Molecular Dynamics Simulations of Weak Detonations

Detonation of a three-dimensional reactive non-isotropic molecular crystal is modeled using molecular dynamics simulations. The detonation process is initiated by an impulse, followed by the creation of a stable fast reactive shock wave. The terminal shock velocity is independent of the initiation conditions. Further analysis shows supersonic propagation decoupled from the dynamics of the decomposed material left behind the shock front. The dependence of the shock velocity on crystal nonlinear compressibility resembles solitary behavior. These properties categorize the phenomena as a weak detonation. The dependence of the detonation wave on microscopic potential parameters was investigated. An increase in detonation velocity with the reaction exothermicity reaching a saturation value is observed. In all other respects the model crystal exhibits typical properties of a molecular crystal.Comment: 38 pages, 20 figures. Submitted to Physical Review

Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular diseases.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability worldwide, yet ASCVD risk factor control and secondary prevention rates remain low. A fixed-dose combination of blood pressure- and cholesterol-lowering and antiplatelet treatments into a single pill, or polypill, has been proposed as one strategy to reduce the global burden of ASCVD. OBJECTIVES: To determine the effect of fixed-dose combination therapy on all-cause mortality, fatal and non-fatal ASCVD events, and adverse events. We also sought to determine the effect of fixed-dose combination therapy on blood pressure, lipids, adherence, discontinuation rates, health-related quality of life, and costs. SEARCH METHODS: We updated our previous searches in September 2016 of CENTRAL, MEDLINE, Embase, ISI Web of Science, and DARE, HTA, and HEED. We also searched two clinical trials registers in September 2016. We used no language restrictions. SELECTION CRITERIA: We included randomised controlled trials of a fixed-dose combination therapy including at least one blood pressure-lowering and one lipid-lowering component versus usual care, placebo, or an active drug comparator for any treatment duration in adults 18 years old or older, with no restrictions on presence or absence of pre-existing ASCVD. DATA COLLECTION AND ANALYSIS: Three review authors independently selected studies for inclusion and extracted the data for this update. We evaluated risk of bias using the Cochrane 'Risk of bias' assessment tool. We calculated risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI) using fixed-effect models when heterogeneity was low (I2 < 50%) and random-effects models when heterogeneity was high (I2 ≥ 50%). We used the GRADE approach to evaluate the quality of evidence. MAIN RESULTS: In the initial review, we identified nine randomised controlled trials with a total of 7047 participants and four additional trials (n = 2012 participants; mean age range 62 to 63 years; 30% to 37% women) were included in this update. Eight of the 13 trials evaluated the effects of fixed-dose combination (FDC) therapy in populations without prevalent ASCVD, and the median follow-up ranged from six weeks to 23 months. More recent trials were generally larger with longer follow-up and lower risk of bias. The main risk of bias was related to lack of blinding of participants and personnel, which was inherent to the intervention. Compared with the comparator groups (placebo, usual care, or active drug comparator), the effects of the fixed-dose combination treatment on mortality (FDC = 1.0% versus control = 1.0%, RR 1.10, 95% CI 0.64 to 1.89,  I2 = 0%, 5 studies, N = 5300) and fatal and non-fatal ASCVD events (FDC = 4.7% versus control = 3.7%, RR 1.26, 95% CI 0.95 to 1.66, I2 = 0%, 6 studies, N = 4517) were uncertain (low-quality evidence). The low event rates for these outcomes and indirectness of evidence for comparing fixed-dose combination to usual care versus individual drugs suggest that these results should be viewed with caution. Adverse events were common in both the intervention (32%) and comparator (27%) groups, with participants randomised to fixed-dose combination therapy being 16% (RR 1.16, 95% CI 1.09 to 1.25, 11 studies, 6906 participants, moderate-quality evidence) more likely to report an adverse event . The mean differences in systolic blood pressure between the intervention and control arms was -6.34 mmHg (95% CI -9.03 to -3.64, 13 trials, 7638 participants, moderate-quality evidence). The mean differences (95% CI) in total and LDL cholesterol between the intervention and control arms were -0.61 mmol/L (95% CI -0.88 to -0.35, 11 trials, 6565 participants, low-quality evidence) and -0.70 mmol/L (95% CI -0.98 to -0.41, 12 trials, 7153 participants, moderate-quality evidence), respectively. There was a high degree of statistical heterogeneity in comparisons of blood pressure and lipids (I2 ≥ 80% for all) that could not be explained, so these results should be viewed with caution. Fixed-dose combination therapy improved adherence to a multidrug strategy by 44% (26% to 65%) compared with usual care (4 trials, 3835 participants, moderate-quality evidence). AUTHORS' CONCLUSIONS: The effects of fixed-dose combination therapy on all-cause mortality or ASCVD events are uncertain. A limited number of trials reported these outcomes, and the included trials were primarily designed to observe changes in ASCVD risk factor levels rather than clinical events, which may partially explain the observed differences in risk factors that were not translated into differences in clinical outcomes among the included trials. Fixed-dose combination therapy is associated with modest increases in adverse events compared with placebo, active comparator, or usual care but may be associated with improved adherence to a multidrug regimen. Ongoing, longer-term trials of fixed-dose combination therapy will help demonstrate whether short-term changes in risk factors might be maintained and lead to expected differences in clinical events based on these changes

Ward based feeding and swallowing training.

Conference posterTITLE OF PAPER: WARD BASED FEEDING AND SWALLOWING TRAINING KEYWORDS: DYSPHAGIA, EVIDENCE BASE WHY THE STUDY WAS UNDERTAKEN This paper summarises the findings of the Northamptonshire Healthcare (NH) Feeding and Swallowing Training programme initiative. The results of the pilot study for this programme were presented at the Royal College of Speech and Language Therapists Conference in 2012. Speech and Language Therapists (SLTs) in the acute setting spend half of their time involved in providing feeding and swallowing care (Bixley, Blagdon, Dean, Langley & Stanton, 2011). As part of the multidisciplinary team, the overall aim of feeding and swallowing intervention is to help clients to meet their nutritional need. A recent Care Quality Commission (2011) report suggested that 51% of hospital trusts were not achieving this standard. Hospital based policies such as protected mealtimes highlight the importance of feeding within the acute sector. Inter professional guidelines (Boaden, 2006) and the evidence base for dysphagia management (Magnus, 2001) also support the use of specific feeding and swallowing training. However delivering comprehensive training within large hospitals is difficult using classroom based packages. Especially in environments where ward teams are large, staff teams change regularly and releasing staff for off ward training is difficult. The Northamptonshire feeding and swallowing programme was introduced to provide a sustainable swallowing training package that could overcome some of these difficulties, by providing training to nursing staff on the ward HOW THE STUDY WAS DONE The NHSLT team evaluated the impact of their innovative feeding and swallowing project by comparing the results of three ward based measures: B1, B2 and B3. The research was carried out on four acute wards, one after another. It was conducted during the hospital wide, one hour protected lunchtime slot. In each of the wards observational and questionnaire measurements (B1) were taken before implementation of a two week, eight day, training package. After the ward based training had occurred two further evaluations were conducted, one immediately after the training package had been delivered (B2) and one two weeks after the programme had been completed (B3). Observational measures were qualitative and recorded general impressions of the feeding practise on the ward. Questionnaire measurements were both quantitative and qualitative and were designed to identify what ward staff understood about feeding and swallowing difficulties. WHAT WAS FOUND Over the course of the ten month research project, twenty four hours of training was provided for fifty four people, on four different wards. Training was provided to 31 health care assistants, 17 nurses, 3 student nurses and 2 assistants and 2 others .Statistical analysis of the ward based knowledge questionnaires suggested that there was a significant difference between the scores obtained in B1 and B2 and B3 (Kruskal Wallis H (2) = 15.537, p=0.014 with a mean rank of 18.64 for B1, 34.83 for B2 and 37.78 for B3). These findings suggest that the feeding training programme had resulted in a measurable difference in ward staff knowledge and this difference was evident after the training programme had been completed. IMPLICATIONS FOR FUTURE POLICY AND PRACTICE The results of this study suggest that ward based feeding programmes are an effective way to deliver training. This type of training targets people who do not normally attend swallowing training courses because they cannot be released from their work. It also means that training can be individualised to the needs of different wards and staff members. This type of training delivery may be a valuable supplement or alternative to classroom based teaching programmes. • REFERENCES Blagdon, B., Bixley, M., Levis, N., Bird, L., Hood, G. & Murphy, K. (2012). Taking dysphagia management out of the classroom: A ward based feeding and swallowing project. Royal College of Speech and Language Therapists Conference, Driving transformation Using Evidence Based Practice, 52. Bixley, M., Blagdon, B., Dean, M., Langley, J. & Stanton, D. (2011). In search of consensus on aphasia management. Royal College of Speech and Language Therapists Bulletin, October, 18-20. Boaden, E. & Davies, S., Storey, L., & Watkins, C. (2006). Interprofessional Dysphagia Framework. www.uclan.aca.uk/facs/health/nursing/research/groups/stroke Care Quality Commission (2011). Dignity and Nutrition Inspection Programme. Newcastle upon Tyne: Care Quality Commission. Magnus, V. (2001). Dysphagia training for nurses in an acute hospital setting – a pragmatic approach. International Journal of Language and Communication Disorders, 36, 375-378

Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar

Conflict resolution in genomic variant interpretation is a critical step toward improving patient care. Evaluating interpretation discrepancies in copy number variants (CNVs) typically involves assessing overlapping genomic content with focus on genes/regions that may be subject to dosage sensitivity (haploinsufficiency (HI) and/or triplosensitivity (TS)). CNVs containing dosage sensitive genes/regions are generally interpreted as â likely pathogenicâ (LP) or â pathogenicâ (P), and CNVs involving the same known dosage sensitive gene(s) should receive the same clinical interpretation. We compared the Clinical Genome Resource (ClinGen) Dosage Map, a publicly available resource documenting known HI and TS genes/regions, against germline, clinical CNV interpretations within the ClinVar database. We identified 251 CNVs overlapping known dosage sensitive genes/regions but not classified as LP or P; these were sent back to their original submitting laboratories for reâ evaluation. Of 246 CNVs reâ evaluated, an updated clinical classification was warranted in 157 cases (63.8%); no change was made to the current classification in 79 cases (32.1%); and 10 cases (4.1%) resulted in other types of updates to ClinVar records. This effort will add curated interpretation data into the public domain and allow laboratories to focus attention on more complex discrepancies.The ClinGen Dosage Sensitivity (DS) Map provides evidenceâ based assessments of the haploinsufficiency and triplosensitivity of genes/genomic regions. We identified 251 clinical copy number variants (CNVs) in ClinVar that overlapped known DS genes/regions but were not interpreted as â likely pathogenicâ or â pathogenic;â these were sent back to their original laboratories for reâ evaluation. Of the 246 that were reâ evaluated, 63.0% resulted in updated classifications, showing that the ClinGen DS Map can be an effective initial step in CNV classification discrepancy resolution.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146425/1/humu23610_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146425/2/humu23610.pd

Comparing mutation calls in fixed tumour samples between the Affymetrix OncoScan® Array and PCR based next-generation sequencing

Background: The importance of accurate and affordable mutation calling in fixed pathology samples is becoming increasingly important as we move into the era of personalised medicine. The Affymetrix OncoScan® Array platform is designed to produce actionable mutation calls in archival material. Methods: We compared calls made using the OncoScan platform with calls made using a custom designed PCR panel followed by next-generation sequencing (NGS), in order to benchmark the sensitivity and specificity of the OncoScan calls in a large cohort of fixed tumour samples. 392 fixed, clinical samples were sequenced, encompassing 641 PCR regions, 403 putative positive calls and 1528 putative negative calls. Results: A small number of mutations could not be validated, either due to large indels or pseudogenes impairing parts of the NGS pipeline. For the remainder, if calls were filtered according to simple quality metrics, both sensitivity and specificity for the OncoScan platform were over 98%. This applied even to samples with poorer sample quality and lower variant allele frequency (5–10%) than product claims indicated. Conclusions: This benchmarking study will be useful to users and potential users of this platform, who wish to compare technologies or interpret their own results

HIV Drug Resistance Surveillance Using Pooled Pyrosequencing

BACKGROUND: Surveillance for HIV transmitted drug resistance (TDR) is performed using HIV genotype results from individual specimens. Pyrosequencing, through its massive parallel sequencing ability, can analyze large numbers of specimens simultaneously. Instead of using pyrosequencing conventionally, to sequence a population of viruses within an individual, we interrogated a single combined pool of surveillance specimens to demonstrate that it is possible to determine TDR rates in HIV protease from a population of individuals. METHODOLOGY/PRINCIPAL FINDINGS: The protease region from 96 treatment naïve, HIV+ serum specimens was genotyped using standard Sanger sequencing method. The 462 bp protease amplicons from these specimens were pooled in equimolar concentrations and re-sequenced using the GS FLX Titanium system. The nucleotide (NT) and amino acid (AA) differences from the reference sequence, along with TDR mutations, detected by each method were compared. In the protease sequence, there were 212 nucleotide and 81 AA differences found using conventional sequencing and 345 nucleotide and 168 AA differences using pyrosequencing. All nucleotide and amino acid polymorphisms found at frequencies >/=5% in pyrosequencing were detected using both methods with the rates of variation highly correlated. Using Sanger sequencing, two TDR mutations, M46L and I84V, were each detected as mixtures at a frequency of 1.04% (1/96). These same TDR mutations were detected by pyrosequencing with a prevalence of 0.29% and 0.34% respectively. Phylogenetic analysis established that the detected low frequency mutations arose from the same single specimens that were found to contain TDR mutations by Sanger sequencing. Multiple clinical protease DR mutations present at higher frequencies were concordantly identified using both methods. CONCLUSIONS/SIGNIFICANCE: We show that pyrosequencing pooled surveillance specimens can cost-competitively detect protease TDR mutations when compared with conventional methods. With few modifications, the method described here can be used to determine population rates of TDR in both protease and reverse transcriptase. Furthermore, this pooled pyrosequencing technique may be generalizable to other infectious agents where a survey of DR rates is required

Indirect calibration between clinical observers - application to the New York Heart Association functional classification system

<p>Abstract</p> <p>Background</p> <p>Previous studies showed an inter-observer agreement for the NYHA classification of approximately 55%. The aim of this study was to calibrate the New York Heart Association (NYHA) classification system between observers, increasing its reliability.</p> <p>Results</p> <p>Among 1136 community-dwellers in Porto, Portugal, aged ≥ 45 years, 265 reporting breathlessness answered a 4-item questionnaire to characterize symptom severity. The questionnaire was administered by 7 physicians who also classified the subject's functional capacity according to NYHA. Each subject was assessed by one physician. We calibrated NYHA classifications by the concurrent method, using 1-parameter logistic graded response model. Discrepancies between observers were assessed by differences in ability thresholds between NYHA classes I-II and II-III. The ability estimated by the model was used to predict the NYHA classification for each observer.</p> <p>Estimates of the first and second thresholds for each observer ranged from -1.92 to 0.46 and from 1.42 to 2.30, respectively. The agreement between estimated ability and the observers' NYHA classification was 88% (kappa = 0.61).</p> <p>Conclusions</p> <p>The study objectively indicates the main reason why several studies have reported low inter-observer is the existence of discrepant thresholds between observers in the definition of NYHA classes. The concurrent method can be used to minimize the reliability problem of NYHA classification.</p

CEACAM1 and MICA as novel serum biomarkers in patients with acute and recurrent pericarditis

BACKGROUND: The immune response plays a significant role in pericarditis, but the mechanisms of disease are poorly defined. Further, efficient monitoring and predictive clinical tools are unavailable. Carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is an immune-inhibitory protein, while MHC class I chain related protein A (MICA) and B (MICB) have an immune-stimulating function. METHODS AND RESULTS: Serum CEACAM1, MICA and MICB concentrations were measured by ELISA in ~50 subjects of each group: acute pericarditis (AP), recurrent pericarditis (RP) and lupus (SLE) patients, metastatic melanoma patients as well as healthy donors. Serum CEACAM1 was dramatically elevated in AP and RP patients, but not in SLE patients, and displayed a highly accurate profile in ROC curve analyses. MICA and MICB were elevated in some pericarditis patients. All markers were enhanced in metastatic melanoma patients irrespective of neoplastic pericardial involvement. Etiology-guided analysis of RP patients showed that very low MICA levels were associated with idiopathic RP, while high MICA was associated with autoimmune and post-operative RP. Importantly, MICA was significantly associated with recurrences, independently of other potentially confounding parameters such as age, time of follow up or treatment modality. CONCLUSIONS: Here we report for the first time on CEACAM1 as a potentially novel biomarker for pericarditis, as well as on MICA as an innovative prognostic marker in these patients. Determination of the roles of these immune factors, as well as their diagnostic and prognostic values should be determined in future prospective studies

Pretreatment with corticosteroids attenuates the efficacy of colchicine in preventing recurrent pericarditis: A multi-centre all-case analysis

Aims Effective prevention of recurrent pericarditis remains an important yet elusive goal. Corticosteroid therapy often needs to be continued for a prolonged period and causes severe side effects. We performed a multi-centre all-case analysis to investigate the efficacy of colchicine in preventing subsequent relapses of pericarditis, and addressed the hypothesis that pretreatment with corticosteroids may attenuate the beneficial effect of colchicine. Methods and results One hundred and forty published and unpublished cases of patients treated with colchicine after at least two relapses of pericarditis were aggregated from European centres. Of those 119 were included in the study group. Only 18% of the patients had relapses under colchicine therapy, and 30% after its discontinuation. There were significantly more relapses among mate patients after colchicine treatment (36 vs. 17%, P = 0.046), and those with previous corticosteroid treatment (43 vs. 13%, P = 0.02). Multivariate logistic regression analysis identified previous corticosteroid therapy (OR 6.68, 95% Cl: 1.65-27.02) and mate gender (OR 4.20, 95% Cl: 1.16-15.21) as independent risk factors for recurrence following colchicine therapy. Conclusion Treatment with colchicine is highly effective in preventing recurrent pericarditis, white pretreatment with corticosteroids exacerbates and extends the course of recurrent pericarditis

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure