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Additional file 2: Table Additional file 2. Mean values for theperceived helpfulness of different types of support.

Additional file 1: Table Additional file 1. Information aboutdemographics, professional role, and qualifications.

Additional file 3: Table Additional file 3. Mean values for theperceived interest in learning more about specific topics.

In this work, the advantage of two-dimensional population balance modeling (2D PBM) for a needle-shaped API is highlighted by comparing the one-dimensional population balance model (1D PBM) developed for an antisolvent crystallization with the 2D PBM. The API utilized for this work had extremely slow desupersaturation, and was not able to achieve solubility concentration despite a ~50 h seed bed age. While the 1D PBM is useful in optimizing the crystallization process to enhance desupersaturation, it is unable to match the particle size quantiles well. 2D PBM was necessary to probe the impact of crystallization process parameters on particle aspect ratio (AR). Simulations utilizing the 2D PBM indicated that regardless of antisolvent addition rate or seed morphology, the final material would still be high aspect ratio. This knowledge saved the investment of much time and efforts in trying to minimize particle AR with changes in crystallization processing parameters alone.

Two national databases were analyzed to determine the effect of varying severity of diabetes mellitus (DM) on ventral hernia repair (VHR) outcomes. The National Surgical Quality Improvement Program (NSQIP) and the National Inpatient Sample (NIS) were queried for patients with and without DM who underwent elective VHR between 2005 to 2012 and 1998 to 2011, respectively. In addition, patients with insulin dependent versus noninsulin-dependent DM were compared in NSQIP; complicated and uncomplicated diabetics were compared in NIS. Univariate and multivariate analyses were used. In NSQIP, 25,819 of 219,625 patients undergoing VHR were diabetic. In open VHR (OVHR), DM patients had an increased complication rate ( P < 0.0001); DM patients requiring insulin had increased odds of wound, minor, and major complications ( P < 0.0001). For laparoscopic VHR (LVHR), insulin dependence did not affect complication rates ( P > 0.05). In NIS, 45,248 of 238,627 patients undergoing VHR were diabetic. In OVHR, patients with complicated diabetes had higher rates of minor complications (17.3% vs 12.7%, P < 0.0001) and had 58 per cent greater odds of major complications than patients with uncomplicated diabetes. LVHR had no difference in complications for complicated versus uncomplicated DM ( P > 0.05). After multivariate analysis, insulin-dependent or complicated DM undergoing OVHR had significantly worse outcomes compared with noninsulin-dependent and uncomplicated diabetics. Preoperative optimization and LVHR should be considered in diabetic patients.

Cardiac Resynchronisation Therapy (CRT) is an effective treatment for selected patients with heart failure. The left ventricular (LV) lead used to achieve this can be hard to place via the coronary sinus in a proportion of patients, and in addition may not be in an optimal position in others. In this thesis, I initially discuss CRT and its technical limitations. Using a large meta-analysis, I elucidate contemporary rates of LV lead placement failure. An alternative method of LV lead placement is endocardial, and I discuss results to date, again using a meta-analysis to summate prior trials and the technique’s risks and benefits. The main subject of the thesis is assessing a novel method of LV endocardial pacing via the interventricular septum. I report a trial of 19 patients in whom conventional CRT was not possible or unsuccessful, showing clinical response to CRT delivered in this manner to be similar to conventional CRT, with acceptable risks. LV lead location in endocardial CRT has been little studied. I go on to investigate optimal LV lead positioning in this group, by assessing acute haemodynamic response (AHR) to CRT with a high-fidelity pressure wire and a multi-level modelling analysis. I show that this technique is reproducible. I compare placement at sites of late mechanical activation and late electrical activation, showing little difference in this cohort or in a parallel study of AHR in 22 patients undergoing conventional CRT. With a multivariate analysis I show that only electrical delay is a consistent predictor of acute response. These results support the use of this novel technique for CRT as a second-line procedure, and I discuss future directions for this. Lead site selection at a site of late electrical activation is supported by my work, and again I summarise the context of this.

Objectives The goal of this study was to assess the contemporary and historical success rates of transvenous left ventricular (LV) lead placement for cardiac resynchronization therapy (CRT), their change over time, and the reasons for failure. Background In selected patients, CRT improves morbidity and mortality, but the placement of the LV lead can be technically challenging. Methods A literature search was used to identify all studies reporting success rates of LV lead placement for CRT via the coronary sinus (CS) route. A total of 164 studies were identified, and a meta-analysis was performed. Results The studies included 29,503 patients: 74% (95% confidence interval [CI]: 72% to 76%) were male; their mean age was 66 years (95% CI: 65 to 67); their mean New York Heart Association functional class was 2.8 (95% CI: 2.7 to 2.9); the mean LV ejection fraction was 26% (95% CI: 25% to 28%); and the mean QRS duration was 155 ms (95% CI: 150 to 160). The overall rate of failure of implantation of an LV lead was 3.6% (95% CI: 3.1 to 4.3). The rate of failure in studies commencing before 2005 was 5.4% (95% CI: 4.4% to 6.5%), and from 2005 onward it was 2.4% (95% CI: 1.9% to 3.1%; p < 0.001). Causes of failure (reported for 39% of failures) also changed over time. Failure to cannulate and navigate the CS decreased from 53% to 30% (p = 0.01), and the absence of any suitable, acceptable vein increased from 39% to 64% (p = 0.007). The proportion of leads in a lateral or posterolateral final position (reported for 26% of leads) increased from 66% to 82% (p = 0.004). Conclusions The reported rate of failure to place an LV lead via the CS has decreased steadily over time. A greater proportion of failures in recent studies are due to coronary venous anatomy that is unsuitable for this technique.

Patienten, die sich einer gefaschirurgischen Operation unterziehen mussen, benotigen intraoperativ haufig weit mehr Flussigkeit als durch praoperative Nuchternheit, intraoperative Flussigkeitsverluste und Beatmung zu erwarten ist. Veranderungen der Starlingkrafte – insbesondere der Gefaspermeabilitat – spielen hier moglicherweise eine Rolle, ohne das diese bisher naher untersucht wurden.

Genome-wide microRNA (miRNA) expression profiling of salivary gland pleomorphic adenomas revealed a distinct expression signature consisting largely of upregulated miRNAs compared with matched normal tissue. Microarray data were confirmed by quantitative real time RT-PCR (q-RTPCR). Five miRNA genes upregulated in the tumours were found in close proximity to fragile sites and/or cancer associated genomic regions. Interestingly, q-RTPCR revealed an increase in the expression of components of the miRNA processing machinery (Dicer, Drosha, DGCR8 and p68) in tumours suggesting that the deregulation of miRNA expression may result from increased miRNA biogenesis. Target gene prediction analysis of the altered miRNAs indicated that genes in a number of signalling pathways important in tumourigenesis including WNT, MAPK and JAK-STAT were overrepresented. Significantly, the oncogene PLAG1 was overexpressed in our cohort and may be potentially regulated by these miRNAs. This is the first study to examine changes in the miRNA milieu in pleomorphic adenoma, the most common salivary gland tumour. This study has demonstrated an upregulation of both miRNAs genes and an upregulation of the miRNA processing machinery. These changes may be potential underlying mechanisms for the development of these benign tumours. © 2009 UICC.

Rising prosperity and a rapidly commercialising economy have transformed China into the world’s most important emerging market. Multinational retailers have rapidly expanded their presence in China since foreign participation in the sector was permitted in 1992. The aim of this project was to investigate and analyse the transfer of management practices and retail concepts by UK multinational retailers to their subsidiaries in China. The study consists of semi-structured interviews of employees at UK owned retail stores in North and East China. The interviews are short as they are conducted on the shop floor while the interviewee is working. The interviews have been translated to English but the odd word is still in Chinese (Mandarin). Some interviews are transcribed while others are in note format. The study forms part of a wider project which also looked at Japanese firms and includes further data not available from the UKDA. Further information is available from the Cultures of Consumption project web page and the ESRC award page.

During surgery of limbs tourniquet up to a maximum of 2 h is frequently applied which may cause ischemia/reperfusion injury (IRI). During this condition the presence of vasomotion may have consequences for the perfusion and nutritive state of the tissues. We used a noninvasive plethysmographic method to investigate periodic changes in limb circumference (volumotion) in healthy male patients (n = 24) undergoing surgery for knee injury. To facilitate surgery a tourniquet was applied to the thigh, which caused an IRI of the leg. Results are given as mean of all values +/- SEM. Immediately after tourniquet release (duration 57.75 +/- 5.19 min) blood lactate levels in the femoral vein increased significantly from 1.40 +/- 0.08 to 2.59 +/- 0.20 mmol/l (p0.001) and pH fell from 7.39 +/- 0.01 to 7.32 +/- 0.01 (p0.001). Preoperatively 10 out of 24 patients (42%) showed signs of volumotion on the injured leg with a periodicity ranging from 0.8 to 6.9 cycles/min, whereas none showed volumotion in the control leg (p0.001). In the second measurement, taken after surgery and reperfusion while peripheral sympathetic nerves were blocked, 7 out of 18 patients (39%) showed volumotion on the injured leg and 0 on the control leg (p0.004). 6 h after IRI, volumotion was observed in 11 out of 17 patients (65%) on the injured leg and in 1 patient (6%) on the control leg (p0.001). The mean volume change in the patients with volumotion on the injured leg was 0.057 +/- 0.007 ml/100 ml tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The isolated perfused submandibular salivary gland of the rabbit has been used in order to make estimates of the filtration coefficient (Kf) and reflection coefficient (sigma d) of the capillary wall to albumin. 2. An isogravimetric preparation was used and in paired experiments the value for Kf obtained in glands perfused with albumin-Krebs solution, 0.96 +/- 0.086 (mean +/- S.E. of mean) ml min-1 mmHg-1 100 g-1, was not significantly different from that in blood-perfused glands, 0.90 +/- 0.15. 3. On analysing the data for reflection coefficient, it was concluded that the above values underestimated Kf by about 30%; using corrected values for Kf, osmotic reflection coefficients were determined from the weight changes following a sudden change in the oncotic pressure of the perfusate. The value for sigma d to albumin lay between 0.79 and 1.0, the lower value being obtained after the Kf correction. 4. The high hydraulic conductivity, combined with sieving properties comparable to those in continuous capillaries, is consistent with other data on fenestrated capillaries. 5. Finally, it was observed that, while the Kf value calculated from the initial flux rate was similar whether measured during fluid efflux from or influx into the microvasculature, on returning to the initial conditions after raising osmotic pressure, efflux was now more rapid than influx. This phenomenon is discussed in relation to readjustment of Starling forces and the possible existence of an asymmetric double membrane in the capillary, interstitium system and cells of the salivary gland.

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Pez is a non-transmembrane tyrosine phosphatase with homology to the FERM (4.1, ezrin, radixin, moesin) family of proteins. The subcellular localisation of Pez in endothelial cells was found to be regulated by cell density and serum concentration. In confluent monolayers Pez was cytoplasmic, but in cells cultured at low density Pez was nuclear, suggesting that it is a nuclear protein in proliferating cells. This notion is supported by the loss of nuclear Pez when cells are serum-starved to induce quiescence, and the rapid return of Pez to the nucleus upon refeeding with serum to induce proliferation. Vascular endothelial cells normally exist as a quiescent confluent monolayer but become proliferative during angiogenesis or upon vascular injury. Using a ‘wound’ assay to mimic these events in vitro, Pez was found to be nuclear in the cells that had migrated and were proliferative at the ‘wound’ edge. TGFbeta, which inhibits cell proliferation but not migration, inhibited the translocation of Pez to the nucleus in the cells at the ‘wound’ edge, further strengthening the argument that Pez plays a role in the nucleus during cell proliferation. Together, the data presented indicate that Pez is a nuclear tyrosine phosphatase that may play a role in cell proliferation.

We have recently shown that an exogenous gradient of interleukin-8 (IL-8) induces the transendothelial migration of neutrophils. Treatment of endothelium with the cytokines IL-1 or tumour necrosis factor (TNF) also causes neutrophil transmigration, and recent evidence suggests that this may be due to endogenous IL-8 produced by the endothelium. We have used specific chemotactic desensitization of neutrophils to investigate the role of IL-8 in transmigration through cytokine-activated endothelium. Preincubation of neutrophils with IL-8 reduced their chemotactic transmigration response to an IL-8 gradient by 81%, demonstrating desensitization. Transmigration in response to cytokine-activated endothelium was inhibited by 104% after IL-8 preincubation, thus tending to support the role of IL-8. However, preincubation with another neutrophil chemotactic factor N-formyl-methionyl-leucyl-phenylalanine (FMLP), which did not affect the IL-8, response, also inhibited transmigration, by 74%. This suggests that FMLP preincubation acts to inhibit a non-IL-8-dependent mechanism of transmigration through cytokine-activated endothelium. Chemotactic factor pretreatment of neutrophils did not reduce their adhesion to activated endothelium, but specifically blocked the transmigration step. We have therefore shown that chemotactic transmigration can be subjected to factor-specific desensitization, and have used this to provide evidence supporting a role for IL-8 in transmigration through cytokine-activated endothelium, as well as suggesting a further IL-8-independent mechanism. These data also provide a mechanism for the observed defect in accumulation of neutrophils at inflammatory sites when chemotactic factors are infused intravenously.

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The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1-positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation. © 2014 Nature America, Inc