Excerpts from Peter Krass's Lecture "Andrew Carnegie: Ruthless Empire Builder and Pioneering Philanthropist"

“What I came to realize about Carnegie is that he is really like a flawed Shakespearean hero… he really did consider the world a stage… and when he was on that stage he wore a variety of masks and behind each mask was a distinct character and you really could not reconcile various characters.” “He would attempt to promote himself and ideas in one direction, but practically speaking it didn’t work. You get an idea that there are these two sides to Carnegie, this idealist side and this practical man.

Highly transient axi-symmetric squeeze flows

The aim of this work was to use experimental, analytical and computational Computational Fluid Dynamic - CFD methodologies to investigate so-called highly transient axi-symmetric squeeze flows. These flows occur between two co-axial and parallel discs which are subjected to an impact, arising from a falling mass, which induces a constant energy squeezing system, as distinct from the traditionally investigated constant force or constant velocity squeezing systems. Experiments were conducted using a test cell comprising two parallel discs of diameter 120 mm with a flexible bladder used to contain fluid. This test cell was bolted onto the base of a drop-weight tester used to induce constant energy squeeze flows. Glycerine was used as the working fluid, the temperature of which was appropriately monitored. Disc separation, together with pressures at three radial positions, were measured throughout the experimental stroke typically less than 10 ms duration. Two additional pressure transducers at the same radial position as the outermost transducer were also used to monitor and subsequently correct for minor non-axi-symmetries that arose in the system. Approximately 150 tests were conducted, embracing combinations of drop height from 0.1 to 1 m, drop mass from 10 to 55 kg and initial disc separation from 3 to 10 mm. Three elementary features were typically observed: a distinct preliminary pressure spike 1 immediately after impact corresponding to very large accelerations exceeding over 6 km/s2 in some experiments, a secondary major pressure spike 2 towards the termination of the stroke corresponding to diminishing disc separations and a bridging region 3 joining the two spikes corresponding to somewhat reduced pressures. While pressure distributions were observed to be closely parabolic during the major pressure spike, some uncertainty was present during the preliminary pressure spike, ascribed to sensitivities to deviations from axi-symmetry, and the likelihood of inertially generated pressures at the edge of the disc. The former feature appears not to have been reported on in the formal literature. iii Four analytical models were considered, invoking the parallel flow assumption in conjunction with the Navier Stokes equations: an inviscid/inertial model, a viscous model the lubrication approximation, a quasi-steady linear QSL model and a quasi-steady corrected linear QSCL model. The first two of these models, on incorporation of measured disc separations, and the derived velocities and accelerations, achieved acceptable correlations with pressure measurements largely within uncertainty bounds during the initial impact and towards the end of the stroke, respectively. The QSL model agreed satisfactorily with measurements throughout the entire duration of the experiment, while the QSCL model, by incorporating non-linear effects in an approximate linear way, yielded somewhat better correlations. By invoking the parallel flow assumption, all four models predict a parabolic radial pressure distribution. Utilizing a hypothetical case in which variations of disc separation, velocity and acceleration were considered employing similar magnitudes and timescales to those that were measured, outputs of the QSL model yielded results that correlated closely with CFD predictions, while the QSCL data were somewhat better. On the basis of the CFD data it was also inferred that, within practical uncertainty bounds, the parallel flow assumption was valid for the range of disc separation to radius ratios embraced in the current investigation

A drop-in clinic for patients with poorly-controlled diabetes: a community pharmacy feasibility study

Background Preparatory work suggests that there may be a role for the pharmacist in managing sub-optimal medication adherence and dose titration of prescribed medicines in patients with type 2 diabetes. Patients have reported that they are receptive towards pharmacists becoming involved in their care providing that this is integrated into the care received from their medical practice. Objective To determine whether a community pharmacy diabetes drop-in clinic is feasible and acceptable to patients with poorly controlled type 2 diabetes. Setting Five community pharmacies in Norfolk, UK. Method Poorly controlled patients, as defined by a national General Practitioner incentive scheme, were invited to participate in the study by a letter posted by their medical practice. One four-hour, pharmacist clinic, where participants were able to "drop-in", was conducted in five pharmacies every week for four to six weeks. Questionnaires before and after the consultation were used to determine the clinic's effect on satisfaction with, and beliefs about, medicines and adherence along with participant satisfaction. Pharmacists had the opportunity to provide feedback via "debrief" interviews. Main outcome measure As a feasibility study, a combination of outcomes were explored including informationsatisfaction and adherence. Results Thirty-three (9.6%) of the 342 patients with type 2 diabetes posted letters were recruited from four pharmacies. Follow-up questionnaire completion rate was 88%. The clinic demonstrated little change in the parameters measured over three months. All of the participants rated their general impression of the service as good or very good and all would be happy to recommend the service to others with diabetes. Sixteen participants (59%) stated that it would make them more likely to consult their pharmacist in the future. Pharmacists enjoyed providing the service as it allowed them to interact more formally, and for longer, with patients. Conclusion This research has demonstrated that a community pharmacy drop-in clinic is feasible and likely to be acceptable to both patients and pharmacists; however, cost effectiveness of such a service should be explored in future studies. Further thought should also be given to how this service can complement that provided by a nurse in the medical practice and how the pharmacist can provide additional benefit to the NHS

An integrated general practice and pharmacy-based intervention to promote the use of appropriate preventive medications among individuals at high cardiovascular disease risk: protocol for a cluster randomized controlled trial

Background: Cardiovascular diseases (CVD) are responsible for significant morbidity, premature mortality, and economic burden. Despite established evidence that supports the use of preventive medications among patients at high CVD risk, treatment gaps remain. Building on prior evidence and a theoretical framework, a complex intervention has been designed to address these gaps among high-risk, under-treated patients in the Australian primary care setting. This intervention comprises a general practice quality improvement tool incorporating clinical decision support and audit/feedback capabilities; availability of a range of CVD polypills (fixed-dose combinations of two blood pressure lowering agents, a statin ± aspirin) for prescription when appropriate; and access to a pharmacy-based program to support long-term medication adherence and lifestyle modification. Methods: Following a systematic development process, the intervention will be evaluated in a pragmatic cluster randomized controlled trial including 70 general practices for a median period of 18 months. The 35 general practices in the intervention group will work with a nominated partner pharmacy, whereas those in the control group will provide usual care without access to the intervention tools. The primary outcome is the proportion of patients at high CVD risk who were inadequately treated at baseline who achieve target blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels at the study end. The outcomes will be analyzed using data from electronic medical records, utilizing a validated extraction tool. Detailed process and economic evaluations will also be performed. Discussion: The study intends to establish evidence about an intervention that combines technological innovation with team collaboration between patients, pharmacists, and general practitioners (GPs) for CVD prevention. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN1261600023342

Quantification of cAMP and cGMP analogs in intact cells: pitfalls in enzyme immunoassays for cyclic nucleotides

Immunoassays are routinely used as research tools to measure intracellular cAMP and cGMP concentrations. Ideally, this application requires antibodies with high sensitivity and specificity. The present work evaluates the cross-reactivity of commercially available cyclic nucleotide analogs with two non-radioactive and one radioactive cAMP and cGMP immunoassay. Most of the tested cyclic nucleotide analogs showed low degree competition with the antibodies; however, with Rp-cAMPS, 8-Br-cGMP and 8-pCPT-cGMP, a strong cross-reactivity with the corresponding cAMP and cGMP, respectively, immunoassays was observed. The determined EIA-binding constants enabled the measurement of the intracellular cyclic nucleotide concentrations and revealed a time- and lipophilicity-dependent cell membrane permeability of the compounds in the range of 10–30% of the extracellular applied concentration, thus allowing a more accurate prediction of the intracellular analog levels in a given experiment

Genetic Networks of Liver Metabolism Revealed by Integration of Metabolic and Transcriptional Profiling

Although numerous quantitative trait loci (QTL) influencing disease-related phenotypes have been detected through gene mapping and positional cloning, identification of the individual gene(s) and molecular pathways leading to those phenotypes is often elusive. One way to improve understanding of genetic architecture is to classify phenotypes in greater depth by including transcriptional and metabolic profiling. In the current study, we have generated and analyzed mRNA expression and metabolic profiles in liver samples obtained in an F2 intercross between the diabetes-resistant C57BL/6 leptinob/ob and the diabetes-susceptible BTBR leptinob/ob mouse strains. This cross, which segregates for genotype and physiological traits, was previously used to identify several diabetes-related QTL. Our current investigation includes microarray analysis of over 40,000 probe sets, plus quantitative mass spectrometry-based measurements of sixty-seven intermediary metabolites in three different classes (amino acids, organic acids, and acyl-carnitines). We show that liver metabolites map to distinct genetic regions, thereby indicating that tissue metabolites are heritable. We also demonstrate that genomic analysis can be integrated with liver mRNA expression and metabolite profiling data to construct causal networks for control of specific metabolic processes in liver. As a proof of principle of the practical significance of this integrative approach, we illustrate the construction of a specific causal network that links gene expression and metabolic changes in the context of glutamate metabolism, and demonstrate its validity by showing that genes in the network respond to changes in glutamine and glutamate availability. Thus, the methods described here have the potential to reveal regulatory networks that contribute to chronic, complex, and highly prevalent diseases and conditions such as obesity and diabetes

Scholarly publishing depends on peer reviewers

The peer-review crisis is posing a risk to the scholarly peer-reviewed journal system. Journals have to ask many potential peer reviewers to obtain a minimum acceptable number of peers accepting reviewing a manuscript. Several solutions have been suggested to overcome this shortage. From reimbursing for the job, to eliminating pre- publication reviews, one cannot predict which is more dangerous for the future of scholarly publishing. And, why not acknowledging their contribution to the final version of the article published? PubMed created two categories of contributors: authors [AU] and collaborators [IR]. Why not a third category for the peer-reviewer