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By analyzing the angular correlations in scanning electron nanodiffraction patterns from a melt-spun Zr36Cu64 glass, the dominant local order was identified as icosahedral clusters. Mapping the extent of this icosahedral short-range order demonstrates that the medium-range order in this material is consistent with a face-sharing or interpenetrating configuration. These conclusions support results from atomistic modeling and a structural basis for the glass formability of this system. [ABSTRACT FROM AUTHOR]

Aim: The aim was to investigate the effects of lotiglipron, a once-daily, oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist, in participants with type 2 diabetes (T2D) or obesity., Materials and Methods: A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study investigated the efficacy and safety of lotiglipron. The study was terminated early for safety reasons after routine data and monitoring review. The planned analyses for the end points were modified prior to unblinding the study., Results: In total, 901 participants were treated with at least one dose of the study drug (T2D cohort: n = 512, obesity cohort: n = 389). Although the majority of participants who were randomly assigned to higher doses did not reach their target maintenance dose, statistically significant changes in HbA1c and body weight were observed. In the T2D cohort, reductions in HbA1c were observed across all lotiglipron doses at week 16 (p < 0.0001), with least squares mean decreases up to -1.44% (90% confidence interval [CI]: -1.63, -1.26) (lotiglipron 80 mg), versus placebo, -0.07% (90% CI: -0.25, 0.11). In the obesity cohort, decreases in body weight were observed across all lotiglipron doses at week 20 (p < 0.01), up to -7.47% (90% CI: -8.50, -6.43) (lotiglipron 200 mg, five-step titration), versus placebo, -1.84% (90% CI: -2.85, -0.83). Across cohorts, the most frequently reported treatment-emergent adverse events were gastrointestinal related (most mild to moderate severity), with nausea being the most common (ranging from 4% [placebo] to 28.8% [80 mg] in the T2D cohort and 12.5% [placebo] to 60.6% [200 mg, four-step titration] in the obesity cohort). Transaminase elevations were observed in a subset of participants (6.6% and 6.0% of participants on lotiglipron in the T2D and obesity cohorts, respectively, compared with 1.6% on placebo in the obesity cohort)., Conclusions: The efficacy (HbA1c and/or body weight) of a range of lotiglipron doses was demonstrated in T2D and obesity cohorts. The safety profile was largely consistent with what has been previously known about the mechanism of action. Our results are unique in reporting elevations in liver transaminases in a subset of participants treated with lotiglipron, with attempts to identify the at-risk population unsuccessful and therefore clinical development of lotiglipron terminated., Clinicaltrials: GOV: NCT05579977., (© 2024 Pfizer,Inc. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Understanding vapor intrusion (VI) temporal variability is key for the design of sampling strategies intended to assess reasonable maximum exposure of indoor air concentrations of volatile organic compounds (VOCs) as well as risk evaluation and mitigation planning. VI temporal variability has previously been shown to be dependent on the complex interactions of multiple independent variables-meteorological, hydrogeological, and human behavioral. Several meteorological variables, including barometric pressure, wind speed, and rainfall, are linked during tropical and extratropical storm events. High-frequency meteorological and indoor VOC data from a series of seven tropical storms and four extratropical storms were collected at a single industrial building with multiple heating, ventilation, and air conditioning (HVAC) zones. The storms and sampling zones showed a variety of effects on trichloroethylene (TCE) concentrations in indoor air. In one zone (supply room), increases in TCE concentrations often, but not always, closely coincided with decreasing barometric pressure, sustained wind speeds over 32 km/h (20 mph), and differential pressures indicating subslab to indoor flow. A second zone, in a restroom, did not show a consistent pattern of temporal correlation between meteorological factors and indoor air concentrations. While peak indoor air concentrations may be associated with the passage of cyclonic storms at some sampling locations, this does not appear to be generalizable to all sampling locations. The observed increase in indoor air concentration potentially attributable to these storms is typically less than an order of magnitude and the duration ranges from a day to a week.

In this work, we present a pair of tools to improve the fiducial tracking and reconstruction quality of cryo-scanning transmission electron tomography (STET) datasets. We then demonstrate the effectiveness of these two tools on experimental cryo-STET data. The first tool, GoldDigger, improves the tracking of fiducials in cryo-STET by accommodating the changed appearance of highly defocussed fiducial markers. Since defocus effects are much stronger in scanning transmission electron microscopy than in conventional transmission electron microscopy, existing alignment tools do not perform well without manual intervention. The second tool, Checkers, combines image inpainting and unsupervised deep learning for denoising tomograms. Existing tools for denoising cryo-tomography often rely on paired noisy image frames, which are unavailable in cryo-STET datasets, necessitating a new approach. Finally, we make the two software tools freely available for the cryo-STET community., Competing Interests: The authors declare no financial or commercial conflict of interest., (© The Author(s) 2024.)

This paper introduces OpenFIBSEM, a universal API to control Focused Ion Beam Scanning Electron Microscopes (FIBSEM). OpenFIBSEM aims to improve the programmability and automation of electron microscopy workflows in structural biology research. The API is designed to be cross-platform, composable, and extendable: allowing users to use any portion of OpenFIBSEM to develop or integrate with other software tools. The package provides core functionality such as imaging, movement, milling, and manipulator control, as well as system calibration, alignment, and image analysis modules. Further, a library of reusable user interface components integrated with napari is provided, ensuring easy and efficient application development. OpenFIBSEM currently supports ThermoFisher and TESCAN hardware, with support for other manufacturers planned. To demonstrate the improved automation capabilities enabled by OpenFIBSEM, several example applications that are compatible with multiple hardware manufacturers are discussed. We argue that OpenFIBSEM provides the foundation for a cross-platform operating system and development ecosystem for FIBSEM systems. The API and applications are open-source and available on GitHub (https://github.com/DeMarcoLab/fibsem)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alex de Marco reports financial support was provided by Australian Research Data Commons (XN006). James Whisstock reports financial support was provided by Australian Research Council (grant ID FL180100019)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Diversity, equity, and inclusion (DEI) are crucial elements of successful veterinary emergency and critical care practices across the world. Embracing the elements of DEI creates a work environment that is safe and welcoming for all the members of the team. The American College of Veterinary Emergency and Critical Care DEI committee was formed to enhance and support efforts to increase racial diversity in veterinary emergency and critical care, as well as provide resources that will generate DEI practices across the country. This article provides an overview of the vision of the committee and some of the steps that have been taken to create a welcoming space for all represented in veterinary emergency and critical care., (© Veterinary Emergency and Critical Care Society 2022.)

Objectives: To investigate and characterise the incidence of iatrogenic complications secondary to closed chest cardiopulmonary resuscitation in dogs., Materials and Methods: Necropsy reports and histologic sections of tissues were retrospectively examined from 180 dogs that had received closed chest cardiopulmonary resuscitation to determine lesions associated with resuscitation., Results: The most common complication was pulmonary haemorrhage (81/163, 49.7%, 95% confidence interval: 42.1 to 57.3), although only nine dogs had pulmonary haemorrhage of at least moderate severity. Liver fractures occurred in 16 of 180 cases (8.9%, 95% confidence interval: 5.5 to 14.0). Blood loss of >15% of blood volume into the abdomen and/or thorax occurred in 13 of 180 cases (7.2%, 95% confidence interval: 4.2 to 12.1)., Clinical Significance: Significant haemorrhage secondary to cardiopulmonary resuscitation may decrease the chances of achieving the return of spontaneous circulation or may cause or compound ischemic damage to critical organs if the return of spontaneous circulation is achieved. Following successful cardiopulmonary resuscitation, animals should be screened for cavitary or pulmonary haemorrhage, as significant haemorrhage could be a factor in recurrence of cardiac arrest., (© 2021 British Small Animal Veterinary Association.)

The medical records of 59 puppies from 6 hospitals undergoing mechanical ventilation (MV) between 2006 and 2020 were reviewed to describe the signalment, underlying disease, duration of ventilation, and outcome. The most common underlying diseases were pneumonia ( n = 18), non-cardiogenic pulmonary edema ( n = 16), and trauma ( n = 8). Twenty-six (44%) puppies were weaned from the ventilator. The overall survival rate was 39% (23/59) including 19 non-brachycephalic dogs and 4 brachycephalics. Median duration of mechanical ventilation was 27 hours (range: 4 to 144 hours). Brachycephalic dogs were less likely to survive than nonbrachycephalic dogs ( P = 0.032). English bulldogs were over-represented with pneumonia. No association between age and survival to discharge ( P = 0.716) or outcome ( P = 0.579) was detected. The survival rate, and underlying disease process and severity for mechanically ventilated puppies was similar to previous studies in adult dogs., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Objective: To describe the use of therapeutic membrane-based plasma exchange (TPE) for treatment of clinical signs associated with suspected acquired myasthenia gravis (MG) in 3 dogs., Case Series Summary: Three dogs presented with clinical signs consistent with acquired MG. All 3 dogs were medically managed prior to being treated with TPE. Two of the 3 dogs had increased acetylcholine receptor antibody titers that decreased after TPE. One dog diagnosed with primary MG became clinically normal after 2 sessions of TPE and continued to do well with medical management several months later. The second dog was diagnosed with a suspect thymoma, and TPE was performed as a bridge to surgery, with marked improvement of clinical signs after TPE. The dog was ultimately diagnosed with a thymic carcinoma. The third dog had a positive acetylcholine antibody titer and was ultimately diagnosed with hemangiosarcoma (spleen and liver) and invasive mediastinal thymoma. This dog developed severe pneumonia, was ventilator dependent, and died of multiple organ dysfunction. No immediate complications were observed secondary to TPE. All 3 dogs were concurrently treated with either immunosuppressive agents, anticholinesterase drugs, or both., New or Unique Information Provided: The use of TPE in dogs with MG appears to be well tolerated and safe. It may be a reasonable adjunct therapy to acetylcholinesterase drugs in cases that are not responding to medical management alone. Therapeutic plasma exchange might also be considered preoperatively to prevent postoperative complications in dogs with severe MG, although further studies should be performed., (© Veterinary Emergency and Critical Care Society 2020.)

Cryo-Electron Tomography (cryo-ET) is a method that enables resolving the structure of macromolecular complexes directly in the cellular environment. However, sample preparation for in situ Cryo-ET is labour-intensive and can require both cryo-lamella preparation through cryo-Focused Ion Beam (FIB) milling and correlative light microscopy to ensure that the event of interest is present in the lamella. Here, we present an integrated cryo-FIB and light microscope setup called the Photon Ion Electron microscope (PIE-scope) that enables direct and rapid isolation of cellular regions containing protein complexes of interest. The PIE-scope can be retrofitted on existing microscopes, although the drawings we provide are meant to work on ThermoFisher DualBeams with small mechanical modifications those can be adapted on other brands., Competing Interests: Competing interestsThe authors declare no competing interests, (Copyright © The Authors; exclusive licensee Bio-protocol LLC.)

Cryo-transmission electron tomography (cryo-ET) in association with cryo-focused ion beam (cryo-FIB) milling enables structural biology studies to be performed directly within the cellular environment. Cryo-preserved cells are milled and a lamella with a typical thickness of 200-300 nm provides an electron transparent window suitable for cryo-ET imaging. Cryo-FIB milling is an effective method, but it is a tedious and time-consuming process, which typically results in ~10 lamellae per day. Here, we introduce an automated method to reproducibly prepare cryo-lamellae on a grid and reduce the amount of human supervision. We tested the routine on cryo-preserved Saccharomyces cerevisiae, mammalian 293 T cells, and lysozyme protein crystals. Here we demonstrate that our method allows an increased throughput, achieving a rate of 5 lamellae/hour without the need to supervise the FIB milling. We demonstrate that the quality of the lamellae is consistent throughout the preparation and their compatibility with cryo-ET analyses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Two similarly designed extension studies evaluated the long-term safety and tolerability of desvenlafaxine for the treatment of children and adolescents with major depressive disorder (MDD). Efficacy was evaluated as a secondary objective., Methods: Both 6-month, open-label, flexible-dose extension studies enrolled children and adolescents who had completed one of two double-blind, placebo-controlled, lead-in studies. One lead-in study included a 1-week transition period prior to the extension study. Patients received 26-week treatment with flexible-dose desvenlafaxine (20-50 mg/d). Safety assessments included comprehensive psychiatric evaluations, vital sign assessments, laboratory evaluations, 12-lead electrocardiogram, physical examination with Tanner assessment, and Columbia-Suicide Severity Rating Scale. Adverse events (AEs) were collected throughout the studies. Efficacy was assessed using the Children's Depression Rating Scale-Revised (CDRS-R)., Results: A total of 552 patients enrolled (completion rates: 66.4 and 69.1%). AEs were reported by 79.4 and 79.1% of patients in the two studies; 8.9 and 5.2% discontinued due to AEs. Treatment-emergent suicidal ideation or behavior was reported for 16.6 and 14.1% of patients in the two studies. Mean (SD) CDRS-R total score decreased from 33.83 (11.93) and 30.92 (10.20) at the extension study baseline to 24.31 (7.48) and 24.92 (8.45), respectively, at week 26., Conclusion: Desvenlafaxine 20 to 50 mg/d was generally safe and well tolerated with no new safety signals identified in children and adolescents with MDD who received up to 6 months of treatment in these studies. Patients maintained the reduction in severity of depressive symptoms observed in all treatment groups at the end of the lead-in study.

Cryo-electron tomography (cryo-ET) is emerging as a revolutionary method for resolving the structure of macromolecular complexes in situ. However, sample preparation for in situ Cryo-ET is labour-intensive and can require both cryo-lamella preparation through cryo-focused ion beam (FIB) milling and correlative light microscopy to ensure that the event of interest is present in the lamella. Here, we present an integrated cryo-FIB and light microscope setup called the P hoton I on E lectron microscope (PIE-scope) that enables direct and rapid isolation of cellular regions containing protein complexes of interest. Specifically, we demonstrate the versatility of PIE-scope by preparing targeted cryo-lamellae from subcellular compartments of neurons from transgenic Caenorhabditis elegans and Drosophila melanogaster expressing fluorescent proteins. We designed PIE-scope to enable retrofitting of existing microscopes, which will increase the throughput and accuracy on projects requiring correlative microscopy to target protein complexes. This new approach will make cryo-correlative workflow safer and more accessible., Competing Interests: SG, GB, GG, TJ, AH, MC, JW, RP, Ad No competing interests declared, (© 2019, Gorelick et al.)

Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC 50 's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Once the general decline in muscle mass, muscle strength and physical performance falls below specific thresholds, the middle aged or older adult will be diagnosed as having sarcopenia (a loss of skeletal muscle mass and strength). Sarcopenia contributes to a range of adverse events in older age including disability, hospitalisation, institutionalisation and falls. One potentially relevant but understudied population for sarcopenia researchers would be Masters athletes. Masters sport is becoming more common as it allows athletes (typically 40 years and older) the opportunity to participate in individual and/or team sports against individuals of similar age. This study examined a variety of measures of anthropometric, physical function and general health markers in the male and female Masters athletes who competed at the 2014 Pan Pacific Masters Games held on the Gold Coast, Australia. Bioelectrical impedance analysis was used to collect body fat percentage, fat mass and fat-free mass; with body mass, height, body mass index (BMI) and sarcopenic status also recorded. Physical function was quantified by handgrip strength and habitual walking speed; with general health described by the number of chronic diseases and prescribed medications. Between group analyses utilised ANOVA and Tukey's post-hoc tests to examine the effect of age group (40-49, 50-59, 60-69 and >70 years old) on the outcome measures for the entire sample as well as the male and female sub-groups. A total of 156 athletes (78 male, 78 female; mean 55.7 years) provided informed consent to participate in this study. These athletes possessed substantially better anthropometric, physical function and general health characteristics than the literature for their less physically active age-matched peers. No Masters athletes were categorised as being sarcopenic, although one participant had below normal physical performance and six participants had below normal muscle strength. In contrast, significant age-related reductions in handgrip strength and increases in the number of chronic diseases and prescribed medications were observed for the overall cohort as well as the male and female sub-groups. Nevertheless, even those aged over 70 years only averaged one chronic disease and one prescribed medication. These results may suggest that participation in Masters sport helps to maintain anthropometry, physical function and general health in middle-aged and older adults. However, it is also possible that only healthier middle-aged and older adults with favourable body composition and physical function may be able to participate in Masters sport. Future research should therefore utilise longitudinal research designs to determine the health and functional benefits of Master sports participation for middle-aged and older adults., Competing Interests: Timothy Henwood is the Group Manager, Connected Living—Community Wellness and Lifestyle of Southern Cross Care (SA & NT) Inc., Adelaide, South Australia, Australia. Justin W.L. Keogh is an Academic Editor for PeerJ.

OBJECTIVE To evaluate the feasibility of laparoscopy versus exploratory laparotomy for the diagnosis of specific lesions in dogs with suspected gastrointestinal obstruction. DESIGN Controlled trial. ANIMALS 16 client-owned dogs with physical and radiographic findings consistent with gastrointestinal obstruction. PROCEDURES Single-incision laparoscopy with intracorporeal and extracorporeal examination of the gastrointestinal tract was performed by 1 surgeon. Immediately afterward, exploratory laparotomy was performed by a second surgeon. Accessibility and gross appearance of organs, surgical diagnoses, incision lengths, procedure duration, and complications were compared between diagnostic techniques. RESULTS Mean (95% confidence interval) incision length was 4.9 cm (3.9 to 5.9 cm) for laparoscopy and 16.4 cm (14.0 to 18.7 cm) for exploratory laparotomy. Mean (95% confidence interval) procedure duration was 36.8 minutes (31.6 to 41.2 minutes) and 12.8 minutes (11.4 to 14.3 minutes), respectively. Diagnoses of the cause of obstruction were the same with both methods. In 13 dogs, the laparoscopic examination was successfully completed, and in the other 3, it was incomplete. In 4 dogs in which laparoscopy was successful, conversion to exploratory laparotomy or considerable extension of the laparoscopic incision would have been required to allow subsequent surgical treatment of identified lesions. No dogs developed major complications, and minor complication rates were similar between procedures. CONCLUSIONS AND CLINICAL RELEVANCE Laparoscopy was feasible and clinically applicable in dogs with suspected gastrointestinal obstruction. Careful patient selection and liberal criteria for conversion to an open surgical approach are recommended when laparoscopy is considered for the diagnosis of gastrointestinal lesions in dogs.

Background: Between 2001 and 2006, the Ontario government introduced a menu of new primary care models, with elements such as patient enrolment and minimum group sizes, and various combinations of fee-for-service, capitation, pay-for-performance and salary. From the statistical perspective of physicians, as opposed to patients, we looked at the distribution of physician characteristics, group size and patient visit patterns across models to describe primary care practice in Ontario., Methods: Using administrative data for fiscal year 2010/11 containing information on physician characteristics, patient rostering status, patient visits and other practice information, we described similarities and differences across primary care models., Results: Our sample included 11 626 family physicians. Compared with physicians in the new primary care models, physicians in fee-for-service models are much more likely to work part-time and many, particularly younger and female physicians, do not work in full-year full-scope practices. Among the new primary care models, physicians in capitated models are slightly younger, are less likely to be an international medical graduate, work in smaller physician teams and do not practice in urban areas. On average, physicians saw and rostered 1888 patients. Although there is still substantial variation within each model, fee-for-service physicians saw the fewest patients; physicians in capitated models saw somewhat more, and those in the noncapitated models saw the most patients., Interpretation: Practice and physician characteristics vary systematically across models. A high percentage of rostered patients see physicians outside the group with which they are rostered. Group-based primary care models may not have a large impact on group integration and continuity in the provision of primary care services., Competing Interests: Logan McLeod, Gioia Buckley and Arthur Sweetman report receiving grants from the Government of Ontario and Ontario SPOR Support Unit. No other competing interests were declared.

Objective: The purpose of this post hoc analysis was to evaluate the incidence and timing of taper/posttherapy-emergent adverse events (TPAEs) following discontinuation of long-term treatment with desvenlafaxine (administered as desvenlafaxine succinate)., Method: This was a phase 4, randomized, double-blind, placebo-controlled study conducted at 38 research centers within the United States between March 2010 and February 2011. Adult outpatients with major depressive disorder (MDD; DSM-IV-TR criteria) who completed 24 weeks of open-label treatment with desvenlafaxine 50 mg/d were randomly assigned to 1 of 3 groups for the double-blind taper phase: desvenlafaxine 50 mg/d for 4 weeks (no discontinuation), desvenlafaxine 25 mg/d for 1 week followed by placebo for 3 weeks (taper), or placebo for 4 weeks (abrupt discontinuation). The primary endpoint, Discontinuation-Emergent Signs and Symptoms Scale (DESS) score over the first 2 weeks of the taper phase, was described previously. Secondary assessments included incidence and timing of TPAEs (any adverse event that started or increased in severity during the double-blind phase) and the percentage of patients who could not continue the taper phase due to discontinuation symptoms. The Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16) assessed MDD status., Results: A total of 480 patients enrolled in the open-label phase; the full analysis set included 357 patients (taper, n = 139; abrupt discontinuation, n = 146; no discontinuation, n = 72). TPAEs occurred in all groups through week 4. The incidence of any TPAE was lower for taper versus abrupt discontinuation at week 1 (P < .001), similar at week 2, and lower for taper versus abrupt discontinuation at weeks 3 and 4 (P ≤ .034). The most common TPAEs (incidence ≥ 3%) in the taper group were nausea and headache (3% each) at week 1 and dizziness (5%) and headache (4%) at week 2. The most common TPAEs in the abrupt discontinuation group were dizziness (8%), headache (8%), nausea (4%), irritability (3%), and diarrhea (3%) at week 1 and headache (3%) at weeks 2 and 3. The most common TPAE in the no discontinuation group was nausea (6%) at week 2., Conclusion: The overall incidence of any TPAE was lower in the taper versus abrupt discontinuation groups., Trial Registration: ClinicalTrials.gov identifier: NCT01056289.

This study exploits a natural experiment in the province of Ontario, Canada, to identify the impact of pay-for-performance (P4P) incentives on the provision of targeted primary care services and whether physicians' responses differ by age, size of patient population, and baseline compliance level. We use administrative data that cover the full population of Ontario and nearly all the services provided by primary care physicians. We employ a difference-in-differences approach that controls for selection on observables and selection on unobservables that may cause estimation bias. We implement a set of robustness checks to control for confounding from other contemporaneous interventions of the primary care reform in Ontario. The results indicate that responses were modest and that physicians responded to the financial incentives for some services but not others. The results provide a cautionary message regarding the effectiveness of employing P4P to increase the quality of health care., (Copyright © 2013 John Wiley & Sons, Ltd.)

The objective of this study was to determine whether the occurrence of discontinuation symptoms was equivalent for abrupt discontinuation versus 1-week taper to desvenlafaxine 25 mg/d after a 24-week treatment with desvenlafaxine 50 mg/d (administered as desvenlafaxine succinate) for major depressive disorder. Adult outpatients with major depressive disorder who completed the 24 weeks of open-label treatment with desvenlafaxine 50 mg/d were randomly assigned to no discontinuation (desvenlafaxine 50 mg/d), taper (desvenlafaxine 25 mg/d), or abrupt discontinuation (placebo) groups for the double-blind (DB) taper phase. The primary end point was Discontinuation-Emergent Signs and Symptoms (DESS) scale total score during the first 2 weeks of the DB phase. The null hypothesis that the absolute difference of greater than 2.5 in DESS scores between taper and abrupt discontinuation groups was tested by calculating the 95% 2-sided confidence interval on the mean difference between the 2 groups. Of the 480 patients enrolled in the open-label phase, 357 (≥1 postrandomization DESS record) were included in the primary analysis. Adjusted mean ± SE DESS scores were 4.1 ± 0.72 for no discontinuation (n = 72), 4.8 ± 0.54 for taper (n = 139), and 5.3 ± 0.52 for abrupt discontinuation (n = 146) groups. The difference in adjusted mean DESS total scores between the abrupt discontinuation and taper groups was 0.50 (95% confidence interval, -0.88 to 1.89) within the prespecified margin (±2.5) for equivalence. The number of patients who discontinued because of adverse events or discontinuation symptoms during the DB period was similar between the taper (2.8%) and abrupt discontinuation (2.1%) groups. These findings indicate that an abrupt discontinuation of desvenlafaxine 50 mg/d produces statistically equivalent DESS scores compared with the 1-week taper using 25 mg/d.

The Institute of Food Technologists held Traceability Research Summits on July 14, August 22, and November 1, 2011, to address how to meet the growing requirement for agriculture and food traceability. Each meeting had a group of about 50 individuals who came from food companies, trade associations, local, state, and federal governments, 3rd-party traceability solution providers, not-for-profit corporations, consultants, and consumer groups. They discussed and deliberated the objectives of traceability and the means to develop product tracing in the food system. A total of 70 people participated in the 3 summits. These individuals were invited to participate in a small workgroup responsible for considering the details related to product tracing and presenting draft concepts to the larger group on November 1, 2011, in Chicago. During this meeting, the larger assembly further refined the concepts and came to an agreement on the basic principles and overall design of the desired approach to traceability., (© 2013 Institute of Food Technologists®)

IFT's Traceability Improvement Initiative aims to advance work in the area of food product tracing through several means including hosted events where thought leaders exchange knowledge and ideas. In August 2011, the Initiative, in collaboration with GS1 US, convened a group of 50 product tracing stakeholders, as a follow-on to a successful event the month prior. Representatives conducting pilots or implementation studies in produce, seafood, dairy, and other industries discussed the objectives, challenges and learnings. Some of the learnings from on-going initiatives included the sense that better information management provides a return of investment; data often exist but may not necessarily be appropriately linked through the supply chain; and enhanced product tracing enables better accountability and quality control. Challenges identified in enabling traceability throughout the supply chain were the distribution complexity; the need for training, communication, and collaboration; improving the reliability, quality and security of data captured, stored and shared as well as the importance of standards in data and interoperability of technology. Several approaches to overcoming these challenges were discussed. The first approach incrementally improves upon the current "one up/one down" system by requiring electronic records and tracking internal as well as external critical tracking events. The benefits of this approach are its similarity to existing regulatory requirements and low cost of implementation; resulting in a higher probability of adoption. The major disadvantage to this process is the longer response time required during a trace (back or forward). The second approach is similar to a "pedigree" approach where historical information about the food travels with it through the value chain. A major advantage of this approach is the quickest response time during a trace. Some of the disadvantages of this approach are potential for misuse of data, the volume of data required to be maintained at value chain end points, and data privacy concerns. The third approach requires individual nodes within the value chain to maintain electronic records for its own data and make them available for querying during a traceback for outbreak investigation. The major advantage of this approach is the protection of confidential information and the potential for quicker access during a trace. However, the primary disadvantage of this approach is the need for greater computational power and a more complex mechanism to linking the value chain through the data. As next steps, a subgroup will work on clarifying the approach to meeting the goals of traceability, better defining critical tracking events, and articulating the strategy and return on investment from a regulatory and industry perspective. This will result in improved alignment of on-going traceability pilots and initiatives as well as a more actionable guidance document for public review., (© 2012 Institute of Food Technologists®)

Objective: Determine the point prevalence of phenoconversion to cytochrome P450 2D6 (CYP2D6) poor metabolizer status in clinical practice., Method: This multicenter, open-label, single-visit naturalistic study was conducted from October 2008 to July 2009 in adult patients (≥ 18 years) who had been receiving venlafaxine extended-release (ER) (37.5-225 mg/d) treatment for up to 8 weeks. A 15-mL blood sample was drawn 4 to 12 hours after patients' last venlafaxine ER dose. Plasma O-desmethylvenlafaxine and venlafaxine concentrations were determined for each patient. CYP2D6 poor metabolizer phenotype was defined as O-desmethylvenlafaxine to venlafaxine ratio < 1 based on published data. CYP2D6 genotype was determined for each patient; patients were classified as poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultrarapid metabolizer. Agreement between poor metabolizer phenotype and genotype classifications was assessed using the McNemar test., Results: Phenoconversion to CYP2D6 poor metabolizer status occurred in 209 of 865 individuals (24%) with a CYP2D6 non-poor metabolizer genotype. The incidence of CYP2D6 poor metabolizer status based on phenotype was almost 7 times higher than that expected based on genotype: only 4% (35/900) of patients were genotypic CYP2D6 poor metabolizers, but 27% (243/900) were phenotypic CYP2D6 poor metabolizers (McNemar test, P < .0001)., Conclusions: CYP2D6 phenotype conversion is common in patients being treated for depression. These results are important because differences in CYP2D6 drug metabolic capacity, whether genetically determined or due to phenoconversion, can affect clinical outcomes in patients treated with drugs substantially metabolized by CYP2D6. These results demonstrate that personalized medicine based solely on genetics can be misleading and support the need to consider drug-induced variability as well., Trial Registration: ClinicalTrials identifier: NCT00788944., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

By analyzing the angular correlations in scanning electron nanodiffraction patterns from a melt-spun Zr(36)Cu(64) glass, the dominant local order was identified as icosahedral clusters. Mapping the extent of this icosahedral short-range order demonstrates that the medium-range order in this material is consistent with a face-sharing or interpenetrating configuration. These conclusions support results from atomistic modeling and a structural basis for the glass formability of this system.

We report the optimization of a series of non-steroidal GR antagonists that led to the identification of compound 7. This compound is efficacious when dosed orally in an olanzapine-induced weight gain model in rats., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To determine if low tidal volume (V(T) ) ventilation is associated with the development of respiratory acidosis and changes in lung function in healthy dogs., Design: Randomized prospective experimental cross-over study., Setting: Pulmonary function laboratory at a university teaching hospital., Animals: Five healthy Beagle dogs., Interventions: Dogs were anesthetized and randomly mechanically ventilated with V(T) of 6, 8, 10, 12, and 15 mL/kg while maintaining a constant minute volume., Measurements and Main Results: Arterial blood gases and pulmonary mechanics were collected after 15 minutes of equilibration at each V(T). Repeated measures ANOVA was used to determine the effect of V(T) with a P-value of <0.05 considered significant, and a Pearson product moment was used to determine correlation between V(T) and pH and PaCO(2). V(T) had a significant effect on PaCO(2) (P < 0.001) and on pH (P < 0.001) with lower V(T) being associated with higher PaCO(2) and lower pH. There was a strong correlation between V(T) and PaCO(2) (r = -0.87) and V(T) and pH (r = 0.83). Increased airway pressures and pulmonary compliance were associated with increasing V(T)., Conclusions: There is a predictable decrease in the pH, decrease in airway pressure, decrease in compliance, and increase in the PaCO(2) associated with lower V(T). Low V(T) ventilation is well tolerated in healthy dogs; the role of low V(T) ventilation in dogs with acute lung injury/acute respiratory distress syndrome as well as the influence of positive end expiratory pressure requires further evaluation., (© Veterinary Emergency and Critical Care Society 2012.)

The MRL/MpJ mouse displays the rare ability amongst mammals to heal injured ear tissue without scarring. Numerous studies have shown that the formation of a blastema-like structure leads to subsequent tissue regeneration in this model, indicating many parallels with amphibian limb regeneration and mammalian embryogenesis. We have recently shown that the MRL/MpJ mouse also possesses an enhanced capacity for peripheral nerve regeneration within the ear wound. Indeed, nerves are vital for the initial phase of blastema formation in the amphibian limb. In this study we investigated the capacity for wound regeneration in a denervated ear. The left ears of MRL/MpJ mice and C57BL/6 (a control strain known to have a poorer regenerative capacity) were surgically denervated at the base via an incision and nerve transection, immediately followed by a 2-mm ear punch wound. Immunohistochemical analysis showed a lack of neurofilament expression in the denervated ear wound. Histology revealed that denervation prevented blastema formation and chrondrogenesis, and also severely hindered normal healing, with disrupted re-epithelialisation, increasing wound size and progressive necrosis towards the ear tip. Denervation of the ear obliterated the regenerative capacity of the MRL/MpJ mouse, and also had a severe negative effect on the ear wound repair mechanisms of the C57BL/6 strain. These data suggest that innervation may be important not only for regeneration but also for normal wound repair processes., (© 2011 The Authors. Journal of Anatomy © 2011 Anatomical Society of Great Britain and Ireland.)

This study investigates the contractile response to 5 hydroxytryptamine (5HT) of chorionic artery and vein segments from normotensive (NT) and pre-eclamptic (PE) placentae. It also looked at the effectiveness of ketanserin (KET), a 5HT(2A) receptor antagonist, in reducing 5HT-mediated vasoconstriction. 5HT induced vasoconstriction in all of the vessels was studied. Compared to NT vessels, Emax (%KCl) was significantly reduced in PE arteries (p<0.05) and veins (p<0.0005). The mean Emax for NT arteries was 104.1 (±10.71) whilst PE arteries showed a mean Emax of 57.02 (±12.13). KET produced a statistically significant reduction of Emax in both vessels in NT and the arteries in PE. However the antagonistic effect of KET was not pronounced in PE veins. The EC50 values for NT and PE arteries and veins did not change significantly. There were no noticeable changes in the expression profiles of 5HT(2A) receptor mRNA and protein expressions. The data from this study suggest that in PE, the vascular reactivity of chorionic vessels to 5HT is reduced and it was not due to the altered expression of 5HT(2A) receptors., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Administration of epinephrine during CPR is recommended for treatment of cardiopulmonary arrest (CPA) in dogs. Administration of epinephrine during CPR might be associated with deleterious adverse effects. Vasopressin has been studied for use in CPR as an alternative., Hypothesis: That administration of vasopressin instead of epinephrine with standard CPR techniques will result in improved outcome., Animals: Seventy-seven client-owned dogs identified in the ER/ICU with CPA were eligible for inclusion., Methods: Randomized, prospective clinical study. Dogs were randomized to receive epinephrine (0.01-0.02 mg/kg) or vasopressin (0.5-1 U/kg) in a blinded fashion. Attending veterinarians were asked to adhere to standardized CPR protocol for the 1st 6 minutes of CPR, during which time doses of the study drug were administered at 3-minute intervals., Results: A total of 60 dogs completed this study with 31 receiving epinephrine and 29 receiving vasopressin. Overall rate of return of spontaneous circulation (ROSC) was 60% (36/60), 32% (19/60) of dogs survived to 20 minutes, 18% (11/60) survived to 1 hour. No difference was seen in rates of ROSC between the 2 groups (P = .20). Dogs receiving epinephrine were more likely to survive to 1 hour (odds ratio 5.86; 95% CI: 1.19-28.95) than those receiving vasopressin (P = .027)., Conclusions and Clinical Importance: ROSC was similar in dogs receiving epinephrine or vasopressin. In this study, a survival advantage at 1 hour was seen in those animals receiving epinephrine. No advantage of routine use of vasopressin over epinephrine was detected. Further studies are required to examine subgroups of dogs that might benefit from specific interventions., (Copyright © 2011 by the American College of Veterinary Internal Medicine.)

The MRL/MpJ mouse displays an accelerated ability to heal ear punch wounds without scar formation (whereas wounds on the dorsal surface of the trunk heal with scar formation), offering a rare opportunity for studying tissue regeneration in adult mammals. A blastema-like structure develops and subsequently the structure of the wounded ear is restored, including cartilage, skin, hair follicles and adipose tissue. We sought to assess if the MRL/MpJ strain also possessed an enhanced capacity for peripheral nerve regeneration. Female MRL/MpJ and C57BL/6 mice were wounded with a 2-mm excisional biopsy punch to the centre of each ear and two 4-mm excisional biopsy punches to the dorsal skin. Immunohistochemical dual staining of pan-neurofilament and CD31 markers was used to investigate reinnervation and vascularisation of both the dorsal surface of the trunk and ear wounds. The MRL/MpJ mouse ear exhibited a significantly (P > 0.01) higher density of regenerated nerves than C57BL/6 between 10 and 21 days post-wounding when the blastema-like structure was forming. Unlike dorsal skin wounds, nerve regeneration in the ear wound preceded vascularisation, recapitulating early mammalian development. Immunohistochemical data suggest that factors within the blastemal mesenchyme, such as aggrecan, may direct nerve regrowth in the regenerating ear tissue., (© 2010 The Authors. Journal of Anatomy © 2010 Anatomical Society of Great Britain and Ireland.)

Optimization of the cellular and pharmacological activity of a novel series of PI3 kinase inhibitors targeting multiple isoforms is described.