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If carotid artery narrowing remains asymptomatic (ie, has caused no recent stroke or other neurological symptoms), successful carotid endarterectomy (CEA) reduces stroke incidence for some years. We assessed the long-term effects of successful CEA. Between 1993 and 2003, 3120 asymptomatic patients from 126 centres in 30 countries were allocated equally, by blinded minimised randomisation, to immediate CEA (median delay 1 month, IQR 0·3–2·5) or to indefinite deferral of any carotid procedure, and were followed up until death or for a median among survivors of 9 years (IQR 6–11). The primary outcomes were perioperative mortality and morbidity (death or stroke within 30 days) and non-perioperative stroke. Kaplan-Meier percentages and logrank p values are from intention-to-treat analyses. This study is registered, number ISRCTN26156392. 1560 patients were allocated immediate CEA versus 1560 allocated deferral of any carotid procedure. The proportions operated on while still asymptomatic were 89·7% versus 4·8% at 1 year (and 92·1% vs 16·5% at 5 years). Perioperative risk of stroke or death within 30 days was 3·0% (95% CI 2·4–3·9; 26 non-disabling strokes plus 34 disabling or fatal perioperative events in 1979 CEAs). Excluding perioperative events and non-stroke mortality, stroke risks (immediate vs deferred CEA) were 4·1% versus 10·0% at 5 years (gain 5·9%, 95% CI 4·0–7·8) and 10·8% versus 16·9% at 10 years (gain 6·1%, 2·7–9·4); ratio of stroke incidence rates 0·54, 95% CI 0·43–0·68, p<0·0001. 62 versus 104 had a disabling or fatal stroke, and 37 versus 84 others had a non-disabling stroke. Combining perioperative events and strokes, net risks were 6·9% versus 10·9% at 5 years (gain 4·1%, 2·0–6·2) and 13·4% versus 17·9% at 10 years (gain 4·6%, 1·2–7·9). Medication was similar in both groups; throughout the study, most were on antithrombotic and antihypertensive therapy. Net benefits were significant both for those on lipid-lowering therapy and for those not, and both for men and for women up to 75 years of age at entry (although not for older patients). Successful CEA for asymptomatic patients younger than 75 years of age reduces 10-year stroke risks. Half this reduction is in disabling or fatal strokes. Net benefit in future patients will depend on their risks from unoperated carotid lesions (which will be reduced by medication), on future surgical risks (which might differ from those in trials), and on whether life expectancy exceeds 10 years. UK Medical Research Council, BUPA Foundation, Stroke Association.

We present an insert-based approach to fabricate scalable and multiplexable microfluidic devices for 3D cell culture and integration with downstream detection modules. Laser-cut inserts with a layer of electrospun fibers are used as a scaffold for 3D cell culture, with the inserts being easily assembled in a 3D-printed fluidic device for flow-based studies. With this approach, the number and types of cells (on the inserts) in one fluidic device can be customized. Moreover, after an investigation (i.e., stimulation) under flowing conditions, the cell-laden inserts can be removed easily for subsequent studies including imaging and cell lysis. In this paper, we first discuss the fabrication of the device and characterization of the fibrous inserts. Two device designs containing two (channel width = 260 μm) and four (channel width = 180 μm) inserts, respectively, were used for different experiments in this study. Cell adhesion on the inserts with flowing media through the device was tested by culturing endothelial cells. Macrophages were cultured and stimulated under different conditions, the results of which indicate that the fibrous scaffolds under flow conditions result in dramatic effects on the amount and kinetics of TNF-α production (after LPS stimulation). Finally, we show that the cell module can be integrated with a downstream absorbance detection scheme. Overall, this technology represents a new and versatile way to culture cells in a more in vivo fashion for in vitro studies with online detection modules.

This dissertation details the use of 3D-printing for the analysis of cellular messengers. First, the significance of culturing cells on a 3D matrix and under flowing conditions is described. Electrospinning is used to fabricate an extracellular matrix mimic for 3D culture. RAW 264.7 macrophages are cultured on fibrous inserts and placed in a 4-insert 3D-printed cell culture device to analyze M1 activation (via TNF-a) in response to flowing or static media containing lipopolysaccharide. Macrophages on polycaprolactone and silk fibroin fibers are studied, with macrophages cultured on ~500 nm silk fibers exhibiting the most in-vivo-like response. Then, the creation of the first 3D-printed microfluidic in-line amperometric detector is described. The design incorporates a three-electrode set-up made possible by threading fabricated and commercially available threaded electrodes into the 3D-printed flow cell. To demonstrate in-line capabilities, the device is modified to include a mixing T for introduction of reagents for chemiluminescent detection of ATP (via the luciferin/luciferase reaction), leading to a single 3D-printed device that can be used to detect norepinephrine and ATP by amperometry and chemiluminescence. Next, the 3D-printed multi-modal device was optimized to simultaneously detect nitric oxide (NO) and adenosine triphosphate (ATP) in red blood cell suspensions prepared from whole blood. NO is detected with a platinum-black/Nafion coated gold working electrode. ATP is detected via chemiluminescence, with the luciferin/luciferase solution continuously pumped into an integrated double mixing T. The device is used to determine the levels of NO and ATP in normoxic and hypoxic red blood cells. The effect of storing red blood cells in a commonly used storage solution is also investigated by monitoring the production of NO and ATP over a three-week storage time. Finally, some preliminary results are presented of a possible configuration coupling the 3D-printed cell culture device to the in-line amperometric detector. The system can be used to study red blood cell-macrophage interactions in multiple sclerosis.

To explore how the concept of randomization is described by clinicians and understood by patients in randomized controlled trials (RCTs) and how it contributes to patient understanding and recruitment. Qualitative analysis of 73 audio recordings of recruitment consultations from five, multicenter, UK-based RCTs with identified or anticipated recruitment difficulties. One in 10 appointments did not include any mention of randomization. Most included a description of the method or process of allocation. Descriptions often made reference to gambling-related metaphors or similes, or referred to allocation by a computer. Where reference was made to a computer, some patients assumed that they would receive the treatment that was “best for them”. Descriptions of the rationale for randomization were rarely present and often only came about as a consequence of patients questioning the reason for a random allocation. The methods and processes of randomization were usually described by recruiters, but often without clarity, which could lead to patient misunderstanding. The rationale for randomization was rarely mentioned. Recruiters should avoid problematic gambling metaphors and illusions of agency in their explanations and instead focus on clearer descriptions of the rationale and method of randomization to ensure patients are better informed about randomization and RCT participation. •Practices commonly used to describe randomisation in RCT recruitment could confuse patients.•Patients found it difficult to comprehend gambling-related metaphors of randomisation.•Computer-agency descriptions led to patients believing they would receive the best treatment.

We employed a flashcard strategy to teach two high school students with mental retardation their math facts. The study was carried out in a typical self-contained classroom public school setting. We measured both correct responses and errors. The effects of employing flashcards were examined in a multiple baseline design across participants. Overall outcomes indicated that when flashcards were employed there was an increase in their correct rate and a decrease in errors. Applicability of employing flashcards was discussed.

The rapid response radiotherapy program (RRRP) at Toronto-Sunnybrook Regional Cancer Center (TSRCC) provides quick access to palliative radiotherapy for patients with a life expectancy of less than 12 months. Patients then return to their referring physician for continued oncologic management. After the initial RRRP consultation, we fax an interim consultation report to the referring physician. The purpose of this study was to assess how useful referring physicians perceive this interim report and whether this report needs to be modified to meet their information needs. Physicians who referred patients to the RRRP and who were faxed an interim consultation report were identified over a 4-month period. These physicians were then faxed a questionnaire that asked how useful the interim report was in patient management, about their satisfaction with the information provided, to critique the report format, and whether the RRRP physician and nurse were easily accessible by telephone. Forty physicians referred patients to the RRRP clinic over the 4-month study period. The response rate to our survey was 58% (23/40). The vast majority of physicians (95%) stated that the interim consultation report was useful in patient management. They felt that treatment details were adequately discussed in the report. The report format was perceived to be clear and concise. Referring physicians wished to be informed about any medication changes. RRRP physicians and nurse were perceived to be easily accessible by telephone if needed. Results showed that referring physicians found the faxed interim consultation report useful in patient management. Suggestions were made on how to improve the report, and they will be used to further enhance physician communication and ultimately patient care.

Despite growing consumer demand for organically produced foods, information based on a systematic review of their nutritional quality is lacking. We sought to quantitatively assess the differences in reported nutrient content between organically and conventionally produced foodstuffs. We systematically searched PubMed, Web of Science, and CAB Abstracts for a Period of 50 y from 1 January 1958 to 29 February 2008, contacted subjects experts, and hand-searched bibliographies. We included peer-reviewed articles with English abstracts in the analysis if they reported nutrient content comparisons between organic and conventional foodstuffs. Two reviewers extracted study characteristics, quality, and data. The analysis were restricted to the most commonly reported nutrients. From a total of 52471 articles, we identified 162 studies (137 crops and 25 livestock products); 55 were of satisfactory quality. In an analysis that included only satisfactory quality studies, conventionally produced crops had a significantly higher content of nitrogen, and organically produced crops had a significantly higher content of phosphorus and titratable acidity. No evidence of a difference was detected for the remaining 8 of 11 crop nutrient categories analyzed. Analysis of the more limited database on livestock products found no evidence of a difference in nutrient content between organically and conventionally produced livestock products. On the basis of a systematic review of studies of satisfactory quality, there is no evidence of a difference in nutrient quality between organically and conventionally produced foodstuffs. The small differences in nutrient content detected are biologically plausible and mostly relate to differences in production methods.

Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in RBCs cultured in vitro or taken from freely behaving mice or humans exhibit and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via NO signaling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.

This study and report is about street trees and intersection safety in urban contexts. The study derives from a rather simple, straightforward observation: that on the best tree-lined streets the trees come close to the corners. They do not stop at some distance back from the intersecting street right-of-way. Indeed, in Paris, a city noted for its street trees, if the regular spacing of trees along the street runs short at an intersection, there is likely to be an extra tree placed at the corner. For at least 250 years, the finest of streets the world over have been associated with trees. Elm or oak shaded residential and commercial main streets remain as memories, but seldom as realities, of the best American urbanism. In the automobile age, a real concern with safety has resulted in street tree standards in the United States that dictate long setbacks from intersections, ostensibly geared to achieving unobstructed sight lines for drivers. But are street trees the safety problem they are purported to be? And are other physical, controllable qualities more important for preserving sight lines at intersections?