Showing papers by "Guy's and St Thomas' NHS Foundation Trust published in 2012"

Acute respiratory distress syndrome: the Berlin Definition.

Abstract: The acute respiratory distress syndrome (ARDS) was defined in 1994 by the American-European Consensus Conference (AECC); since then, issues regarding the reliability and validity of this definition have emerged. Using a consensus process, a panel of experts convened in 2011 (an initiative of the European Society of Intensive Care Medicine endorsed by the American Thoracic Society and the Society of Critical Care Medicine) developed the Berlin Definition, focusing on feasibility, reliability, validity, and objective evaluation of its performance. A draft definition proposed 3 mutually exclusive categories of ARDS based on degree of hypoxemia: mild (200 mm Hg < PaO2/FIO2 ≤ 300 mm Hg), moderate (100 mm Hg < PaO2/FIO2 ≤ 200 mm Hg), and severe (PaO2/FIO2 ≤ 100 mm Hg) and 4 ancillary variables for severe ARDS: radiographic severity, respiratory system compliance (≤40 mL/cm H2O), positive end-expiratory pressure (≥10 cm H2O), and corrected expired volume per minute (≥10 L/min). The draft Berlin Definition was empirically evaluated using patient-level meta-analysis of 4188 patients with ARDS from 4 multicenter clinical data sets and 269 patients with ARDS from 3 single-center data sets containing physiologic information. The 4 ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition. Using the Berlin Definition, stages of mild, moderate, and severe ARDS were associated with increased mortality (27%; 95% CI, 24%-30%; 32%; 95% CI, 29%-34%; and 45%; 95% CI, 42%-48%, respectively; P < .001) and increased median duration of mechanical ventilation in survivors (5 days; interquartile [IQR], 2-11; 7 days; IQR, 4-14; and 9 days; IQR, 5-17, respectively; P < .001). Compared with the AECC definition, the final Berlin Definition had better predictive validity for mortality, with an area under the receiver operating curve of 0.577 (95% CI, 0.561-0.593) vs 0.536 (95% CI, 0.520-0.553; P < .001). This updated and revised Berlin Definition for ARDS addresses a number of the limitations of the AECC definition. The approach of combining consensus discussions with empirical evaluation may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions and to better inform clinical care, research, and health services planning.

The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups

Abstract: The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in 40% of genes, with the landscape dominated by cisand trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Abstract: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

The landscape of cancer genes and mutational processes in breast cancer

Abstract: All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.

The Berlin definition of ARDS: An expanded rationale, justification, and supplementary material

Abstract: Our objective was to revise the definition of acute respiratory distress syndrome (ARDS) using a conceptual model incorporating reliability and validity, and a novel iterative approach with formal evaluation of the definition. The European Society of Intensive Care Medicine identified three chairs with broad expertise in ARDS who selected the participants and created the agenda. After 2 days of consensus discussions a draft definition was developed, which then underwent empiric evaluation followed by consensus revision. The Berlin Definition of ARDS maintains a link to prior definitions with diagnostic criteria of timing, chest imaging, origin of edema, and hypoxemia. Patients may have ARDS if the onset is within 1 week of a known clinical insult or new/worsening respiratory symptoms. For the bilateral opacities on chest radiograph criterion, a reference set of chest radiographs has been developed to enhance inter-observer reliability. The pulmonary artery wedge pressure criterion for hydrostatic edema was removed, and illustrative vignettes were created to guide judgments about the primary cause of respiratory failure. If no risk factor for ARDS is apparent, however, objective evaluation (e.g., echocardiography) is required to help rule out hydrostatic edema. A minimum level of positive end-expiratory pressure and mutually exclusive PaO2/FiO2 thresholds were chosen for the different levels of ARDS severity (mild, moderate, severe) to better categorize patients with different outcomes and potential responses to therapy. This panel addressed some of the limitations of the prior ARDS definition by incorporating current data, physiologic concepts, and clinical trials results to develop the Berlin definition, which should facilitate case recognition and better match treatment options to severity in both research trials and clinical practice.

Assessment of tumor heterogeneity: an emerging imaging tool for clinical practice?

Abstract: Tumor spatial heterogeneity is an important prognostic factor, which may be reflected in medical images Image texture analysis is an approach of quantifying heterogeneity that may not be appreciated by the naked eye. Different methods can be applied including statistical-, model-, and transform-based methods. Early evidence suggests that texture analysis has the potential to augment diagnosis and characterization as well as improve tumor staging and therapy response assessment in oncological practice. This review provides an overview of the application of texture analysis with different imaging modalities, CT, MRI, and PET, to date and describes the technical challenges that have limited its widespread clinical implementation so far. With further efforts to refine its application, image texture analysis has the potential to develop into a valuable clinical tool for oncologic imaging. • Tumor spatial heterogeneity is an important prognostic factor. • Image texture analysis is an approach of quantifying heterogeneity. • Different methods can be applied, including statistical-, model-, and transform-based methods. • Texture analysis could improve the diagnosis, tumor staging, and therapy response assessment.

Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature

Abstract: Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutieres syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.

Frailty in the older surgical patient: a review

Abstract: The rate of surgical procedures in the older population is rising. Despite surgical, anaesthetic and medical advances, older surgical patients continue to suffer from adverse postoperative outcomes. Comorbidities and reduction in physiological reserve are consistently identified as major predictors of poor postoperative outcome in this population. Frailty can be defined as a lack of physiological reserve seen across multiple organ systems and is an independent predictor of mortality, morbidity and institutionalisation after surgery. Despite this identification of frailty as a significant predictor of adverse postoperative outcome, there is not yet a consensus on the definition of frailty or how best to assess and diagnose it. This review describes our current definitions of frailty and discusses the available methods of assessing frailty, the impact on the older surgical population and the emerging potential for modification of this important syndrome.

Fermentable Carbohydrate Restriction Reduces Luminal Bifidobacteria and Gastrointestinal Symptoms in Patients with Irritable Bowel Syndrome

Abstract: Preliminary studies indicate that dietary restriction of fermentable short-chain carbohydrates improves symptoms in irritable bowel syndrome (IBS). Prebiotic fructo-oligosaccharides and galacto-oligosaccharides stimulate colonic bifidobacteria. However, the effect of restricting fermentable short-chain carbohydrates on the gastrointestinal (GI) microbiota has never been examined. This randomized controlled trial aimed to investigate the effects of fermentable carbohydrate restriction on luminal microbiota, SCFA, and GI symptoms in patients with IBS. Patients with IBS were randomized to the intervention diet or habitual diet for 4 wk. The incidence and severity of symptoms and stool output were recorded for 7 d at baseline and follow-up. A stool sample was collected and analyzed for bacterial groups using fluorescent in situ hybridization. Of 41 patients randomized, 6 were withdrawn. At follow-up, there was lower intake of total short-chain fermentable carbohydrates in the intervention group compared with controls (P = 0.001). The total luminal bacteria at follow-up did not differ between groups; however, there were lower concentrations (P < 0.001) and proportions (P < 0.001) of bifidobacteria in the intervention group compared with controls when adjusted for baseline. In the intention-to-treat analysis, more patients in the intervention group reported adequate control of symptoms (13/19, 68%) compared with controls (5/22, 23%; P = 0.005). This randomized controlled trial demonstrated a reduction in concentration and proportion of luminal bifidobacteria after 4 wk of fermentable carbohydrate restriction. Although the intervention was effective in managing IBS symptoms, the implications of its effect on the GI microbiota are still to be determined.

Severe respiratory illness caused by a novel coronavirus, in a patient transferred to the United Kingdom from the Middle East, September 2012.

Abstract: Coronaviruses have the potential to cause severe transmissible human disease, as demonstrated by the severe acute respiratory syndrome (SARS) outbreak of 2003. We describe here the clinical and virological features of a novel coronavirus infection causing severe respiratory illness in a patient transferred to London, United Kingdom, from the Gulf region of the Middle East.

Breast conserving therapy versus mastectomy for stage I–II breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomised trial

Abstract: Summary Background The EORTC 10801 trial compared breast-conserving therapy (BCT) with modified radical mastectomy (MRM) in patients with tumours 5 cm or smaller and axillary node negative or positive disease. Compared with BCT, MRM resulted in better local control, but did not affect overall survival or time to distant metastases. We report 20-year follow-up results. Methods The EORTC 10801 trial was open for accrual between 1980 and 1986 in eight centres in the UK, the Netherlands, Belgium, and South Africa. 448 patients were randomised to BCT and 420 to MRM. Randomisation was done centrally, stratifying patients by institute, carcinoma stage (I or II), and menopausal status. BCT comprised of lumpectomy and complete axillary clearance, followed by breast radiotherapy and a tumour-bed boost. The primary endpoint was time to distant metastasis. This analysis was done on all eligible patients, as they were randomised. Findings After a median follow-up of 22·1 years (IQR 18·5–23·8), 175 patients (42%) had distant metastases in the MRM group versus 207 (46%) in the BCT group. Furthermore, 506 patients (58%) died (232 [55%] in the MRM group and 274 [61%] in the BCT group). No significant difference was observed between BCT and MRM for time to distant metastases (hazard ratio 1·13, 95% CI 0·92–1·38; p=0·23) or for time to death (1·11, 0·94–1·33; 0·23). Cumulative incidence of distant metastases at 20 years was 42·6% (95% CI 37·8–47·5) in the MRM group and 46·9% (42·2–51·6) in the BCT group. 20-year overall survival was estimated to be 44·5% (95% CI 39·3–49·5) in the MRM group and 39·1% (34·4–43·9) in the BCT group. There was no difference between the groups in time to distant metastases or overall survival by age (time to distant metastases: vs ≥50 years 1·16 [0·90–1·50]; overall survival vs ≥50 years 1·10 [0·89–1·37]). Interpretation BCT, including radiotherapy, offered as standard care to patients with early breast cancer seems to be justified, since long-term follow-up in this trial showed similar survival to that after mastectomy. Funding European Organisation for Research and Treatment of Cancer (EORTC).

Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer.

Abstract: The use of neoadjuvant systemic therapy (NST) for the treatment of primary breast cancer has constantly increased, especially in trials of new therapeutic regimens. In the 1980 s, NST was shown to substantially improve breast-conserving surgery rates and was first typically used for patients with inoperable locally advanced or inflammatory breast cancer. Investigators have since also used NST as an in vivo test for chemosensitivity by assessing pathologic complete response. Today, by using pathologic response and other biomarkers as intermediate end points, results from trials of new regimens and therapies that use NST are aimed to precede and anticipate the results from larger adjuvant trials. In 2003, a panel of representatives from various breast cancer clinical research groups was first convened in Biedenkopf to formulate recommendations on the use of NST. The obtained consensus was updated in two subsequent meetings in 2004 and 2006. The most recent conference on recommendations on the use of NST took place in 2010 and forms the basis of this report.

Update on risk factors for food allergy.

Abstract: Despite efforts to prevent food allergy (FA) in children, IgE-mediated FAs are increasing in westernized countries. Previous preventive strategies, such as prolonged exclusive breast-feeding and delayed weaning onto solid foods, have recently been called into question. The present review considers possible risk factors and theories for the development of FA. An alternative hypothesis is proposed, suggesting that early cutaneous exposure to food protein through a disrupted skin barrier leads to allergic sensitization and that early oral exposure to food allergen induces tolerance. Novel interventional strategies to prevent the development of FA are also discussed.

Bonsai Trees in Your Head: How the Pavlovian System Sculpts Goal-Directed Choices by Pruning Decision Trees

Abstract: When planning a series of actions, it is usually infeasible to consider all potential future sequences; instead, one must prune the decision tree. Provably optimal pruning is, however, still computationally ruinous and the specific approximations humans employ remain unknown. We designed a new sequential reinforcement-based task and showed that human subjects adopted a simple pruning strategy: during mental evaluation of a sequence of choices, they curtailed any further evaluation of a sequence as soon as they encountered a large loss. This pruning strategy was Pavlovian: it was reflexively evoked by large losses and persisted even when overwhelmingly counterproductive. It was also evident above and beyond loss aversion. We found that the tendency towards Pavlovian pruning was selectively predicted by the degree to which subjects exhibited sub-clinical mood disturbance, in accordance with theories that ascribe Pavlovian behavioural inhibition, via serotonin, a role in mood disorders. We conclude that Pavlovian behavioural inhibition shapes highly flexible, goal-directed choices in a manner that may be important for theories of decision-making in mood disorders.

Individual common variants exert weak effects on the risk for autism spectrum disorders.

Abstract: While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Lifestyle interventions for overweight and obese pregnant women to improve pregnancy outcome: systematic review and meta-analysis

Abstract: Overweight and obesity pose a big challenge to pregnancy as they are associated with adverse maternal and perinatal outcome. Evidence of lifestyle intervention resulting in improved pregnancy outcome is conflicting. Hence the objective of this study is to determine the efficacy of antenatal dietary, activity, behaviour or lifestyle interventions in overweight and obese pregnant women to improve maternal and perinatal outcomes. A systematic review and meta-analyses of randomised and non-randomised clinical trials following prior registration (CRD420111122 http://www.crd.york.ac.uk/PROSPERO ) and PRISMA guidelines was employed. A search of the Cochrane Library, EMBASE, MEDLINE, CINAHL, Maternity and Infant care and eight other databases for studies published prior to January 2012 was undertaken. Electronic literature searches, study selection, methodology and quality appraisal were performed independently by two authors. Methodological quality of the studies was assessed according to Cochrane risk of bias tool. All appropriate randomised and non-randomised clinical trials were included while exclusions consisted of interventions in pregnant women who were not overweight or obese, had pre-existing diabetes or polycystic ovarian syndrome, and systematic reviews. Maternal outcome measures, including maternal gestational weight gain, gestational diabetes and Caesarean section, were documented. Fetal outcomes, including large for gestational age and macrosomia (birth weight > 4 kg), were also documented. Thirteen randomised and six non-randomised clinical trials were identified and included in the meta-analysis. The evidence suggests antenatal dietary and lifestyle intervention in obese pregnant women reduces maternal pregnancy weight gain (10 randomised clinical trials; n = 1228; -2.21 kg (95% confidence interval -2.86 kg to -1.59 kg)) and a trend towards a reduction in the prevalence of gestational diabetes (six randomised clinical trials; n = 1,011; odds ratio 0.80 (95% confidence interval 0.58 to 1.10)). There were no clear differences reported for other outcomes such as Caesarean delivery, large for gestational age, birth weight or macrosomia. All available studies were assessed to be of low to medium quality. Antenatal lifestyle intervention is associated with restricted gestational weight gain and a trend towards a reduced prevalence of gestational diabetes in the overweight and obese population. These findings need to be interpreted with caution as the available studies were of poor to medium quality.

Myeloproliferative Neoplasm (MPN) Symptom Assessment Form Total Symptom Score: Prospective International Assessment of an Abbreviated Symptom Burden Scoring System Among Patients With MPNs

Abstract: Purpose Myeloproliferative neoplasm (MPN) symptoms are troublesome to patients, and alleviation of this burden represents a paramount treatment objective in the development of MPN-directed therapies. We aimed to assess the utility of an abbreviated symptom score for the most pertinent and representative MPN symptoms for subsequent serial use in assessing response to therapy. Patients and Methods The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS) was calculated as the mean score for 10 items from two previously validated scoring systems. Questions focus on fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Results MPN-SAF TSS was calculable for 1,408 of 1,433 patients with MPNs who had a mean score of 21.2 (standard deviation [SD], 16.3). MPN-SAF TSS results significantly differed among MPN disease subtypes (P < .001), with a mean of 18.7 (SD, 15.3), 21.8 (SD, 16.3), and 25.3 (SD, 17.2) f...

Quadriceps wasting and physical inactivity in patients with COPD

Abstract: Background: respiratory tract injury is the major cause of morbimortality in Cystic fibrosis (CF) patients. Gastroesophageal reflux disease (GORD) might contribute to lung function decline and progression of pulmonary disease in them. Despite the increased gastroesophageal reflux (GOR) symptoms in CF patients, its prevalence and association with gastric aspiration and respiratory impact are not well characterized. Aim: assess prevalence of GORD in CF adults, and study possible associations with genotypes, specific colonizations, lung disease severity and GORD treatment. Methods: retrospective study conducted in 23 CF patients attended at Pneumology Unit of Coimbra University Hospital, through a direct questionnaire (adapted from Mayo GER Questionnaire) concerning GERD symptoms in previous 12 months. Results: Of 23 studied patients, mean age 30 ± 7,6, 70% female; DF508 homozygote was the most frequent genotype. P. Aeruginosa and S.Aureus organisms were the most prevalent pulmonary colonization. In 48% lung function was severely depressed. 21 patients (91%) experienced at least one GERD symptom, 12 (57%) referred the occurrence of 5 or more. Concerning lung function severity, we established significant statistical difference between groups under treatment versus untreated group, being the first the one that presented the worst CVF values (p=0,032). Conclusions: despite the limited evidence that GERD adversely impacts lung function,the possibility that acid suppression improves the outcome of this patients, leads to a strong recommendation for aggressive treatment of GERD. However, according to our study, acid suppression treatment might be insufficient, turning it in a contemporary and scientifically important subject.

The ESHRE PGD Consortium: 10 years of data collection

Abstract: Background Since it was established in 1997, the ESHRE PGD Consortium has been collecting data from international preimplantation genetic diagnosis (PGD) centres. Ten papers have been published, including data from January 1997 to December 2007. Methods The data collection originally used a hard-copy format, then an excel database and finally a FileMaker Pro database. The indications are divided into five categories: PGD for chromosome abnormalities, sexing for X-linked disease, PGD for single gene defects, preimplantation genetic screening (PGS) and PGD for social sexing. The main end-points are pregnancy outcome and follow-up of deliveries. Results In data collection I, 16 centres contributed data, which increased to 57 centres by data X (average of 39 centres per data collection). These centres contributed data on over 27 000 cycles that reached oocyte retrieval. Of these cycles, 61% were for aneuploidy screening, 17% for single gene disorders, 16% for chromosomal abnormalities, 4% for sexing of X-linked disease and 2% for social sexing. Cumulatively, 5187 clinical pregnancies gave rise to 4140 deliveries and 5135 newborns (singletons: 3182, twins: 921, triplets: 37). Conclusions In this paper, we present an overview of the first 10 years of PGD data, highlighting trends. These include the introduction of laser-assisted biopsy, an increase in polar body and trophectoderm biopsy, new strategies, methodologies and technologies for diagnosis, including recently arrays, and the more frequent use of freezing biopsied embryos. The Consortium data reports represent a valuable resource for information about the practice of PGD.

Generalized Arterial Calcification of Infancy and Pseudoxanthoma Elasticum Can Be Caused by Mutations in Either ENPP1 or ABCC6

Abstract: Spontaneous pathologic arterial calcifications in childhood can occur in generalized arterial calcification of infancy (GACI) or in pseudoxanthoma elasticum (PXE). GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. However, the genetic basis in subsets of both disease phenotypes remains elusive. We hypothesized that GACI and PXE are in a closely related spectrum of disease. We used a standardized questionnaire to retrospectively evaluate the phenotype of 92 probands with a clinical history of GACI. We obtained the ENPP1 genotype by conventional sequencing. In those patients with less than two disease-causing ENPP1 mutations, we sequenced ABCC6. We observed that three GACI patients who carried biallelic ENPP1 mutations developed typical signs of PXE between 5 and 8 years of age; these signs included angioid streaks and pseudoxanthomatous skin lesions. In 28 patients, no disease-causing ENPP1 mutation was found. In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). Thus, ABCC6 mutations account for a significant subset of GACI patients, and ENPP1 mutations can also be associated with PXE lesions in school-aged children. Based on the considerable overlap of genotype and phenotype of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than two distinct disorders. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways in tissues beyond the artery.

Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients

Abstract: Purpose Colloids are administered to more patients than crystalloids, although recent evidence suggests that colloids may possibly be harmful in some patients. The European Society of Intensive Care Medicine therefore assembled a task force to compile consensus recommendations based on the current best evidence for the safety and efficacy of the currently most frequently used colloids—hydroxyethyl starches (HES), gelatins and human albumin.

Cognitive behavioural treatment for women who have menopausal symptoms after breast cancer treatment (MENOS 1): a randomised controlled trial

Abstract: Summary Background Hot flushes and night sweats (HFNS) affect 65–85% of women after breast cancer treatment; they are distressing, causing sleep problems and decreased quality of life. Hormone replacement therapy is often either undesirable or contraindicated. Safe, effective non-hormonal treatments are needed. We investigated whether cognitive behavioural therapy (CBT) can help breast cancer survivors to effectively manage HFNS. Methods In this randomised controlled trial, we recruited women from breast clinics in London, UK, who had problematic HFNS (minimum ten problematic episodes a week) after breast-cancer treatment. Participants were randomly allocated to receive either usual care or usual care plus group CBT (1:1). Randomisation was done in blocks of 12–20 participants, stratifying by age (younger than 50 years, 50 years or older), and was done with a computer-generated sequence. The trial statistician and researchers collecting outcome measures were masked to group allocation. Group CBT comprised one 90 min session a week for 6 weeks, and included psycho-education, paced breathing, and cognitive and behavioural strategies to manage HFNS. Assessments were done at baseline, 9 weeks, and 26 weeks after randomisation. The primary outcome was the adjusted mean difference in HFNS problem rating (1–10) between CBT and usual care groups at 9 weeks after randomisation. Analysis of the primary endpoint was done by modified intention to treat. The trial is registered, ISRCTN13771934, and was closed March 15, 2011. Findings Between May 5, 2009, and Aug 27, 2010, 96 women were randomly allocated to group CBT (n=47) or usual care (n=49). Group CBT significantly reduced HFNS problem rating at 9 weeks after randomisation compared with usual care (mean difference −1·67, 95% CI −2·43 to −0·91; p Interpretation Group CBT seems to be a safe and effective treatment for women who have problematic HFNS after breast cancer treatment with additional benefits to mood, sleep, and quality of life. The treatment could be incorporated into breast cancer survivorship programmes and delivered by trained breast cancer nurses. Funding Cancer Research UK.

Inter-study reproducibility of cardiovascular magnetic resonance myocardial feature tracking

Abstract: Background: Cardiovascular magnetic resonance myocardial feature tracking (CMR-FT) is a recently described method of post processing routine cine acquisitions which aims to provide quantitative measurements of circumferentially and radially directed ventricular wall strain. Inter-study reproducibility is important for serial assessments however has not been defined for CMR-FT. Methods: 16 healthy volunteers were imaged 3 times within a single day. The first examination was performed at 0900 after fasting and was immediately followed by the second. The third, non-fasting scan, was performed at 1400. CMR-FT measures of segmental and global strain parameters were calculated. Left ventricular (LV) circumferential and radial strain were determined in the short axis orientation (EccSAX and ErrSAX respectively). LV and right ventricular longitudinal strain and LV radial strain were determined from the 4-chamber orientation (EllLV, EllRV, and ErrLAX respectively). LV volumes and function were also analysed. Inter-study reproducibility and study sample sizes required to demonstrate 5% changes in absolute strain were determined by comparison of the first and second exams. The third exam was used to determine whether diurnal variation affected reproducibility. Results: CMR-FT strain analysis inter-study reproducibility was variable. Global strain assessment was more reproducible than segmental analysis. Overall EccSAX was the most reproducible measure of strain: coefficient of variation (CV) 38% and 20.3% and intraclass correlation coefficient (ICC) 0.68 (0.55-0.78) and 0.7 (0.32-0.89) for segmental and global analysis respectively. The least reproducible segmental measure was EllRV: CV 60% and ICC 0.56 (0.41-0.69) whilst the least reproducible global measure was ErrLAX: CV 33.3% and ICC 0.44 (0–0.77). Variable reproducibility was also reflected in the calculated sample sizes, which ranged from 11 (global EccSAX) to 156 subjects (segmental EllRV). The reproducibility of LV volumes and function was excellent. There was no diurnal variation in global strain or LV volumetric measurements. Conclusions: Inter-study reproducibility of CMR-FT varied between different parameters, as summarized above and was better for global rather than segmental analysis. It was not measurably affected by diurnal variation. CMR-FT may have potential for quantitative wall motion analysis with applications in patient management and clinical trials. However, inter-study reproducibility was relatively poor for segmental and long axis analyses of strain, which have yet to be validated, and may benefit from further development.

The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement

Abstract: Tuberculosis (TB) is a possible complication of solid organ and hematopoietic stem cell transplantation. The identification of candidates for preventive chemotherapy is an effective intervention to protect transplant recipients with latent infection with Mycobacterium tuberculosis from progressing to active disease. The best available proxy for diagnosing latent infection with M. tuberculosis is the identification of an adaptive immune response by the tuberculin skin test or an interferon-γ based ex vivo assay. Risk assessment in transplant recipients for the development of TB depends on, among other factors, the locally expected underlying prevalence of infection with M. tuberculosis in the target population. In areas of high prevalence, preventive chemotherapy for all transplant recipients may be justified without immunodiagnostic testing while in areas of medium and low prevalence, preventive chemotherapy should only be offered to candidates with positive M. tuberculosis-specific immune responses. The diagnosis of TB in transplant recipients can be challenging. Treatment of TB is often difficult due to substantial interactions between anti-TB drugs and immunosuppressive medications. This management guideline summarises current knowledge on the prevention, diagnosis and treatment of TB related to solid organ and hematopoietic stem cell transplantation and provides an expert consensus on questions where scientific evidence is still lacking.

Volume targeted versus pressure support non-invasive ventilation in patients with super obesity and chronic respiratory failure: a randomised controlled trial

Abstract: Introduction Automatic titration modes of non-invasive ventilation, including average volume assured pressure support (AVAPS), are hybrid technologies that target a set volume by automated adjustment of pressure support (PS). These automated modes could offer potential advantages over fixed level PS, in particular, in patients who are super obese. Methods Consecutive patients with obesity hypoventilation syndrome were enrolled in a two-centre prospective single-blind randomised controlled trial of AVAPS versus fixed-level PS using a strict protocolised setup. Measurements The primary outcome was change in daytime arterial PCO2 (PaCO2) at 3 months. Body composition, physical activity (7-day actigraphy) and health-related quality of life (severe respiratory insufficiency questionnaire, SRI) were secondary outcome measures. Results 50 patients (body mass index 5067 kg/m 2 ; 55611 years; 53% men) were enrolled with a mean PaCO2 of 6.960.8 kPa and SRI of 53617. 46 patients (23 AVAPS and 23 PS) completed the trial. At 3 months, improvements in PaCO2 were observed in both groups (AVAPS Δ0.6 kPa, 95% CI 0.2 to 1.1, p<0.01 vs PS Δ0.6 kPa, 95% CI 0.1 to 1.1, p¼0.02) but no betweengroup difference (Δ� 0.1 kPa, 95% CI � 0.7 to 0.6, p¼0.87). SRI also improved in both groups (AVAPS Δ11, 95% CI 6 to 17, p<0.001 vs PS Δ7, 95% CI 1 to 12, p¼0.02; between groups Δ5, 95% CI � 3 to 12, p¼0.21). Secondary analysis of both groups combined showed improvements in daytime physical activity that correlated with reduction in fat mass (r¼0.48; p¼0.01). Conclusion The study demonstrated no differences between automated AVAPS mode and fixed-level PS mode using a strict protocolised setup in patients who were super obese. The data suggest that the management of sleep-disordered breathing may enhance daytime activity and promote weight loss in super-obese patients. Trial registration details available at http:// www.controlled-trials.com/ISRCTN63940700