Tracking decision-making during architectural design

There is a powerful cocktail of circumstances governing the way decisions are made during the architectural design process of a building project. There is considerable potential for misunderstandings, inappropriate changes, change which give rise to unforeseen difficulties, decisions which are not notified to all interested parties, and many other similar problems. The paper presents research conducted within the frame of the EPSRC funded ADS project aiming at addressing the problems linked with the evolution and changing environment of project information to support better decision-making. The paper presents the conceptual framework as well as the software environment that has been developed to support decision-making during building projects, and reports on work carried out on the application of the approach to the architectural design stage. This decision-tracking environment has been evaluated and validated by professionals and practitioners from industry using several instruments as described in the paper

Atomistic studies of transformation pathways and energetics in plutonium

One of the most challenging problems in understanding the structural phase transformations in Pu is to determine the energetically favored, continuous atomic pathways from one crystal symmetry to another. This problem involves enumerating candidate pathways and studying their energetics to garner insight into instabilities and energy barriers. The purpose of this work is to investigate the energetics of two transformation pathways for the delta to alpha' transformation in Pu that were recently proposed [Lookman et al., Phys. Rev. Lett. 100:145504, 2008] on the basis of symmetry. These pathways require the presence of either an intermediate hexagonal closed-packed (hcp) structure or a simple hexagonal (sh) structure. A subgroup of the parent fcc and the intermediate hexagonal structure, which has trigonal symmetry, facilitates the transformation to the intermediate hcp or sh structure. Phonons then break the translational symmetry from the intermediate hcp or sh structure to the final monoclinic symmetry of the alpha' structure. We perform simulations using the modified embedded atom method (MEAM) for Pu to investigate these candidate pathways. Our main conclusion is that the path via hcp is energetically favored and the volume change for both pathways essentially occurs in the second step of the transformation, i.e. from the intermediate sh or hcp to the monoclinic structure. Our work also highlights the deficiency of the current state-of-the-art MEAM potential in capturing the anisotropy associated with the lower symmetry monoclinic structure.Comment: 12 pages, 5 figures, accepted for publication in Philos. Ma

Room reflections and constancy in speech-like sounds: within-band effects

The experiment asks whether constancy in hearing precedes or follows grouping. Listeners heard speech-like sounds comprising 8 auditory-filter shaped noise-bands that had temporal envelopes corresponding to those arising in these filters when a speech message is played. The „context‟ words in the message were “next you‟ll get _to click on”, into which a “sir” or “stir” test word was inserted. These test words were from an 11-step continuum that was formed by amplitude modulation. Listeners identified the test words appropriately and quite consistently, even though they had the „robotic‟ quality typical of this type of 8-band speech. The speech-like effects of these sounds appears to be a consequence of auditory grouping. Constancy was assessed by comparing the influence of room reflections on the test word across conditions where the context had either the same level of reflections, or where it had a much lower level. Constancy effects were obtained with these 8-band sounds, but only in „matched‟ conditions, where the room reflections were in the same bands in both the context and the test word. This was not the case in a comparison „mismatched‟ condition, and here, no constancy effects were found. It would appear that this type of constancy in hearing precedes the across-channel grouping whose effects are so apparent in these sounds. This result is discussed in terms of the ubiquity of grouping across different levels of representation

High-throughput mapping of protein occupancy identifies functional elements without the restriction of a candidate factor approach

There are a variety of in vivo and in vitro methods to determine the genome-wide specificity of a particular trans-acting factor. However there is an inherent limitation to these candidate approaches. Most biological studies focus on the regulation of particular genes, which are bound by numerous unknown trans-acting factors. Therefore, most biological inquiries would be better addressed by a method that maps all trans-acting factors that bind particular regions rather than identifying all regions bound by a particular trans-acting factor. Here, we present a high-throughput binding assay that returns thousands of unbiased measurements of complex formation on nucleic acid. We applied this method to identify transcriptional complexes that form on DNA regions upstream of genes involved in pluripotency in embryonic stem cells (ES cells) before and after differentiation. The raw binding scores, motif analysis and expression data are used to computationally reconstruct remodeling events returning the identity of the transcription factor(s) most likely to comprise the complex. The most significant remodeling event during ES cell differentiation occurred upstream of the REST gene, a transcriptional repressor that blocks neurogenesis. We also demonstrate how this method can be used to discover RNA elements and discuss applications of screening polymorphisms for allelic differences in binding

High-resolution mucociliary transport measurement in live excised large animal trachea using synchrotron X-ray imaging

Background: The Australian Synchrotron Imaging and Medical Beamline (IMBL) was designed as the world's widest synchrotron X-ray beam, enabling both clinical imaging and therapeutic applications for humans as well as the imaging of large animal models. Our group is developing methods for imaging the airways of newly developed CF animal models that display human-like lung disease, such as the CF pig, and we expect that the IMBL can be utilised to image airways in animals of this size. Methods: This study utilised samples of excised tracheal tissue to assess the feasibility, logistics and protocols required for airway imaging in large animal models such as pigs and sheep at the IMBL. We designed an image processing algorithm to automatically track and quantify the tracheal mucociliary transport (MCT) behaviour of 103 μm diameter high refractive index (HRI) glass bead marker particles deposited onto the surface of freshly-excised normal sheep and pig tracheae, and assessed the effects of airway rehydrating aerosols. Results: We successfully accessed and used scavenged tracheal tissue, identified the minimum bead size that is visible using our chosen imaging setup, verified that MCT could be visualised, and that our automated tracking algorithm could quantify particle motion. The imaging sequences show particles propelled by cilia, against gravity, up the airway surface, within a well-defined range of clearance speeds and with examples of 'clumping' behaviour that is consistent with the in vivo capture and mucus-driven transport of particles. Conclusion: This study demonstrated that the wide beam at the IMBL is suitable for imaging MCT in ex vivo tissue samples. We are now transitioning to in vivo imaging of MCT in live pigs, utilising higher X-ray energies and shorter exposures to minimise motion blur.Martin Donnelley, Kaye S. Morgan, Maged Awadalla, Nigel R. Farrow, Chris Hall and David W. Parson

Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study

$\textbf{Background}$ Psychosis is a common presenting feature in antibody-mediated encephalitis, for which prompt recognition and treatment usually leads to remission. We aimed to investigate whether people with circumscribed schizophrenia-like illnesses have such antibodies—especially antibodies against the N-methyl-D-aspartate receptor (NMDAR)—more commonly than do healthy controls. $\textbf{Methods}$ We recruited patients aged 14–35 years presenting to any of 35 mental health services sites across England with first-episode psychosis, less than 6 weeks of treatment with antipsychotic medication, and a score of 4 or more on at least one selected Positive and Negative Syndrome Scale (PANSS) item. Patients and controls provided venous blood samples. We completed standardised symptom rating scales (PANSS, ACE-III, GAF) at baseline, and tested serum samples for antibodies against NMDAR, LGI1, CASPR2, the GABAA receptor, and the AMPA receptor using live cell-based assays. Treating clinicians assessed outcomes of ICD diagnosis and functioning (GAF) at 6 months. We included healthy controls from the general population, recruited as part of another study in Cambridge, UK. $\textbf{Findings}$ Between Feb 1, 2013, and Aug 31, 2014, we enrolled 228 patients with first-episode psychosis and 105 healthy controls. 20 (9%) of 228 patients had serum antibodies against one or more of the neuronal cell surface antibodies compared with four (4%) of 105 controls (unadjusted odds ratio 2·4, 95% CI 0·8–7·3). These associations remained non-significant when adjusted for current cigarette smoking, alcohol consumption, and illicit drug use. Seven (3%) patients had NMDAR antibodies compared with no controls (p=0·0204). The other antibodies did not differ between groups. Antibody-positive patients had lower PANSS positive, PANSS total, and catatonia scores than did antibody-negative patients. Patients had comparable scores on other PANSS items, ACE-III, and GAF at baseline, with no difference in outcomes at 6 months. $\textbf{Interpretation}$ Some patients with first-episode psychosis had antibodies against NMDAR that might be relevant to their illness, but did not differ from patients without NMDAR antibodies in clinical characteristics. Our study suggests that the only way to detect patients with these potentially pathogenic antibodies is to screen all patients with first-episode psychosis at first presentation.Medical Research Counci

A mixed methods study to evaluate the feasibility of using the Adolescent Diabetes Needs Assessment Tool App in paediatric diabetes care in preparation for a longitudinal cohort study

An evaluation study was carried out to determine the feasibility of integrating the Adolescent Diabetes Needs Assessment Tool (ADNAT) App into UK paediatric diabetes care, to ascertain best practice standards and to determine methodological recommendations for a future cohort study. Methods A non-randomised, cohort, mixed methods study design was used to ensure equality of access to ADNAT for all participants at three sites in the North West of England. Following UK Medical Research Council guidance, the RE-AIM (reach, effectiveness (potential and perceived), adoption, implementation, maintenance) framework was used to guide study objectives and feasibility outcomes. Patients who completed ADNAT (completers) were compared with those who failed to complete (non-completers). Patients’ glycaemic control (HbA1c) was accessed from their clinical data at baseline and at 6 months, alongside their ADNAT scores which were correlated with changes in HbA1c levels. The diabetes teams (respondents) completed a web-based survey and attended focus group interviews. Results Eighty-nine patients were recruited. Withdrawal rates were low at 4.5% (n = 4). Forty-four patients (49.4%) completed ADNAT, leaving 45 (50.6%) non-completers. There were large baseline differences in HbA1c and variable rates of change at 6 months. After adjusting for baseline HbA1C and site in an analysis of covariance, completers had a lower post-ADNAT mean HbA1C level than non-completers at 6 months (-5.42 mmol/mol, 95% CI −11.48, 0.64). Patients’ glycaemic control (HbA1c) at 6 months correlated reasonably well with their ADNAT scores (Spearman’s rho = 0.46). Survey and focus group data showed that ADNAT was judged to be an effective clinical tool by the diabetes teams. Value to patients was perceived by the teams to be linked to parental support, age and previous diabetes education. The combined data triangulated. It served to capture different dimensions which were used to define changes to achieve practice standards and methodological recommendations. Conclusions The combined data showed that ADNAT has the potential to be a clinically viable tool. It has demonstrated the need for a randomised design that is tailored for a ‘hard to reach’ adolescent population. A cluster randomised controlled trial that involves sequential but random rollout of ADNAT over multiple time periods may be the most appropriate and is currently being considered for the larger study

Treatment for hepatorenal syndrome in people with decompensated liver cirrhosis: a network meta‐analysis

Background: Hepatorenal syndrome is defined as renal failure in people with cirrhosis in the absence of other causes. In addition to supportive treatment such as albumin to restore fluid balance, the other potential treatments include systemic vasoconstrictor drugs (such as vasopressin analogues or noradrenaline), renal vasodilator drugs (such as dopamine), transjugular intrahepatic portosystemic shunt (TIPS), and liver support with molecular adsorbent recirculating system (MARS). There is uncertainty over the best treatment regimen for hepatorenal syndrome. Objectives: To compare the benefits and harms of different treatments for hepatorenal syndrome in people with decompensated liver cirrhosis. Search methods: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trial registers until December 2018 to identify randomised clinical trials on hepatorenal syndrome in people with cirrhosis. Selection criteria: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adults with cirrhosis and hepatorenal syndrome. We excluded randomised clinical trials in which participants had previously undergone liver transplantation. Data collection and analysis: Two authors independently identified eligible trials and collected data. The outcomes for this review included mortality, serious adverse events, any adverse events, resolution of hepatorenal syndrome, liver transplantation, and other decompensation events. We performed a network meta‐analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, hazard ratio (HR), and mean difference (MD) with 95% credible intervals (CrI) based on an available‐case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. Main results: We included a total of 25 trials (1263 participants; 12 interventions) in the review. Twenty‐three trials (1185 participants) were included in one or more outcomes. All the trials were at high risk of bias, and all the evidence was of low or very low certainty. The trials included participants with liver cirrhosis of varied aetiologies as well as a mixture of type I hepatorenal syndrome only, type II hepatorenal syndrome only, or people with both type I and type II hepatorenal syndrome. Participant age ranged from 42 to 60 years, and the proportion of females ranged from 5.8% to 61.5% in the trials that reported this information. The follow‐up in the trials ranged from one week to six months. Overall, 59% of participants died during this period and about 35% of participants recovered from hepatorenal syndrome. The most common interventions compared were albumin plus terlipressin, albumin plus noradrenaline, and albumin alone. There was no evidence of a difference in mortality (22 trials; 1153 participants) at maximal follow‐up between the different interventions. None of the trials reported health‐related quality of life. There was no evidence of differences in the proportion of people with serious adverse events (three trials; 428 participants), number of participants with serious adverse events per participant (two trials; 166 participants), proportion of participants with any adverse events (four trials; 402 participants), the proportion of people who underwent liver transplantation at maximal follow‐up (four trials; 342 participants), or other features of decompensation at maximal follow‐up (one trial; 466 participants). Five trials (293 participants) reported number of any adverse events, and five trials (219 participants) reported treatment costs. Albumin plus noradrenaline had fewer numbers of adverse events per participant (rate ratio 0.51, 95% CrI 0.28 to 0.87). Eighteen trials (1047 participants) reported recovery from hepatorenal syndrome (as per definition of hepatorenal syndrome). In terms of recovery from hepatorenal syndrome, in the direct comparisons, albumin plus midodrine plus octreotide and albumin plus octreotide had lower recovery from hepatorenal syndrome than albumin plus terlipressin (HR 0.04; 95% CrI 0.00 to 0.25 and HR 0.26, 95% CrI 0.07 to 0.80 respectively). There was no evidence of differences between the groups in any of the other direct comparisons. In the network meta‐analysis, albumin and albumin plus midodrine plus octreotide had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin. Funding: two trials were funded by pharmaceutical companies; five trials were funded by parties who had no vested interest in the results of the trial; and 18 trials did not report the source of funding. Authors' conclusions: Based on very low‐certainty evidence, there is no evidence of benefit or harm of any of the interventions for hepatorenal syndrome with regards to the following outcomes: all‐cause mortality, serious adverse events (proportion), number of serious adverse events per participant, any adverse events (proportion), liver transplantation, or other decompensation events. Low‐certainty evidence suggests that albumin plus noradrenaline had fewer 'any adverse events per participant' than albumin plus terlipressin. Low‐ or very low‐certainty evidence also found that albumin plus midodrine plus octreotide and albumin alone had lower recovery from hepatorenal syndrome compared with albumin plus terlipressin. Future randomised clinical trials should be adequately powered; employ blinding, avoid post‐randomisation dropouts or planned cross‐overs (or perform an intention‐to‐treat analysis); and report clinically important outcomes such as mortality, health‐related quality of life, adverse events, and recovery from hepatorenal syndrome. Albumin plus noradrenaline and albumin plus terlipressin appear to be the interventions that should be compared in future trials

Induction immunosuppression in adults undergoing liver transplantation: a network meta-analysis

BACKGROUND: Liver transplantation is considered the definitive treatment for people with liver failure. As part of post-liver transplantation management, immunosuppression (suppressing the host immunity) is given to prevent graft rejections. Immunosuppressive drugs can be classified into those that are used for a short period during the beginning phase of immunosuppression (induction immunosuppression) and those that are used over the entire lifetime of the individual (maintenance immunosuppression), because it is widely believed that graft rejections are more common during the first few months after liver transplantation. Some drugs such as glucocorticosteroids may be used for both induction and maintenance immunosuppression because of their multiple modalities of action. There is considerable uncertainty as to whether induction immunosuppression is necessary and if so, the relative efficacy of different immunosuppressive agents. OBJECTIVES: To assess the comparative benefits and harms of different induction immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different induction immunosuppressive regimens according to their safety and efficacy. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until July 2019 to identify randomised clinical trials in adults undergoing liver transplantation. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or status) in adults undergoing liver transplantation. We excluded randomised clinical trials in which participants had multivisceral transplantation and those who already had graft rejections. DATA COLLECTION AND ANALYSIS: We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio (OR), rate ratio, and hazard ratio (HR) with 95% credible intervals (CrIs) based on an available case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance. MAIN RESULTS: We included a total of 25 trials (3271 participants; 8 treatments) in the review. Twenty-three trials (3017 participants) were included in one or more outcomes in the review. The trials that provided the information included people undergoing primary liver transplantation for various indications and excluded those with HIV and those with renal impairment. The follow-up in the trials ranged from three to 76 months, with a median follow-up of 12 months among trials. All except one trial were at high risk of bias, and the overall certainty of evidence was very low. Overall, approximately 7.4% of people who received the standard regimen of glucocorticosteroid induction died and 12.2% developed graft failure. All-cause mortality and graft failure was lower with basiliximab compared with glucocorticosteroid induction: all-cause mortality (HR 0.53, 95% CrI 0.31 to 0.93; network estimate, based on 2 direct comparison trials (131 participants; low-certainty evidence)); and graft failure (HR 0.44, 95% CrI 0.28 to 0.70; direct estimate, based on 1 trial (47 participants; low-certainty evidence)). There was no evidence of differences in all-cause mortality and graft failure between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). There was also no evidence of differences in serious adverse events (proportion), serious adverse events (number), renal failure, any adverse events (proportion), any adverse events (number), liver retransplantation, graft rejections (any), or graft rejections (requiring treatment) between other induction immunosuppressants and glucocorticosteroids in either the direct comparison or the network meta-analysis (very low-certainty evidence). However, because of the wide CrIs, clinically important differences in these outcomes cannot be ruled out. None of the studies reported health-related quality of life. FUNDING: the source of funding for 14 trials was drug companies who would benefit from the results of the study; two trials were funded by neutral organisations who have no vested interests in the results of the study; and the source of funding for the remaining nine trials was unclear. AUTHORS' CONCLUSIONS: Based on low-certainty evidence, basiliximab induction may decrease mortality and graft failure compared to glucocorticosteroids induction in people undergoing liver transplantation. However, there is considerable uncertainty about this finding because this information is based on small trials at high risk of bias. The evidence is uncertain about the effects of different induction immunosuppressants on other clinical outcomes, including graft rejections. Future randomised clinical trials should be adequately powered, employ blinding, avoid post-randomisation dropouts (or perform intention-to-treat analysis), and use clinically important outcomes such as mortality, graft failure, and health-related quality of life