. We explored whether systemic inflammation, in response to surgical trauma, triggers hippocampal inflammation and subsequent memory impairment, in a mouse model of orthopedic surgery. METHODS: C57BL/6J, knock out (lacking interleukin [IL]-1 receptor, IL-1R(-/-)) and wild type mice underwent surgery of the tibia under general anesthesia. Separate cohorts of animals were tested for memory function with fear conditioning tests, or euthanized at different times to assess levels of systemic and hippocampal cytokines and microglial activation; the effects of interventions, designed to interrupt inflammation (specifically and nonspecifically), were also assessed. RESULTS: Surgery caused hippocampal-dependent memory impairment that was associated with increased plasma cytokines, as well as reactive microgliosis and IL-1beta transcription and expression in the hippocampus. Nonspecific attenuation of innate immunity with minocycline prevented surgery-induced changes. Functional inhibition of IL-1beta, both in mice pretreated with IL-1 receptor antagonist and in IL-1R(-/-) mice, mitigated the neuroinflammatory effects of surgery and memory dysfunction. INTERPRETATION: A peripheral surgery-induced innate immune response triggers an IL-1beta-mediated inflammatory process in the hippocampus that underlies memory impairment. This may represent a viable target to interrupt the pathogenesis of postoperative cognitive dysfunction.

BACKGROUND: Self-monitoring of blood pressure (BP) appears to reduce BP in hypertension but important questions remain regarding effective implementation and which groups may benefit most. This individual patient data (IPD) meta-analysis was performed to better understand the effectiveness of BP self-monitoring to lower BP and control hypertension. METHODS AND FINDINGS: Medline, Embase, and the Cochrane Library were searched for randomised trials comparing self-monitoring to no self-monitoring in hypertensive patients (June 2016). Two reviewers independently assessed articles for eligibility and the authors of eligible trials were approached requesting IPD. Of 2,846 articles in the initial search, 36 were eligible. IPD were provided from 25 trials, including 1 unpublished study. Data for the primary outcomes-change in mean clinic or ambulatory BP and proportion controlled below target at 12 months-were available from 15/19 possible studies (7,138/8,292 [86%] of randomised participants). Overall, self-monitoring was associated with reduced clinic systolic blood pressure (sBP) compared to usual care at 12 months (-3.2 mmHg, [95% CI -4.9, -1.6 mmHg]). However, this effect was strongly influenced by the intensity of co-intervention ranging from no effect with self-monitoring alone (-1.0 mmHg [-3.3, 1.2]), to a 6.1 mmHg (-9.0, -3.2) reduction when monitoring was combined with intensive support. Self-monitoring was most effective in those with fewer antihypertensive medications and higher baseline sBP up to 170 mmHg. No differences in efficacy were seen by sex or by most comorbidities. Ambulatory BP data at 12 months were available from 4 trials (1,478 patients), which assessed self-monitoring with little or no co-intervention. There was no association between self-monitoring and either lower clinic or ambulatory sBP in this group (clinic -0.2 mmHg [-2.2, 1.8]; ambulatory 1.1 mmHg [-0.3, 2.5]). Results for diastolic blood pressure (dBP) were similar. The main limitation of this work was that significant heterogeneity remained. This was at least in part due to different inclusion criteria, self-monitoring regimes, and target BPs in included studies. CONCLUSIONS: Self-monitoring alone is not associated with lower BP or better control, but in conjunction with co-interventions (including systematic medication titration by doctors, pharmacists, or patients; education; or lifestyle counselling) leads to clinically significant BP reduction which persists for at least 12 months. The implementation of self-monitoring in hypertension should be accompanied by such co-interventions.

OBJECTIVE: To investigate the impact of childbirth on the sexual health of primiparous women and identify factors associated with dyspareunia. DESIGN: Cross-sectional study using obstetric records, and postal survey six months after delivery. SETTING: Department of Obstetrics and Gynaecology, St George's Hospital, London. POPULATION: All primiparous women (n = 796) delivered of a live birth in a six month period. METHODS: Quantitative analysis of obstetric and survey data. MAIN OUTCOME MEASURES: Self reported sexual behaviour and sexual problems (e.g. vaginal dryness, painful penetration, pain during sexual intercourse, pain on orgasm, vaginal tightness, vaginal looseness, bleeding/irritation after sex, and loss of sexual desire); consultation for postnatal sexual problems. RESULTS: Of the 484 respondents (61% response rate), 89% had resumed sexual activity within six months of the birth. Sexual morbidity increased significantly after the birth: in the first three months after delivery 83% of women experienced sexual problems, declining to 64% at six months, although not reaching pre-pregnancy levels of 38% . Dyspareunia in the first three months after delivery was, after adjustment, significantly associated with vaginal deliveries (P = 0 x 01) and previous experience of dyspareunia (P = 0 x 03). At six months the association with type of delivery was not significant (P = 0 x 4); only experience of dyspareunia before pregnancy (P < 0 x 0001) and current breastfeeding were significant (P = 0 x 0006). Only 15% of women who had a postnatal sexual problem reported discussing it with a health professional. CONCLUSIONS: Sexual health problems were very common after childbirth, suggesting potentially high levels of unmet need.

Introduction: Intravenous(IV) immunoglobulin(Ig) treatment is known to alleviate behavioral deficits in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Methods: Sepsis was induced by cecal ligation perforation(CLP) in rats. The animals were divided into five groups; sham, control, CLP + saline, CLP + immunoglobulin G IgG(250 mg/kg,iv), and CLP + immunoglobulins enriched with immunoglobulin M-IgGAM(250 mg/kg,iv). Blood and brain samples were taken in two sets of experiments after CLP to see the early(24 hrs) and late(10 days) effects of treatment. Total complement activity, complement 3(C3) and soluble complement C5b-9 levels were measured in sera of rats using ELISA-based methods. Cerebral complement content was analyzed by Western Blot. Immune cell infiltration and gliosis were examined by immunohistochemistry using cluster of differentiation 3, CD4, CD8, CD11b, CD19 and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining and Western Blot-based semi-quantitative evaluation of brain homogenates by bax and bcl-2 antibodies. Results: IV IgG and IgGAM administration significantly reduced systemic complement activity but increased serum C3 and soluble C5b-9 levels. Likewise, Western Blot data showed slightly increased C5b-9 expression and significantly reduced C1q expression in brain samples of IgGAM-treated but not IgG-treated septic rats especially in the first day of administration. No cerebral cellular infiltrates were observed in treated and non-treated septic rats. By contrast, IV IgG and IgGAM treatment induced considerable amelioration in glial cell proliferation which was increased in non-treated rats. IgG and IgGAM treated rats exhibited significantly reduced numbers of apoptotic neurons and cerebral expression levels of bax and bcl-2 as compared to nontreated rats. Conclusions: We suggest that IV IgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. IgGAM treatment might be suppressing classical complement pathway by reducing C1q expression.

Previous studies have shown that mouse dermis is composed of functionally distinct fibroblast lineages. To explore the extent of fibroblast heterogeneity in human skin, we used a combination of comparative spatial transcriptional profiling of human and mouse dermis and single-cell transcriptional profiling of human dermal fibroblasts. We show that there are at least four distinct fibroblast populations in adult human skin, not all of which are spatially segregated. We define markers permitting their isolation and show that although marker expression is lost in culture, different fibroblast subpopulations retain distinct functionality in terms of Wnt signaling, responsiveness to IFN-γ, and ability to support human epidermal reconstitution when introduced into decellularized dermis. These findings suggest that ex vivo expansion or in vivo ablation of specific fibroblast subpopulations may have therapeutic applications in wound healing and diseases characterized by excessive fibrosis.

BACKGROUND: Diagnosis of Clostridium difficile infection is controversial because of many laboratory methods, compounded by two reference methods. Cytotoxigenic culture detects toxigenic C difficile and gives a positive result more frequently (eg, because of colonisation, which means that individuals can have the bacterium but no free toxin) than does the cytotoxin assay, which detects preformed toxin in faeces. We aimed to validate the reference methods according to clinical outcomes and to derive an optimum laboratory diagnostic algorithm for C difficile infection. METHODS: In this prospective, multicentre study, we did cytotoxigenic culture and cytotoxin assays on 12,420 faecal samples in four UK laboratories. We also performed tests that represent the three main targets for C difficile detection: bacterium (glutamate dehydrogenase), toxins, or toxin genes. We used routine blood test results, length of hospital stay, and 30-day mortality to clinically validate the reference methods. Data were categorised by reference method result: group 1, cytotoxin assay positive; group 2, cytotoxigenic culture positive and cytotoxin assay negative; and group 3, both reference methods negative. FINDINGS: Clinical and reference assay data were available for 6522 inpatient episodes. On univariate analysis, mortality was significantly higher in group 1 than in group 2 (72/435 [16·6%] vs 20/207 [9·7%], p=0·044) and in group 3 (503/5880 [8·6%], p<0·001), but not in group 2 compared with group 3 (p=0·4). A multivariate analysis accounting for potential confounders confirmed the mortality differences between groups 1 and 3 (OR 1·61, 95% CI 1·12-2·31). Multistage algorithms performed better than did standalone assays. INTERPRETATION: We noted no increase in mortality when toxigenic C difficile alone was present. Toxin (cytotoxin assay) positivity correlated with clinical outcome, and so this reference method best defines true cases of C difficile infection. A new diagnostic category of potential C difficile excretor (cytotoxigenic culture positive but cytotoxin assay negative) could be used to characterise patients with diarrhoea that is probably not due to C difficile infection, but who can cause cross-infection.

Hemodynamic monitoring plays a fundamental role in the management of acutely ill patients. With increased concerns about the use of invasive techniques, notably the pulmonary artery catheter, to measure cardiac output, recent years have seen an influx of new, less-invasive means of measuring hemodynamic variables, leaving the clinician somewhat bewildered as to which technique, if any, is best and which he/she should use. In this consensus paper, we try to provide some clarification, offering an objective review of the available monitoring systems, including their specific advantages and limitations, and highlighting some key principles underlying hemodynamic monitoring in critically ill patients.

Thoracic Endovascular Aortic Repair (TEVAR) for the treatment of aortic diseases: a position statement from the European Association for Cardio-Thoracic Surgery (EACTS) and the European Society of Cardiology (ESC), in collaboration with the European Association of Percutaneous Cardiovascular Interventions (EAPCI)

This paper is an analysis of the concept of empowerment and its use in nursing practice, education, research and health promotion. The paper adopts an eclectic approach to concept analysis, incorporating the methods advocated by Walker & Avant and Rodgers. The concept is analysed and a theoretical definition given. Defining attributes, related concepts, antecedents and consequences of empowerment are proposed and a model case presented. The analysis demonstrates that empowerment is: a helping process; a partnership valuing self and others; mutual decision making; and freedom to make choices and accept responsibility. Implications for practice conclude the paper.

BACKGROUND: Meta-analyses of previous randomised controlled trials concluded that the smooth muscle relaxant drugs tamsulosin and nifedipine assisted stone passage for people managed expectantly for ureteric colic, but emphasised the need for high-quality trials with wide inclusion criteria. We aimed to fulfil this need by testing effectiveness of these drugs in a standard clinical care setting. METHODS: For this multicentre, randomised, placebo-controlled trial, we recruited adults (aged 18-65 years) undergoing expectant management for a single ureteric stone identified by CT at 24 UK hospitals. Participants were randomly assigned by a remote randomisation system to tamsulosin 400 μg, nifedipine 30 mg, or placebo taken daily for up to 4 weeks, using an algorithm with centre, stone size (≤5 mm or >5 mm), and stone location (upper, mid, or lower ureter) as minimisation covariates. Participants, clinicians, and trial personnel were masked to treatment assignment. The primary outcome was the proportion of participants who did not need further intervention for stone clearance within 4 weeks of randomisation, analysed in a modified intention-to-treat population defined as all eligible patients for whom we had primary outcome data. This trial is registered with the European Clinical Trials Database, EudraCT number 2010-019469-26, and as an International Standard Randomised Controlled Trial, number 69423238. FINDINGS: Between Jan 11, 2011, and Dec 20, 2013, we randomly assigned 1167 participants, 1136 (97%) of whom were included in the primary analysis (17 were excluded because of ineligibility and 14 participants were lost to follow-up). 303 (80%) of 379 participants in the placebo group did not need further intervention by 4 weeks, compared with 307 (81%) of 378 in the tamsulosin group (adjusted risk difference 1·3% [95% CI -5·7 to 8·3]; p=0·73) and 304 (80%) of 379 in the nifedipine group (0·5% [-5·6 to 6·5]; p=0·88). No difference was noted between active treatment and placebo (p=0·78), or between tamsulosin and nifedipine (p=0·77). Serious adverse events were reported in three participants in the nifedipine group (one had right loin pain, diarrhoea, and vomiting; one had malaise, headache, and chest pain; and one had severe chest pain, difficulty breathing, and left arm pain) and in one participant in the placebo group (headache, dizziness, lightheadedness, and chronic abdominal pain). INTERPRETATION: Tamsulosin 400 μg and nifedipine 30 mg are not effective at decreasing the need for further treatment to achieve stone clearance in 4 weeks for patients with expectantly managed ureteric colic. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

The classical psychedelic drugs, including psilocybin, lysergic acid diethylamide and mescaline, were used extensively in psychiatry before they were placed in Schedule I of the UN Convention on Drugs in 1967. Experimentation and clinical trials undertaken prior to legal sanction suggest that they are not helpful for those with established psychotic disorders and should be avoided in those liable to develop them. However, those with so-called 'psychoneurotic' disorders sometimes benefited considerably from their tendency to 'loosen' otherwise fixed, maladaptive patterns of cognition and behaviour, particularly when given in a supportive, therapeutic setting. Pre-prohibition studies in this area were sub-optimal, although a recent systematic review in unipolar mood disorder and a meta-analysis in alcoholism have both suggested efficacy. The incidence of serious adverse events appears to be low. Since 2006, there have been several pilot trials and randomised controlled trials using psychedelics (mostly psilocybin) in various non-psychotic psychiatric disorders. These have provided encouraging results that provide initial evidence of safety and efficacy, however the regulatory and legal hurdles to licensing psychedelics as medicines are formidable. This paper summarises clinical trials using psychedelics pre and post prohibition, discusses the methodological challenges of performing good quality trials in this area and considers a strategic approach to the legal and regulatory barriers to licensing psychedelics as a treatment in mainstream psychiatry. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Generalized lymphatic dysplasia (GLD) is a rare form of primary lymphoedema characterized by a uniform, widespread lymphoedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. This may present prenatally as non-immune hydrops. Here we report homozygous and compound heterozygous mutations in PIEZO1, resulting in an autosomal recessive form of GLD with a high incidence of non-immune hydrops fetalis and childhood onset of facial and four limb lymphoedema. Mutations in PIEZO1, which encodes a mechanically activated ion channel, have been reported with autosomal dominant dehydrated hereditary stomatocytosis and non-immune hydrops of unknown aetiology. Besides its role in red blood cells, our findings indicate that PIEZO1 is also involved in the development of lymphatic structures.

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Abdominal aortic aneurysms (AAA) are characterized by pathological remodeling of the aortic extracellular matrix (ECM). However, besides the well-characterized elastolysis and collagenolysis little is known about changes in other ECM proteins. Previous proteomics studies on AAA focused on cellular changes without emphasis on the ECM. In the present study, ECM proteins and their degradation products were selectively extracted from aneurysmal and control aortas using a solubility-based subfractionation methodology and analyzed by gel-liquid chromatography-tandem MS and label-free quantitation. The proteomics analysis revealed novel changes in the ECM of AAA, including increased expression as well as degradation of collagen XII, thrombospondin 2, aortic carboxypeptidase-like protein, periostin, fibronectin and tenascin. Proteomics also confirmed the accumulation of macrophage metalloelastase (MMP-12). Incubation of control aortic tissue with recombinant MMP-12 resulted in the extensive fragmentation of these glycoproteins, most of which are novel substrates of MMP-12. In conclusion, our proteomics methodology allowed the first detailed analysis of the ECM in AAA and identified markers of pathological ECM remodeling related to MMP-12 activity. Abdominal aortic aneurysms (AAA) are characterized by pathological remodeling of the aortic extracellular matrix (ECM). However, besides the well-characterized elastolysis and collagenolysis little is known about changes in other ECM proteins. Previous proteomics studies on AAA focused on cellular changes without emphasis on the ECM. In the present study, ECM proteins and their degradation products were selectively extracted from aneurysmal and control aortas using a solubility-based subfractionation methodology and analyzed by gel-liquid chromatography-tandem MS and label-free quantitation. The proteomics analysis revealed novel changes in the ECM of AAA, including increased expression as well as degradation of collagen XII, thrombospondin 2, aortic carboxypeptidase-like protein, periostin, fibronectin and tenascin. Proteomics also confirmed the accumulation of macrophage metalloelastase (MMP-12). Incubation of control aortic tissue with recombinant MMP-12 resulted in the extensive fragmentation of these glycoproteins, most of which are novel substrates of MMP-12. In conclusion, our proteomics methodology allowed the first detailed analysis of the ECM in AAA and identified markers of pathological ECM remodeling related to MMP-12 activity. Abdominal aortic aneurysms (AAA) 1The abbreviations used are:AAAAbdominal aortic aneurysmACLPAortic carboxypeptidase-like proteinECMExtracellular matrixeSODextracellular superoxide dismutaseLTQLinear trap quadrupoleMMPMatrix metalloproteinaseTIMPTissue inhibitor of metalloproteinasesLCliquid chromatographyMS/MStandem MS. affect 2–10% of the elderly population (1Alcorn H.G. Wolfson Jr., S.K. Sutton-Tyrrell K. Kuller L.H. O'Leary D. Risk factors for abdominal aortic aneurysms in older adults enrolled in The Cardiovascular Health Study.Arterioscler. Thromb. Vasc. Biol. 1996; 16: 963-970Crossref PubMed Scopus (284) Google Scholar, 2Baumgartner I. Hirsch A.T. Abola M.T. Cacoub P.P. Poldermans D. Steg P.G. Creager M.A. Bhatt D.L. Cardiovascular risk profile and outcome of patients with abdominal aortic aneurysm in out-patients with atherothrombosis: data from the Reduction of Atherothrombosis for Continued Health (REACH) Registry.J Vasc Surg. 2008; 48: 808-814Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar) and are histopathologically characterized by the extensive degeneration of the aortic extracellular matrix (ECM) (3Golledge J. Tsao P.S. Dalman R.L. Norman P.E. Circulating markers of abdominal aortic aneurysm presence and progression.Circulation. 2008; 118: 2382-2392Crossref PubMed Scopus (209) Google Scholar). The breakdown of structural proteins, in particular medial elastin and collagen I and III, is responsible for the inability of the aortic wall to withstand the hemodynamic forces (4Hellenthal F.A. Buurman W.A. Wodzig W.K. Schurink G.W. Biomarkers of AAA progression. Part 1: extracellular matrix degeneration.Nat Rev Cardiol. 2009; 6: 464-474Crossref PubMed Scopus (132) Google Scholar). Transmural inflammatory infiltrates (5Shiraya S. Miyake T. Aoki M. Yoshikazu F. Ohgi S. Nishimura M. Ogihara T. Morishita R. Inhibition of development of experimental aortic abdominal aneurysm in rat model by atorvastatin through inhibition of macrophage migration.Atherosclerosis. 2009; 202: 34-40Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar) combined with a reduction in the number of medial smooth muscle cells trigger the destruction of the aortic connective tissue via unregulated proteinase activity (6Shah P.K. Inflammation, metalloproteinases, and increased proteolysis: an emerging pathophysiological paradigm in aortic aneurysm.Circulation. 1997; 96: 2115-2117Crossref PubMed Scopus (248) Google Scholar, 7Shimizu K. Shichiri M. Libby P. Lee R.T. Mitchell R.N. Th2-predominant inflammation and blockade of IFN-gamma signaling induce aneurysms in allografted aortas.J. Clin. Invest. 2004; 114: 300-308Crossref PubMed Scopus (188) Google Scholar). However, apart from the well-established elastolysis and collagenolysis, little is known about other changes in ECM composition and turnover in AAA. Recent proteomics studies on aneurysms have used whole tissue lysates (8Liao M. Liu Z. Bao J. Zhao Z. Hu J. Feng X. Feng R. Lu Q. Mei Z. Liu Y. Wu Q. Jing Z. A proteomic study of the aortic media in human thoracic aortic dissection: implication for oxidative stress.J. Thorac. Cardiovasc. Surg. 2008; 136 (72, e61–63.): 65-72Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 9Pilop C. Aregger F. Gorman R.C. Brunisholz R. Gerrits B. Schaffner T. Gorman 3rd, J.H. Matyas G. Carrel T. Frey B.M. Proteomic analysis in aortic media of patients with Marfan syndrome reveals increased activity of calpain 2 in aortic aneurysms.Circulation. 2009; 120: 983-991Crossref PubMed Scopus (50) Google Scholar) and reported significant changes in cellular proteins but provided limited insights into matrix remodeling. Regarding the ECM these approaches had several limitations: first, whole tissue lysates are rich in cellular proteins, which mask the identification of scarce extracellular components, including proteinases and proteinase inhibitors. Second, ECM proteins are difficult to solubilize and analyze by proteomics because of their unique biochemical properties (aggregation, cross-linking, and glycosylation). Third, during pathological processes, such as aneurysm formation, the ECM undergoes extensive turnover with continuous degradation as well as deposition of newly synthesized matrix proteins. In analysis of whole tissue lysates, newly synthesized ECM proteins cannot be readily discerned from existing matrix proteins and only abundant degradation products are detected (9Pilop C. Aregger F. Gorman R.C. Brunisholz R. Gerrits B. Schaffner T. Gorman 3rd, J.H. Matyas G. Carrel T. Frey B.M. Proteomic analysis in aortic media of patients with Marfan syndrome reveals increased activity of calpain 2 in aortic aneurysms.Circulation. 2009; 120: 983-991Crossref PubMed Scopus (50) Google Scholar). To overcome these shortcomings we have recently developed a solubility-based, protein subfractionation procedure, which facilitates the selective extraction of newly synthesized ECM proteins and degradation products, reduces the contamination with cellular proteins, and ensures the solubilization of the interstitial ECM and its associated proteins, thereby improving their analysis by proteomics (10Didangelos A. Yin X. Mandal K. Baumert M. Jahangiri M. Mayr M. Proteomics characterization of extracellular space components in the human aorta.Mol. Cell Proteomics. 2010; 9: 2048-2062Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). In this study, we applied this subfractionation method to AAA. Our aim was to characterize the changes in ECM and associated proteins involved in the pathological remodeling process. We achieved the most detailed proteomics characterization of the aneurysmal ECM to date and revealed major differences between healthy and AAA tissues including the increased deposition and fragmentation of collagen XII, thrombospondin 2, aortic carboxypeptidase-like protein (ACLP), periostin, and fibronectin. In addition, we were able to show that these glycoproteins are novel proteolytic targets of MMP-12. Thus, our proteomics approach can serve as a platform for the identification of candidate markers of pathological remodeling in clinical samples (11Mayr M. Zhang J. Greene A.S. D. J. P. development of in and Cell Proteomics. Full Text Full Text PDF PubMed Scopus Google Scholar). Abdominal aortic aneurysm carboxypeptidase-like protein matrix extracellular superoxide trap inhibitor of MS. study was by the of and patients AAA were from patients of during aneurysm on aneurysm in and are in control samples from patients without connective tissue and to were during aortic from of the that were of were known during of clinical and tissues were and in for extraction the tissue were and of tissue aortic were in to The was with proteinase inhibitor which and with a for and and and inhibitor which and to a of In addition, were to inhibition of the tissue samples were in the were with a into to the of and the extraction of extracellular proteins as the proteomics methodology we used healthy aortic and AAA The samples were first in a with proteinase and inhibitor as and The of the was to of the tissue in The samples were for The were with using the were with for were with for and the were and in the aortic samples were with to tissue including proteinase and inhibitor and The samples were to of the for The was and for the samples were in a to tissue proteinase and inhibitor and was to to the of R. The of the Part of and the of a from Full Text PDF PubMed Scopus Google Scholar). The samples were for and to the of matrix proteins. the extraction was by the samples with for were with for and the were with and in of of the was achieved in a with proteinase and for The from the of and to on and of from A of from from in and of and from of were from the were with for to that the samples were of and protein was by of the contamination with that in the tissue in the we used the to for Jr., of of protein without PubMed Scopus Google Scholar). The and were and in and and for of protein were and on were the samples were using the was used for to with X. F. Mayr Z. M. M. Mayr M. Proteomics analysis of the reveals in Cell Proteomics. 2010; 9: Full Text Full Text PDF PubMed Scopus Google Scholar) were in and were were to using an were on a and with a in in in and in A is in and is in The was to a using the the was and the in the of the R. S. J. D. M. A novel method of the Cell Proteomics. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). were from a using the MS was on the in MS using the with were by and to human protein using and of was as and of as The was for the and for were was used to the and to and protein A. R. model to the of by and PubMed Scopus Google Scholar, A. R. A model for proteins by PubMed Scopus Google Scholar). to the in the were be as by the A. R. model to the of by and PubMed Scopus Google Scholar). were in the were be A. R. A model for proteins by PubMed Scopus Google Scholar) with and a of of the ECM proteins identified for the first by proteomics in the as well as ECM proteins with were to the of the identified of the and were with and of protein were and on as were on were in in and for with and smooth muscle thrombospondin 2 fibronectin and MMP-12 from and and from The were for from were used in The were with the a the were using and were developed on an The for the from developed for collagen XII, thrombospondin 2, periostin, and was using the aortic from patients without connective tissue were into and were in The tissue were with and which was used with human recombinant human recombinant from was by with in for MMP-12 was in for to was by through a was also through a for The were with the proteinase inhibitor to proteinase activity. the of the aortic tissue with the the tissue were and using to collagen XII, thrombospondin 2, fibronectin and MMP-12 was also used on human recombinant and thrombospondin 2 from and on human fibronectin of protein were in with proteinase inhibitor for with without MMP-12. from AAA and control aortic samples were in and used to on a The were and in for were with and with the activity was using a in for were with to MMP-12 from were used 2 was using developed with from were with and 2 were using for were by a to clinical and AAA, and biochemical and we a using the The reported as for protein was as the of samples and and AAA, for protein were used for analysis protein were using the by and the number of identified in the number of to protein by the of the and the number of in that were using in the and to protein are in The in for identified extracellular protein between control and AAA was using A of was proteins identified with unique were in the analysis and were with a significant in between control and AAA samples were into in between proteins and samples was using The and were using the M. T. J. J. P. PubMed Scopus Google Scholar). The in is by a were The between the and the of was using A of was tissue were medial degeneration with inflammatory infiltrates by and of smooth muscle cells were in AAA. are in The macrophage was detected in aortic in AAA to smooth muscle The ECM and its associated proteins were extracted from AAA and control aortas our (10Didangelos A. Yin X. Mandal K. Baumert M. Jahangiri M. Mayr M. Proteomics characterization of extracellular space components in the human aorta.Mol. Cell Proteomics. 2010; 9: 2048-2062Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). The proteomics is in in the first the of the is to solubilize extracellular proteins that are to the ECM of with J. PubMed Scopus Google including newly synthesized ECM proteins R. S. Gorman of extracellular matrix and using extraction and label-free Cell Proteomics. 2010; 9: Full Text Full Text PDF PubMed Scopus Google which are degradation products and other proteins present in the extracellular In the the samples are using to the abundant cellular proteins. in the the extraction of the ECM glycoproteins, and is achieved using a The methodology is on a subfractionation of the which its associated proteins and degradation are extracted in proteins protein that are to the including newly synthesized ECM proteins and degradation In addition, proteinases such as are also Second, are with to cellular proteins. the ECM proteins are extracted using to solubilize the In the the identified are by healthy tissue with recombinant to novel proteolytic targets and characterize their proteolytic activity in proteins in the and were by to and analyzed by using a trap to the to a for The in a for data proteins identification are in and and to the proteins in the and proteins in the were ECM proteins glycoproteins, and proteins associated with the ECM such as extracellular and the identified extracellular proteins were only in the proteins were unique to the most unique proteins in the were factors such as protein, and the proteins to the were matrix proteins such as protein protein, matrix protein, and collagen for ECM proteins were increased in the protein of AAA In in the the for ECM proteins as well as the number of in the were between control and matrix and associated proteins identified by proteomics in the samples with samples with proteins identified for the first by proteomics in the and glycoproteins carboxypeptidase-like ECM protein protein matrix proteins superoxide protein protein protein inhibitor protein, of protein protein protein 136 in a matrix and associated proteins identified by proteomics in the samples with samples with proteins identified for the first by proteomics in the and glycoproteins carboxypeptidase-like and protein inhibitor protein protein matrix protein protein protein proteins protein protein extracellular matrix protein superoxide of inhibitor protein protein, and protein protein protein protein protein protein and protein protein in a in protein between control and AAA were using were can be in of the extracellular proteins in the and the control and AAA samples and major differences in their ECM composition of I and and the collagen XII, and 2, and were in the of AAA proteins, were also abundant in the of AAA that are components of the aneurysmal ECM. 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Full Text Full Text PDF PubMed Scopus Google Scholar). our methodology allowed the of matrix as well as scarce proteins in clinical The in the fragmentation of collagen XII, thrombospondin 2, and in the AAA detailed of the data revealed that a number of were identified in the of these proteins the presence of proteolytic products in the aneurysmal including have to matrix during aneurysm S. and of macrophage in abdominal aortic Clin. Invest. PubMed Scopus Google Scholar, Libby P. for between matrix and their in human aortic 1997; PubMed Scopus Google Scholar, R. Lee D. of matrix development of experimental abdominal aortic Clin. Invest. PubMed Scopus Google MMP-12 was the only that was increased in our proteomics analysis To the between the fragmentation of these glycoproteins and the presence of we human aortic with recombinant MMP-12 in in AAA Y. of matrix and in abdominal aortic Thromb. PubMed Google as an MMP-12 extensive fragmentation of fibronectin and collagen XII, and 2 was products In to MMP-12 had on the degradation of collagen XII, and thrombospondin 2, the of from the aortic by limited with proteinases resulted in an of the of fibronectin A. B. D. and characterization of rat PubMed Scopus Google other glycoproteins are novel substrates for MMP-12. The proteinase had a and on these glycoproteins in the aortic its proteolytic on the tissue was by In addition, MMP-12 was able to human recombinant and thrombospondin 2 in a known MMP-12 was used as a The proteolytic of MMP-12 on was and the of on this M.T. M.A. M.A. Lee carboxypeptidase-like protein, a novel protein with and carboxypeptidase-like is during smooth muscle Biol. Full Text Full Text PDF PubMed Scopus (71) Google Scholar) in we to its by In AAA, extracellular was present in the of the media tissue is with and of inflammatory and in the inflammatory connective tissue is In MMP-12 was in the inflammatory and and was an in the of the proteins, the proteolytic of MMP-12 on in the are in and The destruction of the aortic connective tissue in aneurysms is by a inflammatory and the degradation of the aortic ECM. However, the of cellular proteins in the and the biochemical properties of matrix components have limited the characterization of the ECM in M. Mayr Yin X. S. Hu Y. Q. Proteomic and of from in oxidative and Thromb. Vasc. Biol. PubMed Scopus Google Scholar). In this study we a solubility-based, protein subfractionation methodology that the detailed characterization of the ECM and its associated proteins in AAA. this approach novel insights into the pathological remodeling and allowed to changes in the turnover of ECM proteins to the increased of MMP-12 in AAA. Proteomics revealed differences in the ECM composition between control and AAA a of the pathological the protein of aneurysms was in ECM fragmentation of the identified protein changes have reported in AAA, including collagen XII, thrombospondin 2, periostin, and is a collagen and in tissues to forces J. M. M. and of collagen expression by changes in Cell PubMed Scopus Google Scholar) and thrombospondin 2 are glycoproteins involved in cellular and D. by is a for and and Google Scholar, D. S. P. 2 by Biol. PubMed Scopus Google Scholar). is an extracellular which is known to in the ECM associated with collagen M.T. M.A. M.A. Lee carboxypeptidase-like protein, a novel protein with and carboxypeptidase-like is during smooth muscle Biol. Full Text Full Text PDF PubMed Scopus (71) Google but its is well that is a of in the Liu X. M.A. carboxypeptidase-like protein is in human and its J. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). is the of tissue fragmentation of a Cell PubMed Scopus Google Scholar) and this its accumulation in the aortic expression reported in AAA and was associated with the accumulation of J. Y. R. P. T. expression is associated with a inflammatory in abdominal aortic Vasc. Surg. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). Our proteomics data also revealed the fragmentation of these ECM proteins products the pathological remodeling in AAA. In the of AAA was a reduction in the major and as well as protein, the which to a study that was in aneurysms I. A. abdominal aortic aneurysm is characterized by and of Full Text Full Text PDF PubMed Scopus Google is known about the of and to this J. J. Q. P. of abdominal aortic of of by smooth muscle Vasc. Surg. Full Text Full Text PDF PubMed Scopus Google Scholar, J. R. C. The aneurysm and are associated with abdominal aortic 2010; PubMed Scopus Google Scholar). The of these major is to have major on and but also affect the and of in the extracellular space including extracellular and factors T. M. M. R. J. an of to PubMed Scopus Google Scholar). extracellular superoxide was in AAA is in the extracellular space to such as K. J. A. of in Invest. Google Scholar). A of these in of and other extracellular proteins, thereby the of the the proteolytic activity in human tissues on and to on proteinases and their inhibitors. and have detected in of AAA and their proteolytic activity to aneurysm S. and of macrophage in abdominal aortic Clin. Invest. PubMed Scopus Google Scholar, Libby P. for between matrix and their in human aortic 1997; PubMed Scopus Google Scholar, R. Lee D. of matrix development of experimental abdominal aortic Clin. Invest. PubMed Scopus Google Scholar). little is known about their in AAA. A of is that the is only on the protein but also on the and of the with cannot be a proteomics approach an of proteinases and degradation products in proteomics studies focused on cellular proteins and to in AAA (8Liao M. Liu Z. Bao J. Zhao Z. Hu J. Feng X. Feng R. Lu Q. Mei Z. Liu Y. Wu Q. Jing Z. A proteomic study of the aortic media in human thoracic aortic dissection: implication for oxidative stress.J. Thorac. Cardiovasc. Surg. 2008; 136 (72, e61–63.): 65-72Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 9Pilop C. Aregger F. Gorman R.C. Brunisholz R. Gerrits B. Schaffner T. Gorman 3rd, J.H. Matyas G. Carrel T. Frey B.M. Proteomic analysis in aortic media of patients with Marfan syndrome reveals increased activity of calpain 2 in aortic aneurysms.Circulation. 2009; 120: 983-991Crossref PubMed Scopus (50) Google our subfractionation method the of MMP-12. the presence of other but that MMP-12 is abundant and its in the of AAA T. S. MMP-12 a in abdominal aortic aneurysms in Full Text Full Text PDF PubMed Scopus Google Scholar, Y. P. B. S. J. G. C. A. Z. activity inflammatory aortic aneurysm and in Clin. Invest. 2010; 120: PubMed Scopus Google Scholar). and and the proteinases and were also identified but only was increased in AAA was recently to in aneurysms T. D. P. M. C. I. in abdominal aortic Thromb. Vasc. Biol. 2010; PubMed Scopus Google Scholar). from its well-established and properties S. and of macrophage in abdominal aortic Clin. Invest. PubMed Scopus Google little is known about the of MMP-12 to other substrates in the the presence of proteolytic products from known targets by using the substrates R.C. Libby P. for increased collagenolysis by interstitial and in human PubMed Scopus Google Scholar). Our subfractionation methodology allowed a analysis of the ECM in AAA. in the protein we only an but also a degradation of collagen XII, thrombospondin 2, and healthy aortic tissue was with recombinant the proteinase was able to these in was that MMP-12 be responsible for the degradation of these proteins in AAA. the fragmentation MMP-12 was to the in the is because the proteolytic activity in tissues is a by the of with and other inhibitors. In with studies D. of matrix and in human abdominal aortic Vasc. Surg. Full Text PDF PubMed Scopus Google we that and were increased in and a of the proteins in AAA was MMP-12 was able to in analysis by confirmed an of the for and MMP-12 in the inflammatory of AAA and that the proteinase in The in this study, the of proteins and the of proteolytic degradation in on protein fragmentation is in The label-free on the of protein 3rd, A model for and of protein in 2004; PubMed Scopus Google Scholar) and a with approaches on B. of from and for proteomic analysis using PubMed Scopus Google Scholar) and K. A. of label-free for human proteins by Cell Proteomics. Full Text Full Text PDF PubMed Scopus Google Scholar). However, its is limited to differences and proteins with be in the of changes and the of scarce proteins D. Mayr C. A. M. A. A. M. R. S. S. Q. Mayr M. proteomics reveals of smooth muscle in extracellular matrix Thromb. Vasc. Biol. 2010; PubMed Scopus Google Scholar). In this study we analyzed and extracellular proteins were by to the of our proteomics The changes between healthy and aneurysmal tissues were to be the number of clinical are by are healthy control tissue only be from the thoracic of the study is the first to a solubility-based extraction to study the ECM composition in human AAA by Our methodology to the identification of novel candidate markers of pathological tissue remodeling and identified proteolytic targets of of the proteinases in AAA.

OBJECTIVE: To determine the risks of stillbirth and neonatal complications by gestational age in uncomplicated monochorionic and dichorionic twin pregnancies. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, and Cochrane databases (until December 2015). REVIEW METHODS: Databases were searched without language restrictions for studies of women with uncomplicated twin pregnancies that reported rates of stillbirth and neonatal outcomes at various gestational ages. Pregnancies with unclear chorionicity, monoamnionicity, and twin to twin transfusion syndrome were excluded. Meta-analyses of observational studies and cohorts nested within randomised studies were undertaken. Prospective risk of stillbirth was computed for each study at a given week of gestation and compared with the risk of neonatal death among deliveries in the same week. Gestational age specific differences in risk were estimated for stillbirths and neonatal deaths in monochorionic and dichorionic twin pregnancies after 34 weeks' gestation. RESULTS: 32 studies (29 685 dichorionic, 5486 monochorionic pregnancies) were included. In dichorionic twin pregnancies beyond 34 weeks (15 studies, 17 830 pregnancies), the prospective weekly risk of stillbirths from expectant management and the risk of neonatal death from delivery were balanced at 37 weeks' gestation (risk difference 1.2/1000, 95% confidence interval -1.3 to 3.6; I(2)=0%). Delay in delivery by a week (to 38 weeks) led to an additional 8.8 perinatal deaths per 1000 pregnancies (95% confidence interval 3.6 to 14.0/1000; I(2)=0%) compared with the previous week. In monochorionic pregnancies beyond 34 weeks (13 studies, 2149 pregnancies), there was a trend towards an increase in stillbirths compared with neonatal deaths after 36 weeks, with an additional 2.5 per 1000 perinatal deaths, which was not significant (-12.4 to 17.4/1000; I(2)=0%). The rates of neonatal morbidity showed a consistent reduction with increasing gestational age in monochorionic and dichorionic pregnancies, and admission to the neonatal intensive care unit was the commonest neonatal complication. The actual risk of stillbirth near term might be higher than reported estimates because of the policy of planned delivery in twin pregnancies. CONCLUSIONS: To minimise perinatal deaths, in uncomplicated dichorionic twin pregnancies delivery should be considered at 37 weeks' gestation; in monochorionic pregnancies delivery should be considered at 36 weeks. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014007538.

OBJECTIVE: To assess whether A level grades (achievement) and intelligence (ability) predict doctors' careers. DESIGN: Prospective cohort study with follow up after 20 years by postal questionnaire. SETTING: A UK medical school in London. PARTICIPANTS: 511 doctors who had entered Westminster Medical School as clinical students between 1975 and 1982 were followed up in January 2002. MAIN OUTCOME MEASURES: Time taken to reach different career grades in hospital or general practice, postgraduate qualifications obtained (membership/fellowships, diplomas, higher academic degrees), number of research publications, and measures of stress and burnout related to A level grades and intelligence (result of AH5 intelligence test) at entry to clinical school. General health questionnaire, Maslach burnout inventory, and questionnaire on satisfaction with career at follow up. RESULTS: 47 (9%) doctors were no longer on the Medical Register. They had lower A level grades than those who were still on the register (P < 0.001). A levels also predicted performance in undergraduate training, performance in postregistration house officer posts, and time to achieve membership qualifications (Cox regression, P < 0.001; b=0.376, SE=0.098, exp(b)=1.457). Intelligence did not independently predict dropping off the register, career outcome, or other measures. A levels did not predict diploma or higher academic qualifications, research publications, or stress or burnout. Diplomas, higher academic degrees, and research publications did, however, significantly correlate with personality measures. CONCLUSIONS: Results of achievement tests, in this case A level grades, which are particularly used for selection of students in the United Kingdom, have long term predictive validity for undergraduate and postgraduate careers. In contrast, a test of ability or aptitude (AH5) was of little predictive validity for subsequent medical careers.