Characterization of dispersive and distributive mixing in a co-rotating twin-screw compounding extruder

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.A new design of closely intermeshing co-rotating twin-screw compounding extruder, developed at Brunel University, has been utilized in the development of quantitative techniques for characterization of dispersive and distributive mixing in thermoplastics materials prepared by extrusion compounding. Image analysis procedures were used to quantify mixing of polypropylene composites containing calcium carbonate filler using reflected light microscopy on polished surfaces, and transmitted light microscopy of microtomed pigmented sections. Stereological statistics have been applied to raw sample data; results are discussed in relation to mechanistic phenomena influencing particle agglomeration, dispersion and distribution of fillers in thermoplastics. Dispersive or intensive mixing determined from calcium carbonate filled polypropylene specimens showed that processing parameters had no significant influence except when filler was added midway along the machine although the melting zone was highlighted as having a marked effect on the rate of filler dispersion. Premixing of filler and polymer introduced additional agglomeration into the filler. A series of model experiments were undertaken to assess the influence of specific parameters. In this context moisture content emerged as having the single most important effect on filler compaction. Distributive or extensive mixing of carbon black pigmented specimens was very significantly affected by the presence of segmented disc elements at the end of the screws. These elements produced more than a six-fold increase in distributive mixing in the extrudate.Polymer Engineering Directorate of the Science and Engineering Research Council; Croxton and Garry Ltd

A Comparative Study of Forecasting Techniques for the US Air Force Medical Material Management System

A computer simulation experiment was conducted to evaluate and compare five individual forecasting models across nine different demand patterns. The models were based on the Medical Materiel Management System used by the US Air Force hospitals. Results indicated the best model varied depending on the demand pattern, the safety stock level, the noise level of the demand pattern, and the measure of forecast error. Across all demand patterns, exponential smoothing and 12-month moving average were best for the short term forecast used by the system, regardless of noise level in the demand patterns. Analysis of models within a single demand pattern showed, in most cases, several models as ranking equally well. When overall system requirements were considered, the exponential smoothing method was by far the best choice

Dirhodium-catalyzed C-H arene amination using hydroxylamines

Primary and N-alkyl arylamine motifs are key functional groups in pharmaceuticals, agrochemicals, and functional materials, as well as in bioactive natural products. However, there is a dearth of generally applicable methods for the direct replacement of aryl hydrogens with NH2/NH(alkyl) moieties. Here, we present a mild dirhodium-catalyzed C-H amination for conversion of structurally diverse monocyclic and fused aromatics to the corresponding primary and N-alkyl arylamines using NH2/NH(alkyl)-O-(sulfonyl)hydroxylamines as aminating agents; the relatively weak RSO2O-N bond functions as an internal oxidant. The methodology is operationally simple, scalable, and fast at or below ambient temperature, furnishing arylamines in moderate-to-good yields and with good regioselectivity. It can be readily extended to the synthesis of fused N-heterocycles

Prevalence, risk factors and molecular epidemiology of highly resistant gram negative rods in hospitalized patients in the Dutch region Kennemerland

Abstract Background This paper describes (1) the Highly Resistant Gram Negative Rod (HR-GNR) prevalence rate, (2) their genotypes, acquired resistance genes and (3) associated risk factors of HR-GNR colonization among the hospitalized population in the Dutch region Kennemerland. Methods Between 1 October 2013 and 31 March 2014, cross-sectional prevalence measurements were performed in three regional hospitals as part of each hospitals infection control program. Rectal swabs were analyzed at the Regional Public Health Laboratory Kennemerland by direct culturing. Genotypes and acquired resistance genes of positive isolates were determined using Whole Genome Sequencing with the MiSeq instrument (Illumina). Association between several independent variables and HR-GNR positivity was examined using logistic regression models. Results Out of 427 patients, 24 HR-GNR positive isolates were recovered from 22 patients, resulting in a regional HR-GNR colonization prevalence (95 % CI) of 5.2 % (3.6–7.9). Of these 22 positive patients, 15 were Extended Spectrum Beta-Lactamase (ESBL) positive (3.5 % (2.1–5.7)), 7 patients were positive for a Fluoroquinolones and Aminoglycosides (Q&A) resistant Enterobacteriaceae (1.6 % (0.8–3.3)) and from one patient (0.2 % (0–1.3)) a Stenotrophomonas maltophilia resistant towards co-trimoxazole was isolated. No carbapenemase producing Enterobacteriaceae (CPE), multi-resistant Acinetobacter species or multi-resistant Pseudomonas aeruginosa were isolated. The ESBL genes found were bla CTX-M-1 (n = 4, 25.0 %), bla CTX-M-15 (n = 3, 18.8 %), bla CTX-M-27 (n = 2, 12.5 %), bla CTX-M-14b (n = 2, 12.5 %), bla CTX-M-9 (n = 2, 12.5 %), bla CTX-M-14 (n = 1, 6.3 %), bla CTX-M-3 (n = 1, 6.3 %), bla SHV-11 (n = 1, 6.3 %) and bla SHV-12 (n = 1, 6.3 %). Being known HR-GNR positive in the past was the only significant associated risk factor for HR-GNR positivity, odds ratio (95 % CI): 7.32 (1.82–29.35), p-value = 0.005. Conclusions Similar ESBL prevalence rates and genotypes (3.5 %) were found in comparison to other Dutch studies. When previously HR-GNR positive patients are readmitted, they should be screened for HR-GNR colonization since colonization with GR-GNRs could be prolonged. We recommend for future studies to include all defined HR-GNRs in addition to ESBLs in prevalence studies, in order to obtain a more comprehensive overview of colonization with HR-GNRs

Reactivity of Biarylazacyclooctynones in Copper-Free Click Chemistry

The 1,3-dipolar cycloaddition of cyclooctynes with azides, also called "copper-free click chemistry", is a bioorthogonal reaction with widespread applications in biological discovery. The kinetics of this reaction are of paramount importance for studies of dynamic processes, particularly in living subjects. Here we performed a systematic analysis of the effects of strain and electronics on the reactivity of cyclooctynes with azides through both experimental measurements and computational studies using a density functional theory (DFT) distortion/interaction transition state model. In particular, we focused on biarylazacyclooctynone (BARAC) because it reacts with azides faster than any other reported cyclooctyne and its modular synthesis facilitated rapid access to analogues. We found that substituents on BARAC's aryl rings can alter the calculated transition state interaction energy of the cycloaddition through electronic effects or the calculated distortion energy through steric effects. Experimental data confirmed that electronic perturbation of BARAC's aryl rings has a modest effect on reaction rate, whereas steric hindrance in the transition state can significantly retard the reaction. Drawing on these results, we analyzed the relationship between alkyne bond angles, which we determined using X-ray crystallography, and reactivity, quantified by experimental second-order rate constants, for a range of cyclooctynes. Our results suggest a correlation between decreased alkyne bond angle and increased cyclooctyne reactivity. Finally, we obtained structural and computational data that revealed the relationship between the conformation of BARAC's central lactam and compound reactivity. Collectively, these results indicate that the distortion/interaction model combined with bond angle analysis will enable predictions of cyclooctyne reactivity and the rational design of new reagents for copper-free click chemistry

Mps1 Phosphorylation of Dam1 Couples Kinetochores to Microtubule Plus Ends at Metaphase

Duplicated chromosomes are equally segregated to daughter cells by a bipolar mitotic spindle during cell division. By metaphase, sister chromatids are coupled to microtubule (MT) plus ends from opposite poles of the bipolar spindle via kinetochores. Here we describe a phosphorylation event that promotes the coupling of kinetochores to microtubule plus ends

Cost effectiveness of pediatric pneumococcal conjugate vaccines: a comparative assessment of decision-making tools

BACKGROUND: Several decision support tools have been developed to aid policymaking regarding the adoption of pneumococcal conjugate vaccine (PCV) into national pediatric immunization programs. The lack of critical appraisal of these tools makes it difficult for decision makers to understand and choose between them. With the aim to guide policymakers on their optimal use, we compared publicly available decision-making tools in relation to their methods, influential parameters and results. METHODS: The World Health Organization (WHO) requested access to several publicly available cost-effectiveness (CE) tools for PCV from both public and private provenance. All tools were critically assessed according to the WHO's guide for economic evaluations of immunization programs. Key attributes and characteristics were compared and a series of sensitivity analyses was performed to determine the main drivers of the results. The results were compared based on a standardized set of input parameters and assumptions. RESULTS: Three cost-effectiveness modeling tools were provided, including two cohort-based (Pan-American Health Organization (PAHO) ProVac Initiative TriVac, and PneumoADIP) and one population-based model (GlaxoSmithKline's SUPREMES). They all compared the introduction of PCV into national pediatric immunization program with no PCV use. The models were different in terms of model attributes, structure, and data requirement, but captured a similar range of diseases. Herd effects were estimated using different approaches in each model. The main driving parameters were vaccine efficacy against pneumococcal pneumonia, vaccine price, vaccine coverage, serotype coverage and disease burden. With a standardized set of input parameters developed for cohort modeling, TriVac and PneumoADIP produced similar incremental costs and health outcomes, and incremental cost-effectiveness ratios. CONCLUSIONS: Vaccine cost (dose price and number of doses), vaccine efficacy and epidemiology of critical endpoint (for example, incidence of pneumonia, distribution of serotypes causing pneumonia) were influential parameters in the models we compared. Understanding the differences and similarities of such CE tools through regular comparisons could render decision-making processes in different countries more efficient, as well as providing guiding information for further clinical and epidemiological research. A tool comparison exercise using standardized data sets can help model developers to be more transparent about their model structure and assumptions and provide analysts and decision makers with a more in-depth view behind the disease dynamics. Adherence to the WHO guide of economic evaluations of immunization programs may also facilitate this process. Please see related article: http://www.biomedcentral.com/1741-7007/9/55

Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations

Background Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations. Methods Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required. Results Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals. Conclusions Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families