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Challenges for data storage during drug development have become increasingly complex as the pharmaceutical industry expands in an environment that requires on-demand availability of data and resources for users across the globe. While the efficiency and relative low cost of cloud services have become increasingly attractive, hesitancy toward the use of cloud services has decreased and there has been a significant shift toward real-world implementation. Within GxP laboratories, the considerations for cloud storage of data include data integrity and security, as well as access control and usage for users around the globe. In this review, challenges and considerations when using cloud storage options for the storage of laboratory-based GxP data are discussed and best practices are defined.

Objective During fenestrated endovascular aneurysm repair (FEVAR), accurate alignment of the fenestration and the target artery is necessary to prevent complications. This study's objective is to determine the incidence of clinical outcomes following fenestration misalignment during FEVAR. Methods A single-center, retrospective chart review was performed for all elective FEVARs between January 2008 and April 2015. Data were gathered from patient records and intraoperative imaging. Native vessel angles were calculated using the vessel centerlines. Intraoperative stent graft orientation was determined by changing the angle of the image intensifier as the fenestration was profiled for cannulation. Vertical fenestration misalignment was defined as 4 mm or greater and is the distance from the center of the fenestration markers to the center of the target vessel ostium at the time of cannulation. Horizontal stent graft misalignment was defined as a difference between the native vessel angle and the intraoperative fenestration angle of 15° or more. Early and late clinical outcomes were analyzed with respect to the presence of either vertical or horizontal misalignment of the renal artery fenestrations. Results The study cohort includes 65 patients who underwent FEVAR during this study period. A horizontal misalignment of 15° or more occurred in 40% of patients (n = 26) and 30° or more in 9.2% of patients (n = 6). A vertical misalignment of 4 mm or greater occurred in 32.3% of patients (n = 21). The incidence of severe postoperative complications, defined as any in-hospital end-organ ischemia and/or death, was significantly greater for patients with stent graft misalignment—31% (n = 11) vs 3% (n = 1) in the aligned group. There was a trend toward higher rates of target vessel cannulation failure in patients with stent graft misalignment 3% (n = 99 fenestrations) vs 0% (n = 76 fenestrations). The combined incidence of any intraoperative target vessel complication was significantly higher in patients with misalignment, 8.1% (4, 15) vs 1.3% (0, 8). Long-term survival was significantly lower in patients with stent graft misalignment, which was primarily driven by high intraoperative and in-hospital mortality rates (P Conclusions Intraoperative stent graft misalignment is associated with higher rates of procedural target vessel complications and severe postoperative adverse events. Patients with stent graft misalignment should be considered at high risk for early postoperative complications. These results highlight an important need for improved FEVAR planning.

Introduction: During endovascular aneurysm repair, the iliac artery typically serves as a conduit for device delivery. The degree of tortuosity and calcification in the iliac artery ultimately determines whether the device can successfully traverse the vessel. These 2 parameters can be assessed using qualitative approaches or calculated using quantitative methods based on the Society for Vascular Surgery (SVS) reporting standards. The objective of this study was to determine whether qualitative methods are sufficient to accurately assess iliac artery tortuosity and calcification by calculating interobserver variability and comparing them to the SVS Reporting Standards. Methods: Three vascular surgeons reviewed preoperative computed tomography scans for 50 patients who underwent fenestrated endovascular aneurysm repair and qualitatively assessed left and right iliac artery tortuosity and calcification. Iliac artery geometries were segmented from these image sets. Tortuosity index and calcification length ratio were calculated and categorized based on the SVS Reporting Standards. Results: Interobserver variability was calculated for the qualitative assessments using interclass correlation coefficients. For tortuosity index, among the 3 observers, good agreement was found for the left iliac artery and fair agreement was found for the right. For calcification length ratio, excellent agreement was found for both iliac arteries. When compared to the quantitative assessment, the qualitative assessments underpredicted tortuosity in 2.3% of cases, matched the quantitative values in 16.7% of cases, and overpredicted tortuosity in 81.0% of cases. The qualitative assessments underpredicted calcification in 46.3% of cases, matched the quantitative values in 49.3% of cases, and overpredicted calcification in 4.3% of cases. Conclusion: Qualitative assessment of iliac artery tortuosity showed fair-to-good interobserver agreement and poor agreement to SVS Reporting Standards. Qualitative assessment of iliac artery calcification showed excellent interobserver agreement and fair agreement to SVS Reporting Standards. These trends should be considered when qualitative reporting methodologies are used.

Substantial heterogeneity and defects in lithium-ion battery films can be a cause of material and battery failure. Although non-uniformity has been observed previously, the physical origin of electronic impedance non-uniformities in cathode materials has not been well-studied. We show that the local microscopic structure of materials strongly affects the resulting local impedance as measured by a micro-four-line probe, demonstrates large variation, and that these variations occur over sub-millimeter and larger distances on two different commercial cathode materials. These experimental results are further compared to modeled electronic and ionic transport pathways through the observed structure. By elucidating the extent and origins of heterogeneity in battery electrode films we provide a key principle through which batteries can be optimally designed to increase their safety, energy density, power, and longevity.

Objective Advanced endovascular aneurysm repair (EVAR) with fenestrated and branched stent grafts is increasingly being used to repair complex aortic aneurysms; however, these devices can rotate unpredictably during deployment, leading to device misalignment. The objectives of this study were to quantify the short-term clinical outcomes in patients with intraoperative stent graft rotation and to identify quantitative anatomic markers of the arterial geometry that can predict stent graft rotation preoperatively. Methods A prospective study evaluating all patients undergoing advanced EVAR was conducted at two university-affiliated hospitals between November 2015 and December 2016. Stent graft rotation (defined as ≥10 degrees) was measured on intraoperative fluoroscopic video of the deployment sequence. Standard preoperative computed tomography angiography imaging was used to calculate the geometric properties of the arterial anatomy. Any in-hospital and 30-day complications were prospectively documented, and a composite outcome of any end-organ ischemia or death was used as the primary end point. Results Thirty-nine patients undergoing advanced EVAR were enrolled in the study with a mean age of 75 years (interquartile range [IQR], 71-80 years) and a mean aneurysm diameter of 64 mm (IQR, 59-65 mm). The incidence of stent graft rotation was 37% (n = 14), with a mean rotation of 25 degrees (IQR, 21-28 degrees). A nominal logistic regression model identified iliac artery torsion, volume of iliac artery calcification, and stent graft length as the primary predictive factors. The total net torsion and the total volume of calcific plaque were higher in patients with stent graft rotation, 8.9 ± 0.8 mm −1 vs 4.1 ± 0.5 mm −1 ( P 3 vs 525 ± 83 mm 3 ( P P P = .004). In addition, patients with stent graft rotation had significantly higher combined rates of type Ib and type III endoleaks (43% vs 8%; P = .03). Conclusions Patients with intraoperative stent graft rotation have a significantly higher rate of severe postoperative complications, and this is strongly associated with higher levels of iliac artery torsion, calcification, and stent graft length. These findings suggest that preoperative quantitative analysis of iliac artery torsion and calcification may improve risk stratification of patients before advanced EVAR.

Endovascular aneurysm repair is a minimally-invasive method for the treatment of abdominal aortic aneurysms. For aneurysms that involve the visceral arteries, a custom-made stent graft with fenestrations for the branch arteries is required. The purpose of the current study is to evaluate the structural impact of misaligned fenestrations with respect to luminal patency and proximal aortic neck apposition in an in vitro model.A custom apparatus was used to evaluate seven Anaconda and three Zenith fenestrated stent grafts. All stent grafts were evaluated at 10° increments of stent/fenestration misalignment up to 80°. Images were captured at each interval and the luminal cross-sectional area and wall apposition were measured.The Anaconda stent graft, which has an unsupported main body, demonstrated a linear reduction in luminal patency at increasing angles of misalignment (P 0.0001). Stent/fenestration misalignments of 20° and 80° resulted in decreases in mean luminal patency of 14% and 54% respectively. The Zenith stent graft demonstrated a similar decrease in luminal patency, starting at misalignments of ≥40° (P 0.0001). However, with stent/fenestration misalignments of ≥30°, apposition between the Zenith stent graft and the simulated aortic neck was compromised suggesting the creation of a type Ia endoleak.Both the Anaconda and Zenith devices behave adversely at extreme angles of misalignment with luminal narrowing in the Anaconda device and loss of wall apposition in the Zenith device; however, both stent grafts appear to be equivalent at low angles of misalignment.

Purpose: To develop a mechanically realistic aortoiliac model to evaluate anatomic variables associated with stent-graft rotation and to assess common deployment techniques that may contribute to rotation. Materials and Methods: Idealized aortoiliac geometries were constructed either through direct 3-dimensional (3D) printing (rigid) or through casting with polyvinyl alcohol using 3D-printed molds (flexible). Flexible model bending rigidity was controlled by altering wall thickness. Three flexible patient-specific models were also created based on the preoperative computed tomography angiograms. Zenith infrarenal and fenestrated devices were used in this study. The models were pressurized to 100 mm Hg with normal saline. Deployments were performed under fluoroscopy at 37°C. Rotation was calculated by tracking the change in position of gold markers affixed to the devices. Results: In the rigid idealized models, stent-graft rotation increased with increasing torsion; torsion levels of 1.6, 2.6, and 3.6 mm−1 had mean rotations of 5.2°±0.03°, 11.2°±4.8°, and 27.6°±13.0°, respectively (p−1 net torsion and 254 N·m2 flexural rigidity). No rotation was observed in the absence of torsion. Applying torque to the device during insertion significantly increased stent-graft rotation by an average of 28° across all levels of torsion (p

A mechanistic model of the immune response was evaluated for its ability to predict anti-drug antibody (ADA) and their impact on pharmacokinetics (PK) and pharmacodynamics (PD) for a biotherapeutic in a phase 1 clinical trial. Observed ADA incidence ranged from 33 to 67% after single doses and 27–50% after multiple doses. The model captured the single dose incidence well; however, there was overprediction after multiple dosing. The model was updated to include a T-regulatory (Treg) cell mediated tolerance, which reduced the overprediction (relative decrease in predicted incidence rate of 21.5–59.3% across multidose panels) without compromising the single dose predictions (relative decrease in predicted incidence rate of 0.6–13%). The Treg-adjusted model predicted no ADA impact on PK or PD, consistent with the observed data. A prospective phase 2 trial was simulated, including co-medication effects in the form of corticosteroid-induced immunosuppression. Predicted ADA incidences were 0–10%, depending on co-medication dosage. This work demonstrates the utility in applying an integrated, iterative modeling approach to predict ADA during different stages of clinical development.

Fenestrated endovascular aneurysm repair (FEVAR) is a minimally invasive method of abdominal aortic aneurysm (AAA) repair utilized in patients with complex vessel anatomies. Stent grafts (SG) used in this process contain fenestrations within the device that need to be aligned with the visceral arteries upon successful SG deployment. Proper alignment is crucial to maintain blood flow to these arteries and avoid surgical complications. During fenestrated SG deployment, rotation of the SG can occur during the unsheathing process. This leads to misalignment of the vessels, and the fenestrations and is associated with poor clinical outcomes. The aim of this study was to develop a computational model of the FEVAR process to predict SG rotation. Six patient-specific cases are presented and compared with surgical case data. Realistic material properties, frictional effects, deployment methods, and boundary conditions are included in the model. A mean simulation error of 2 deg (range 1–4 deg) was observed. This model was then used to conduct a parameter study of frictional properties to see if rotation could be minimized. This study showed that increasing or decreasing the coefficients of friction (COF) between the sheath and the vessel walls would decrease the amount of rotation observed. Our model accurately predicts the amount of SG rotation observed during FEVAR and can be used as a preoperative planning tool within the surgical workflow.

Introduction: A complication of fenestrated endovascular aneurysm repair is the potential for stent graft rotation during deployment causing fenestration misalignment and branch artery occlusion. The objective of this study is to demonstrate that this rotation is caused by a buildup of rotational energy as the device is delivered through the iliac arteries and to quantify iliac artery geometric properties associated with device rotation. Methods: A retrospective clinical study was undertaken in which iliac artery geometric properties were assessed from preoperative imaging for 42 cases divided into 2 groups: 27 in the nonrotation group and 15 in the rotation group. Preoperative computed tomography scans were segmented, and the iliac artery centerlines were determined. Iliac artery tortuosity, curvature, torsion, and diameter were calculated from the centerline and the segmented vessel geometry. Results: The total iliac artery net torsion was found to be higher in the rotation group compared to the nonrotation group (23.5 ± 14.7 vs 14.6 ± 12.8 mm−1; P = .05). No statistically significant differences were found for the mean values of tortuosity, curvature, torsion, or diameter between the 2 groups. Conclusion: Stent graft rotation occurred in 36% of the cases considered in this study. Cases with high iliac artery total net torsion were found to be more likely to have stent graft rotation upon deployment. This retrospective study provides a framework for prospectively studying the influence of iliac artery geometric properties on fenestrated stent graft rotation.

We developed a homogeneous bridging anti-drug antibody (ADA) assay on an electro chemiluminescent immunoassay (ECLIA) platform to support the immunogenicity evaluation of a dimeric domain antibody (dAb) therapeutic in clinical studies. During method development we evaluated the impact of different types of acid at various pH levels on polyclonal and monoclonal ADA controls of differing affinities and on/off rates. The data shows for the first time that acids of different pH can have a differential effect on ADA of various affinities and this in turn impacts assay sensitivity and drug tolerance as defined by these surrogate controls. Acid treatment led to a reduction in signal of intermediate and low affinity ADA, but not high affinity or polyclonal ADA. We also found that acid pretreatment is a requisite for dissociation of drug bound high affinity ADA, but not for low affinity ADA-drug complexes. Although we were unable to identify an acid that would allow a 100% retrieval of ADA signal post-treatment, use of glycine pH3.0 enabled the detection of low, intermediate and high affinity antibodies (Abs) to various extents. Following optimization, the ADA assay method was validated for clinical sample analysis. Consistencies within various parameters of the clinical data such as dose dependent increases in ADA rates and titers were observed, indicating a reliable ADA method. Pre- and post-treatment ADA negative or positive clinical samples without detectable drug were reanalyzed in the absence of acid treatment or presence of added exogenous drug respectively to further assess the effectiveness of the final acid treatment procedure. The overall ADA results indicate that assay conditions developed and validated based on surrogate controls sufficed to provide a reliable clinical data set. The effect of low pH acid treatment on possible pre-existing ADA or soluble multimeric target in normal human serum was also evaluated, and preliminary data indicate that acid type and pH also affect drug-specific signal differentially in individual samples. The results presented here represent the most extensive analyses to date on acid treatment of a wide range of ADA affinities to explore sensitivity and drug tolerance issues. They have led to a refinement of our current best practices for ADA method development and provide a depth of data to interrogate low pH mediated immune complex dissociation.

The failure of investigators to publish research in peer-reviewed journals following acceptance at a national or international meeting can lead to significant publication biases in the literature. Our objective was to evaluate the abstract to manuscript conversion rate for abstracts presented at the Canadian Society for Vascular Surgery (CSVS) annual meeting and to evaluate the conversion rate for CSVS-awarded research grants.We searched for authors of abstracts accepted at the CSVS Annual Meeting (2007-2013) and recipients of CSVS research awards (2005-2013) on Scopus and PubMed databases to identify related publications.We identified 84 publications from 188 research abstracts (45%) and 17 publications from 39 research grants (44%). The mean time to publication was 1.8 years and the mean impact factor was 2.7. Studies related to endovascular therapies demonstrated a trend toward a higher rate of publication relative to open surgical therapies (64 [56%] v. 37 [27%]). Additionally, we observed a similar trend in research grant topics related to endovascular therapies relative to open surgical therapies (9 [67%] v. 8 [38%]). Finally, CSVS research grant recipients who subsequently published had a significantly higher h-index at the time of receipt than those who had not published.The CSVS annual meeting's abstract to publication conversion rate is comparable to that of its Canadian peers as well as to other medical specialties; however, a substantial publication gap remains. We identified several potential areas that may help to improve the effectiveness of CSVS research grants.Le fait que des chercheurs ne publient pas leurs recherches dans des revues évaluées par les pairs après acceptation de leur résumé à un congrès national ou international peut entraîner des biais de publication importants dans la littérature scientifique. Notre but était d'évaluer le taux de conversion de résumé à manuscrit pour les résumés présentés au congrès annuel de la Société canadienne de chirurgie vasculaire (SCCV) ainsi que le taux de conversion dans le cas des subventions de recherche accordées par la SCCV.Nous avons interrogé les bases de données de Scopus et PubMed afin d'identifier les auteurs de résumés acceptés au congrès annuel de la SCCV (2007-2013) ainsi que les récipiendaires de subventions de recherche de la SCCV (2005-2013) et les publications connexes.Nous avons relevé 84 publications à partir de 188 résumés de recherche (45 %) ainsi que 17 publications liées à 39 subventions de recherche (44 %). Le délai moyen de publication était de 1,8 année et le facteur d'impact moyen, de 2,7. Les études sur les thérapies endovasculaires avaient un taux de publication plus élevé comparativement à celles sur les traitements chirurgicaux ouverts (64 [56 %] c. 37 [27 %]). De plus, nous avons observé une tendance similaire lorsque le sujet des recherche subventionnées était lié aux thérapies endovasculaires comparativement aux traitements chirurgicaux ouverts (9 [67 %] c. 8 [38 %]). Enfin, les récipiendaires de subventions de recherche de la SCCV qui publiaient par la suite avaient un indice h beaucoup plus élevé au moment de recevoir la subvention que les chercheurs qui n'avaient pas publié.Le taux de conversion de résumé à publication du congrès annuel de la SCCV est comparable à celui de ses pairs au Canada et à celui d'autres spécialités médicales. Il reste néanmoins une lacune importante au niveau de la publication. Nous avons cerné plusieurs aspects susceptibles d'améliorer l'efficacité des subventions de recherche de la SCCV.

Endovascular aneurysm repair (EVAR) is a minimally invasive method for the treatment of abdominal aortic aneurysms; however, the implementation of this technique is often limited by the aortic pathology, especially in the urgent or emergent setting. An 82-year-old male with a 7.3 cm symptomatic juxtarenal aneurysm presented at our centre for assessment. He was diagnosed as a high-risk candidate for open repair and therefore, not suitable for a conventional EVAR. Fortunately, a custom two-vessel fenestrated stent graft, which was originally constructed for another patient, was available. This device was implanted with no complications and all branches remain unobstructed; clear of aneurysms at 1 year. We present the use of ‘in-stock’ fenestrated grafts as a potential option to be considered in the urgent or emergent repair of abdominal aortic aneurysms.

Objective In situ fenestration of endovascular stent grafts has been used as a method for branch vessel revascularization in urgent and emergent settings. The objective of this manuscript was to review the clinical and experimental evidence related to this technique. Methods PubMed, MEDLINE, and Embase databases were searched for papers published until December 2015 describing in situ fenestration of aortic stent grafts. Benchtop, animal, and human studies were included. Results The literature review identified 118 articles, of which 28 studies were selected for inclusion. These included 16 clinical papers (2 case series and 14 case reports) reporting in situ fenestration of 46 aortic branch vessels in 44 patients. There were 42 retrograde and 4 antegrade instances of in situ fenestration. The most frequent target vessel for in situ fenestration was the left subclavian artery (72%), and the most frequent indication for stent graft implantation was a degenerative aortic aneurysm (43%). Technical success was reported in 44 of 46 attempted fenestrations (96%). The combined rate of perioperative mortality, stroke, and paralysis was 7%. In situ fenestration was predominantly performed with the Talent (Medtronic, Santa Rosa, Calif) stent graft (54%), followed by the Zenith (Cook Medical, Bloomington, Ind) stent graft (37%) and the TAG (W. L. Gore & Associates, Newark, Del) stent graft (9%). In vitro benchtop evaluations of in situ fenestration showed minimal change in fenestration size after 1 year of pulsatile fatigue testing. The use of energy-based fenestration techniques (radiofrequency or laser) has been associated with less fabric fraying than in needle-based techniques. The larger caliber initial fenestration created by these devices also avoids the need for cutting balloons, which have also been linked with increased fabric tears and fraying of the fibers surrounding the fenestration. In addition, the Zenith stent graft was shown in benchtop testing to be the strongest in postfenestration mechanical testing, but it was also the most resistant to balloon dilation. Conclusions In the short to moderate term, in situ fenestration appears to be a reasonable and effective method to extend the proximal landing zone for revascularization of the left subclavian artery. However, longer follow-up is needed to fully assess the long-term durability of this procedure. Based on studies of material properties, an energy-based fenestration technique (radiofrequency or laser) is recommended, along with the avoidance of cutting balloons for dilation of the fenestration.

AMP-activated protein kinase (AMPK) has a broad role in the regulation of glucose and lipid metabolism making it a promising target in the treatment of type 2 diabetes mellitus. We therefore sought to characterise for the first time the effects of chronic AMPK activation on skeletal muscle carbohydrate metabolism in carriers of the rare gain-of-function mutation of the gene encoding AMPKgamma(3) subunit, PRKAG3 R225W.Aspects of fuel metabolism were studied in vitro in myocytes isolated from vastus lateralis of PRKAG3 R225W carriers and matched control participants. In vivo, muscular strength and fatigue were evaluated by isokinetic dynamometer and surface electromyography, respectively. Glucose uptake in exercising quadriceps was determined using [(18)F]fluorodeoxyglucose and positron emission tomography.Myotubes from PRKAG3 R225W carriers had threefold higher mitochondrial content (p0.01) and oxidative capacity, higher leak-dependent respiration (1.6-fold, p0.05), higher basal glucose uptake (twofold, p0.01) and higher glycogen synthesis rates (twofold, p0.05) than control myotubes. They also had higher levels of intracellular glycogen (p0.01) and a trend for lower intramuscular triacylglycerol stores. R225W carriers showed remarkable resistance to muscular fatigue and a trend for increased glucose uptake in exercising muscle in vivo.Through the enhancement of skeletal muscle glucose uptake and increased mitochondrial content, the R225W mutation may significantly enhance exercise performance. These findings are also consistent with the hypothesis that the gamma(3) subunit of AMPK is a promising tissue-specific target for the treatment of type 2 diabetes mellitus, a condition in which glucose uptake and mitochondrial function are impaired.

Purpose To evaluate the effects of in situ fenestration on the fabric of stent grafts deployed in a patient-specific phantom of a juxtarenal abdominal aortic aneurysm. Materials and Methods Four patient-specific juxtarenal abdominal aortic aneurysm polyurethane models were created, and bifurcated Zenith (Cook, Inc, Bloomington, Indiana) and Endurant (Medtronic, Minneapolis, Minneapolis) endografts were deployed into the models, covering the renal arteries. Antegrade in situ fenestration was carried out with radiofrequency puncture followed by balloon dilation with either conventional or cutting balloons. Renal covered stents were deployed and flared. Specimens were mounted onto an accelerated fatigue tester for 40M cycles (1 patient life-year), and evaluated with microscopy, caliper measurements, and fabric counts. Results Cutting balloons resulted in more fabric fraying. None of the fenestrations grew beyond the targeted 6-mm diameter despite accelerated fatigue. Fluoroscopic images demonstrated a very prominent waist of the renal fenestration in the Cook device when a conventional balloon was used compared with a cutting balloon. The average fenestration diameter for the Cook device was only 3.1 mm with the conventional balloon compared with 4.8 mm with the cutting balloon. The average fenestration diameter for the Medtronic device was 3.8 mm with the conventional balloon compared with 5.1 mm with the cutting balloon. The fabric counts suggested crowding of yarns around the fenestrations with conventional balloons but less with cutting balloons. Conclusions This experimental work suggests that the size of in situ renal fenestrations does not expand beyond the target diameter despite cyclic fatigue. Although the small number of devices tested and selected aortorenal anatomy in this study may limit conclusions, textile analysis suggests that cutting balloons should be used for the Cook Zenith device, whereas conventional balloons should be used for the Medtronic Endurant device when performing in situ fenestration.

Diffusion to solid-water interfaces is directly related to shear velocity. Shear velocities at the walls and bottoms of experimental ecosystem enclosures of different sizes and shapes (the Mul- tiscale Experiment Ecosystem Research Center pelagic/benthic (MEERC P/B) tanks at the University of Maryland Center for Environmental Science, Horn Point Laboratory) were measured using hot- film sensors. Spatially averaged bottom and wall shear velocities were related to internal mixing, which was produced by rotating internal paddles and measured using a combination of gypsum dis- solution and direct turbulence measurements. Shear velocities always increased with increasing mix- ing, but relationships between mixing and shear velocity changed with tank volume and shape. Spa- tially averaged bottom shear velocities decreased with increasing tank volume at an internal mixing level of 2 cm s -1 , but average wall shear velocities were similar for most tanks. In contrast, the rate of increase in bottom shear velocity with increasing mixing was similar for most tanks, but the rate of increase in wall shear velocity with increasing mixing was lower for the larger tanks. A bulk impeller Reynolds number captured some, but not all, of the scale dependence of ratios of boundary shear velocity to internal mixing intensity; mixing design and tank geometry were also important. Levels of all shear velocities in the MEERC P/B tanks were lower than levels in natural coastal environments for equivalent internal mixing. Realistic levels of internal mixing in the tanks resulted in unrealisti- cally low boundary shear velocities. As a result, wall diffusive sublayer thicknesses were similar to those found in deep-sea environments, and benthic diffusive sublayer thicknesses were even larger. Most current mesocosm designs are likely to be affected similarly. The artificially low-energy benthic environment may have particularly important consequences for ecosystem processes affected by pelagic-benthic coupling.

We present general nondimensional solutions for uptake across a solid-water boundary, considering the combined influences of mass transfer flux limitation and uptake reaction kinetics. Mass transfer processes are represented by a general mass transfer velocity. Reaction kinetics are represented by first-order and Monod models. Mathematical solutions are well approximated by standard mass transfer models for low values of the derived nondimensional mass transfer velocity and by standard kinetic models for high values. Approximate limiting values of the nondimensional mass transfer velocity are defined for mass transfer control and kinetic control. The intermediate region, where both mass transfer and kinetics influence the solution, is relatively broad for first-order kinetics and Monod kinetics in oligotrophic environments. Both limits decrease as concentration increases in the Monod solution, such that under increasingly eutrophic conditions mass transfer control becomes less important, the intermediate range shrinks, and kinetic control becomes an increasingly good approximation. Example calculations using data from experimental ecosystems indicate that boundary nutrient uptake was mass transfer controlled or intermediate under oligotrophic conditions. Nutrient pulses applied to the systems caused temporary eutrophication, which resulted in temporary kinetic control.

Bariatric surgery is an effective long-term solution for weight loss in the severely obese. Prevalence of bariatric surgery has increased over the recent years; however, the attrition rate of those referred who actually undergo surgery is high. The purpose of this study was to examine patients' attrition rates after referral for bariatric surgery at an academic tertiary care institution. When and why patients who were referred for bariatric surgery did not ultimately undergo surgical treatment was examined.Charts of 1,237 patients referred to the Toronto Western Hospital Bariatric Program from program inception to February 2011 were retrospectively reviewed. Patient demographics, appointment dates, no shows and cancellations, and when and why patients did not undergo surgery were summarized.Patients' mean age was 47. Most patients were female, and the mean body mass index was 47. Half (50.6 %) of the total persons referred left the program prior to being seen by a health-care professional, and only 36.2 % underwent surgical treatment. Only 2.75 % of persons were ineligible for surgery. A total of 60.6 % of persons self-removed from our program. Reasons for self-removal varied, with the most common reason for leaving the program recorded as "unknown."Our multidisciplinary program with in-hospital psychosocial resources resulted in very few persons being excluded from receiving surgical treatment. However, less than half of those referred underwent surgery as most persons self-removed from our program for unknown reasons. Further investigation is required to determine which patient, administrative, and system factors play a role in the patients' decision to not undergo bariatric surgical treatment.

Bariatric surgery is recognized as a treatment for severe obesity; however, little is known about factors influencing patient surgery non-completion. This study explored the relationship between psychiatric factors and patient non-completion during the pre-bariatric surgery suitability assessment.A total of 367 individuals underwent a structured psychiatric interview and were classified as either surgery completers (SC) or surgery non-completers (SNC) if they attended at least one pre-surgery assessment appointment but did not receive surgery.The results showed that in comparison to the SC group, the SNC group had significantly higher rates of overall past Axis I psychiatric disorders (58.1 vs. 46.6 %, p = 0.035), past anxiety disorders (17.4 vs. 9.4 %, p = 0.03), and past substance use disorders (8.7 vs. 3.7 %, p = 0.03). For specific past psychiatric disorders, the SNC group exhibited significantly higher rates of a past post-traumatic stress disorder (PTSD) (5 vs. 1 %, p = 0.029) and past substance dependence disorder (7 vs. 1 %, p = 0.005). Although overall current psychiatric disorders did not significantly differ between groups, the SNC group had significantly higher rates of current PTSD (2 vs. 0 %, p = 0.049) and current generalized anxiety disorder (4 vs. 0 %, p = 0.005).A past history of an anxiety or substance use disorder may play a role in patients not completing the assessment component of the bariatric surgery process. Additional psychosocial support, such as cognitive behavioral therapy or targeted psychoeducation, may help improve patient completion of the pre-surgery assessment phase.

Background Infection with HIV-1 results in marked immunologic insults and structural damage to the intestinal mucosa, including compromised barrier function. While the development of highly active antiretroviral therapy (HAART) has been a major advancement in the treatment of HIV-1 infection, the need for novel complementary interventions to help restore intestinal structural and functional integrity remains unmet. Known properties of pre-, pro-, and synbiotics suggest that they may be useful tools in achieving this goal. Methods This was a 4-week parallel, placebo-controlled, randomized pilot trial in HIV-infected women on antiretroviral therapy. A synbiotic formulation (Synbiotic 2000®) containing 4 strains of probiotic bacteria (1010 each) plus 4 nondigestible, fermentable dietary fibers (2.5 g each) was provided each day, versus a fiber-only placebo formulation. The primary outcome was bacterial translocation. Secondary outcomes included the levels of supplemented bacteria in stool, the activation phenotype of peripheral T-cells and monocytes, and plasma levels of C-reactive protein and soluble CD14. Results Microbial translocation, as measured by plasma bacterial 16S ribosomal DNA concentration, was not altered by synbiotic treatment. In contrast, the synbiotic formulation resulted in significantly elevated levels of supplemented probiotic bacterial strains in stool, including L. plantarum and P. pentosaceus, with the colonization of these two species being positively correlated with each other. T-cell activation phenotype of peripheral blood lymphocytes showed modest changes in response to synbiotic exposure, with HLA-DR expression slightly elevated on a minor population of CD4+ T-cells which lack expression of HLA-DR or PD-1. In addition, CD38 expression on CD8+ T-cells was slightly lower in the fiber-only group. Plasma levels of soluble CD14 and C-reactive protein were unaffected by synbiotic treatment in this study. Conclusions Synbiotic treatment for 4 weeks can successfully augment the levels of probiotic species in the gut during chronic HIV-1 infection. Associated changes in microbial translocation appear to be absent, and markers of systemic immune activation appear largely unchanged. These findings may help inform future studies aimed at testing pre- and probiotic approaches to improve gut function and mucosal immunity in chronic HIV-1 infection. Trial registration Clinical Trials.gov: NCT00688311

Obesity is an important risk factor for the development of type 2 diabetes, but not all obese individuals develop this complication. The clinical signs of type 2 diabetes can often be reversed with weight loss; however, it is unknown whether the skeletal muscle oxidative stress associated with type 2 diabetes remains after weight loss. We hypothesised that chronic exposure to high glucose and insulin would re-elicit impaired metabolism in primary myotubes from patients with a history of type 2 diabetes.Obese participants with or without type 2 diabetes completed a standardised weight loss protocol, following which all participants were euglycaemic and had similar indices of insulin sensitivity. Satellite cells were isolated from muscle biopsies and differentiated under low or high glucose and insulin conditions (HGI).Cells from participants with no history of type 2 diabetes showed robust increases in mitochondrial content, citrate synthase and cytochrome c oxidase activities when exposed to HGI. This increase in oxidative capacity was absent in cells from patients with a history of type 2 diabetes. High glucose and insulin caused increased oxidative damage in cells from the latter, despite higher superoxide dismutase expression. Cells from patients with a history of type 2 diabetes were unable to decrease mitochondrial membrane potential in response to HGI, potentially due to lower levels of uncoupling protein-3.This is the first report to note that primary myotubes from patients with a history of type 2 diabetes are unable to adapt to a hyperglycaemic-hyperinsulinaemic challenge. We have demonstrated that impaired mitochondrial biogenesis and an inability to manage oxidative stress define a muscle phenotype at risk of obesity-associated type 2 diabetes.

The yeast sir2 gene and its orthologues in Drosophila and C. elegans have well-established roles in lifespan determination and response to caloric restriction. We have studied mice carrying two null alleles for SirT1, the mammalian orthologue of sir2, and found that these animals inefficiently utilize ingested food. These mice are hypermetabolic, contain inefficient liver mitochondria, and have elevated rates of lipid oxidation. When challenged with a 40% reduction in caloric intake, normal mice maintained their metabolic rate and increased their physical activity while the metabolic rate of SirT1-null mice dropped and their activity did not increase. Moreover, CR did not extend lifespan of SirT1-null mice. Thus, SirT1 is an important regulator of energy metabolism and, like its orthologues from simpler eukaryotes, the SirT1 protein appears to be required for a normal response to caloric restriction.