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Laudet, Alexandre B., Stephen Magura, Howard S. Vogel, and Edward L. Knight. "Participation in 12-Step-Based Fellowships Among Dually-Diagnosed Persons." Alcoholism Treatment Quarterly 21, no. 2 (July 10, 2003): 19–39. http://dx.doi.org/10.1300/j020v21n02_02.
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Magura, Stephen. "The Relationship Between Substance User Treatment and 12-Step Fellowships: Current Knowledge and Research Questions." Substance Use & Misuse 42, no. 2-3 (January 2007): 343–60. http://dx.doi.org/10.1080/10826080601142071.
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Rodriguez-Morales, Lymarie. "In Your Own Skin: The Experience of Early Recovery from Alcohol-Use Disorder in 12-Step Fellowships." Alcoholism Treatment Quarterly 35, no. 4 (August 14, 2017): 372–94. http://dx.doi.org/10.1080/07347324.2017.1355204.
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Matusow, Harlan, Honoria Guarino, Andrew Rosenblum, Howard Vogel, Thomas Uttaro, Sadiqua Khabir, Martin Rini, Thomas Moore, and Stephen Magura. "Consumers’ Experiences in Dual Focus Mutual Aid for Co-occurring Substance Use and Mental Health Disorders." Substance Abuse: Research and Treatment 7 (January 2013): SART.S11006. http://dx.doi.org/10.4137/sart.s11006.
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Mutual aid fellowships have been shown to improve outcomes for those with co-occurring substance use and mental illness disorders. Processes associated with usefulness include helper therapy (the assumption of a helping role to foster commitment) and reciprocal learning (the sharing of problems and solutions among members). The present qualitative investigation used focus groups comprised a subset of participants in Double Trouble in Recovery (DTR), a 12-step mutual aid group for those with co-occurring disorders, to gather their subjective perceptions of the groups. Participants emphasized that in linking them to others with similar problems, the DTR groups played a vital emotional role in their lives and provided a needed venue for information sharing that might have been otherwise unavailable.
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Laudet, Alexandre B., Keith Morgen, and William L. White. "The Role of Social Supports, Spirituality, Religiousness, Life Meaning and Affiliation with 12-Step Fellowships in Quality of Life Satisfaction Among Individuals in Recovery from Alcohol and Drug Problems." Alcoholism Treatment Quarterly 24, no. 1-2 (January 2006): 33–73. http://dx.doi.org/10.1300/j020v24n01_04.
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KELEMEN, GABOR, and MARTA B. ERDOS. "THE CODE OF GRACE: A CULTURAL APPROACH TO 12-STEP FELLOWSHIP PROGRAMS IN HUNGARY." International Journal of Self Help and Self Care 2, no. 3 (March 1, 2005): 187–203. http://dx.doi.org/10.2190/uqwd-57eu-48rk-6ae5.
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Hite, Rebecca, and Jeff Milbourne. "A Proposed Conceptual Framework for K–12 STEM Master Teacher (STEMMaTe) Development." Education Sciences 8, no. 4 (December 14, 2018): 218. http://dx.doi.org/10.3390/educsci8040218.
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Recent reports from federal agencies and legislation call for explicit avenues to incorporate K–12 STEM master teacher voice into the policy space. National initiatives, federal legislation, and teacher recognition programs have sought to identify K–12 STEM master teachers and harness their potential. These efforts warrant a conceptual framework to quantify attributes of K–12 STEM master teachers, to foster pathways for the development of current and future leaders. Using a sample of 10 individuals from two extant programs of K–12 STEM master teachers (Albert Einstein Distinguished Educator Fellowship and Presidential Awards for Excellence in Mathematics and Science Teaching), data from their career trajectories (sourced from Curriculum Vitae) were sequenced to construct and confirm the STEM Master Teacher (STEMMaTe) conceptual framework. This framework may be used to guide programmatic development to increase national capacity for K–12 STEM master teachers. Recommendations are discussed for the creation of pathways to develop STEM master teachers and increase their participation in the broader education system.
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Gold, Mark S. "Neurobiology of addiction and recovery: The brain, the drive for the drug, and the 12-step fellowship." Journal of Substance Abuse Treatment 11, no. 2 (March 1994): 93–97. http://dx.doi.org/10.1016/0740-5472(94)90022-1.
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Parker, Kimberly A., Lauren Roberson, Bobi Ivanov, Richard Carter, and Natalie Riney. "Participating in 12-Step Programs in Recovery Homes: The Positive Experience of Structure, Fellowship, and Community of Support." International Journal of Interdisciplinary Social and Community Studies 16, no. 1 (2021): 139–47. http://dx.doi.org/10.18848/2324-7576/cgp/v16i01/139-147.
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Ferentzy, Peter, Wayne Skinner, and Paul Antze. "Gamblers Anonymous and the 12 Steps: How an informal society has altered a recovery process in accordance with the special needs of problem gamblers." Journal of Gambling Issues, no. 23 (June 1, 2009): 42. http://dx.doi.org/10.4309/jgi.2009.23.3.
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This paper discusses how Gamblers Anonymous (GA) members approach the 12 Steps of recovery, originally advanced by Alcoholics Anonymous (AA) as a spiritual solution to alcoholism. GA's approach finds unique expression in its fourth step, which in AA involves a written "moral inventory." In GA, members are expected to make a financial inventory alongside the moral one. Pecuniary matters are important to gamblers given the debt loads many of them carry. Debt, which is technically a Step 4 and Step 9 (making amends) issue, in practice is typically addressed early in the program, with preceding steps addressed later. The spiritual process central to 12 Step programs will normally not proceed in the expected manner when gamblers are substituted for substance abusers. For one, the process is not as linear for gamblers. GA members often work on the ninth step well before addressing those coming before it. The process assumes a pragmatic, and even haphazard, flavor. GA has altered a time-honored process of recovery - by means of grassroots wisdom and practice - to apply to the realities of problem gambling. While the paper's primary focus is GA's unique approach to the 12 Steps, this is addressed in the context of the changing nature of GA as a whole. Shifting spousal and gender roles along with a greater appreciation of the 12 Steps themselves are all endemic to a GA fellowship that seems to be in transition. While these changes have had some effect, many aspects of GA's approach to the 12 Steps remain intact: the focus on debt entails solutions seemingly unique to the special needs of problem gamblers.
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Laudet, Alexandre B., Stephen Magura, Charles M. Cleland, Howard S. Vogel, Edward L. Knight, and Andrew Rosenblum. "The Effect of 12-Step-Based Fellowship Participation on Abstinence Among Dually Diagnosed Persons: A Two-Year Longitudinal Study." Journal of Psychoactive Drugs 36, no. 2 (June 2004): 207–16. http://dx.doi.org/10.1080/02791072.2004.10399731.
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Sanders, Elmer, Vanessa Barth, Leigh-Ann Cruz, Ilesha Sherrer, Jacob Olson, Emily Speidell, Elvia Solis, Sharon Harrison, Amy Hinshaw, and James A. McAteer. "4539 Building a Translational Science pipeline: The Indiana CTSI STEM K-12 Program." Journal of Clinical and Translational Science 4, s1 (June 2020): 57–58. http://dx.doi.org/10.1017/cts.2020.203.
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OBJECTIVES/GOALS: Develop strong network of science teachers interested in promoting scientific research to their students.Place students in an immersive summer research internship that, when possible, matches their career interests.Expose students to the numerous career paths within the STEM field.METHODS/STUDY POPULATION: The program recruits socio-economically disadvantaged students and provides them a stipend, and also accepts students who can participate unpaid.Local school teachers are engaged in a summer fellowship to learn biotechnologies and research. In Spring these teachers help recruit students and during the subsequent Fall help students with college and scholarship applications.Students are placed in a variety of laboratories within the Schools of Medicine, Science, Dentistry, Public Health, Informatics, Health and Human Sciences, Engineering and Technology, especially in biomedical engineering. Students are also placed in industry laboratories such as Eli Lilly and the Indiana Bioscience Research Institute.Long-term program follow-up is done through post-internship surveys to assess impact on graduate and professional school admission.RESULTS/ANTICIPATED RESULTS: Since the Indiana CTSI was established in 2008, 872 students have participated in the summer internship.71% of past interns are underrepresented minorities in science or classified as disadvantaged by NIH criteria.17% of students interned during grade 10, 72% during grade 11, and 11% during grade 12.21% of students engage in the program for more than one year.100% of past interns are currently enrolled in or have graduated college.Over 60% of those with a bachelors degree proceed to graduate and professional schools and over 80% stay in STEM related fields. These rates are equal for interns from underrepresented minorities or those classified as disadvantaged by NIH criteria.DISCUSSION/SIGNIFICANCE OF IMPACT: Students engaged in the Indiana CTSI STEM program are progressing through the translational science pipeline based on their graduating from college and remaining in the STEM field.
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Vuong, Lan N., Vu N. A. Ho, Tuong M. Ho, Vinh Q. Dang, Tuan H. Phung, Nhu H. Giang, Anh H. Le, et al. "In-vitro maturation of oocytes versus conventional IVF in women with infertility and a high antral follicle count: a randomized non-inferiority controlled trial." Human Reproduction 35, no. 11 (September 24, 2020): 2537–47. http://dx.doi.org/10.1093/humrep/deaa240.
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Abstract STUDY QUESTION Is one cycle of IVM non-inferior to one cycle of conventional in IVF with respect to live birth rates in women with high antral follicle counts (AFCs)? SUMMARY ANSWER We could not demonstrate non-inferiority of IVM compared with IVF. WHAT IS KNOWN ALREADY IVF with ovarian hyperstimulation has limitations in some subgroups of women at high risk of ovarian stimulation, such as those with polycystic ovary syndrome. IVM is an alternative ART for these women. IVM may be a feasible alternative to IVF in women with a high AFC, but there is a lack of data from randomized clinical trials comparing IVM with IVF in women at high risk of ovarian hyperstimulation syndrome. STUDY DESIGN, SIZE, DURATION This single-center, randomized, controlled non-inferiority trial was conducted at an academic infertility center in Vietnam from January 2018 to April 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 546 women with an indication for ART and a high AFC (≥24 follicles in both ovaries) were randomized to the IVM (n = 273) group or the IVF (n = 273) group; each underwent one cycle of IVM with a prematuration step versus one cycle of IVF using a standard gonadotropin-releasing hormone antagonist protocol with gonadotropin-releasing hormone agonist triggering. The primary endpoint was live birth rate after the first embryo transfer. The non-inferiority margin for IVM versus IVF was −10%. MAIN RESULTS AND THE ROLE OF CHANCE Live birth after the first embryo transfer occurred in 96 women (35.2%) in the IVM group and 118 women (43.2%) in the IVF group (absolute risk difference –8.1%; 95% confidence interval (CI) –16.6%, 0.5%). Cumulative ongoing pregnancy rates at 12 months after randomization were 44.0% in the IVM group and 62.6% in the IVF group (absolute risk difference –18.7%; 95% CI –27.3%, –10.1%). Ovarian hyperstimulation syndrome did not occur in the IVM group, versus two cases in the IVF group. There were no statistically significant differences between the IVM and IVF groups with respect to the occurrence of pregnancy complications, obstetric and perinatal complications, preterm delivery, birth weight and neonatal complications. LIMITATIONS, REASONS FOR CAUTION The main limitation of the study was its open-label design. In addition, the findings are only applicable to IVM conducted using the prematuration step protocol used in this study. Finally, the single ethnicity population limits the external generalizability of the findings. WIDER IMPLICATIONS OF THE FINDINGS Our randomized clinical trial compares live birth rates after IVM and IVF. Although IVM is a viable and safe alternative to IVF that may be suitable for some women seeking a mild ART approach, the current study findings approach inferiority for IVM compared with IVF when cumulative outcomes are considered. Future research should incorporate multiple cycles of IVM in the study design to estimate cumulative fertility outcomes and better inform clinical decision-making. STUDY FUNDING/COMPETING INTEREST(S) This work was partly supported by Ferring grant number 000323 and funded by the Vietnam National Foundation for Science and Technology Development (NAFOSTED) and by the Fund for Research Flanders (FWO). LNV has received speaker and conference fees from Merck, grant, speaker and conference fees from Merck Sharpe and Dohme, and speaker, conference and scientific board fees from Ferring; TMH has received speaker fees from Merck, Merck Sharp and Dohme, and Ferring; RJN has received conference and scientific board fees from Ferring, is a minor shareholder in an IVF company, and receives grant funding from the National Health and Medical Research Council (NHMRC) of Australia; BWM has acted as a paid consultant to Merck, ObsEva and Guerbet, and is the recipient of grant money from an NHMRC Investigator Grant; RBG reports grants and fellowships from the NHMRC of Australia; JS reports lecture fees from Ferring Pharmaceuticals, Biomérieux, Besins Female Healthcare and Merck, grants from Fund for Research Flanders (FWO), and is co-inventor on granted patents on CAPA-IVM methodology in the US (US10392601B2) and Europe (EP3234112B1); TDP, VQD, VNAH, NHG, AHL, THP and RW have no financial relationships with any organizations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER NCT03405701 (www.clinicaltrials.gov). TRIAL REGISTRATION DATE 16 January 2018. DATE OF FIRST PATENT’S ENROLMENT 25 January 2018.
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Brown, Cameron. "Can 12 step fellowship and cognitive behaviour therapy work together? A hypothesis on an integrated treatment approach for mild dual diagnosis." Advances in Dual Diagnosis 5, no. 3 (August 10, 2012): 115–21. http://dx.doi.org/10.1108/17570971211253694.
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Testa, Edward J., Jeremiah T. Lowe, Surena Namdari, Robert J. Gillespie, Benjamin W. Sears, Peter S. Johnston, and Andrew Jawa. "Operative duration-based learning period analysis for reverse and total shoulder arthroplasty: A multicenter study." Shoulder & Elbow 12, no. 1_suppl (November 14, 2018): 23–30. http://dx.doi.org/10.1177/1758573218811635.
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Background A surgical learning period may be quantified after which operative duration is significantly reduced. We sought to retrospectively quantify and compare surgeon’s learning experience for total shoulder arthroplasty and reverse shoulder arthroplasty. Methods We reviewed 2055 shoulder arthroplasty cases from 2011 to 2015 for four early-career and four later-career fellowship-trained shoulder surgeons from four institutions. We plotted consecutive case number versus operative time for each surgeon separately for total shoulder arthroplasty or reverse shoulder arthroplasty. Two-step regression approach was used to determine a plateau point or end of the learning period. Additionally, the mean annual volume of reverse shoulder arthroplasty and total shoulder arthroplasty for each surgeon was plotted against mean surgery duration. Early- and later-career surgeons were compared with regression analysis. Results Early-career surgeons demonstrated a significant decrease in operative time with increasing annual case volume for reverse shoulder arthroplasty ( p = 0.01; m = −1.1) and total shoulder arthroplasty ( p = 0.02; m = −0.8). Three of four early-career surgeons reached a plateau point for either reverse shoulder arthroplasty or total shoulder arthroplasty between 12 and 86 cases. Conclusion For only early-career surgeons, higher case volume yields decreased operative duration, with improvement more pronounced for reverse shoulder arthroplasty compared to total shoulder arthroplasty. Though the learning period varies, it may be fewer than 90 cases.
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Vrabel, Maura, Jake Schulman, and David Zaharoff. "457 Intratumoral interleukin-12 administered after cryoablation does not improve survival in multiple bilateral murine models." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A484—A485. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0457.
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BackgroundClinically, cryoablation is used to treat certain early stage prostate, liver, and kidney tumors in addition to bone and soft tissue sarcomas. However, for late-stage cancers, ablation is only an auxiliary step before complete resection. This leaves a gap of patients with advanced and inoperable tumors, where up to 90% of all pancreatic, and 80–85% of all prostate cancers are unresectable at diagnosis.1 2 Because cryoablation can release large amounts of antigen, it is uniquely capable of not only treating advanced, unresectable tumors, but also may induce an in situ vaccination response when combined with the appropriate immunotherapy. Previously, our results in single primary tumor models indicated that the addition of interleukin-12 (IL-12) to cryoablation (cryo) improved tumor burden and survival We hypothesized that intratumoral injection of IL-12 after cryo would activate a strong T cell response and induce systemic immunity in bilateral tumor models.MethodsPanc02 cells were purchased from ATCC; MC38 and MB49 cells were acquired from the NIH. Female C57BL/6 mice were purchased from Jackson Laboratory. For primary tumor implantation, 1 × 106 Panc02 cells and 3 × 105 MC38 cells were injected subcutaneously (s.c.) in the right flank. For rechallenge, the same dose of cells was implanted on the left flank of cured mice. For bilateral models, in both the MB49 and MC38 models, 3 × 105 and 1.5 × 105 cells were injected s.c. in the right and left flanks respectively on the same day. For the Panc02 model, 1 × 106 cells were implanted s.c. on both the right and left flanks on the same day. Tumor volume was calculated as 0.5*a*b2 given the perpendicular long (a) and short (b) dimensions. Tumors measuring between 150–300 mm3 were cryoablated with three cycles of freeze/thaw using the Visual-ICETM Cryoablation System (Boston Scientific). The dose of IL-12 was 1 µg/mouse in 1.5% (w/v) chitosan acetate (CS) dissolved in DPBS, and then injected intratumorally within an hour after cryoablation. For the anti-PD-1 and isotype antibodies (BioXCell, clone: RMP1.14). 300µg was injected intraperitoneally every 3 days starting on the day of cryoablation for a total of 4 doses.ResultsIn the bilateral MB49 mouse bladder cancer model, the median survival for the cryo alone group was 20 days post treatment (p.t.) compared to 23 days p.t. for cryo + CS/IL-12, which was not significant, and 12 days for the untreated control group. In the bilateral Panc02 model, the median survival for both the cryo alone and cryo + CS/IL-12 groups was the same at 20.5 days p.t., compared to 10 days p.t. for the untreated control. In the bilateral MC38 model, the addition of anti-PD-1 to cryo + CS/IL-12 did not significantly improve survival compared to isotype + cryo + CS/IL-12, with a median survival of 24 days p.t. and 16 days p.t. respectively (p=0.53, Log-rank test) (figure 1). However, addition of anti-PD-1 did significantly delay abscopal tumor growth up to 500 mm3 when compared to the isotype + cryo + CS/IL-12 (p=0.0398, Unpaired t test) (figure 2). Finally, the addition of IL-12 worsens memory in the MC38 model, where 100% of rechallenged cryo alone mice were protected (5/5) compared to only 43% protected of the cryo + CS/IL-12 group (3/7).Abstract 457 Figure 1Survival of bilateral MC38MC38 cells were implanted s.c. in the right and left flanks of C57/BL6 mice at 3 × 105 and 1.5 × 105 cells per 100 uL respectively. The tumor was allowed to grow to between 150 to 300 mm3 prior to cryoablation. CS/IL-12 was injected intratumorally within an hour after cryoablation. Criteria for euthanasia was a tumor burden greater than or equal to 2000 mm3 or if mouse became moribund. The median survival for each group was 8 days p.t. (Isotype), 11 days p.t. (a-PD-1), 15 days (Iso + Cryo), 14 days p.t. (a-PD-1 + Cryo), 16 days p.t. (Iso + Cryo + CS/IL-12), 24 days p.t. (a-PD-1 + Cryo + CS/Il-12), p < 0.0001 (Log-rank test). The number of subjects for each group is given in parenthesis in the legend. Abbreviations: CS, chitosan acetate; p.t., post treatmentAbstract 457 Figure 2Days p.t. for untreated MC38 to reach 500 mm3Days post treatment to reach 500 mm3 was determined as the day on which the untreated tumor volume measurement exceeded 500 mm3 for the first time and growth continued to increase afterward for at least two days. Statistics: One-way ANOVA * p<0.05, ** p<0.01ConclusionsConclusions: While cryoablation in combination with immunotherapy has the potential to treat advanced, unresectable primary tumors and distant untreated tumors, the addition of a single injection of IL-12 is not enough to induce a strong abscopal effect. Furthermore, it may actually worsen the establishment of effector memory cells. The addition of anti-PD-1 only slows abscopal tumor growth. Future work is needed to understand the mechanism of T cell priming in the context of the post-ablative tumor.AcknowledgementsThis work is supported by Boston Scientific, the NC State University Provost’s Fellowship, the NSF Graduate Research Fellowship and startup funds provided by the College of Engineering at NC State University.Referencesvan der Geest LGM. et al. Trends in treatment and survival of patients with nonresected, nonmetastatic pancreatic cancer: a population-based study. Cancer Med 2018; 7, 4943–4951.Takaki H. et al. Thermal ablation and immunomodulation: from preclinical experiments to clinical trials. Diagn. Interv. Imaging 2017; 98:651–659.
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You, Jae S., Sergio E. Flores, James M. Friedman, Drew A. Lansdown, and Alan L. Zhang. "The Learning Curve for Hip Arthroscopic Surgery: A Prospective Evaluation With 2-Year Outcomes in Patients With Femoroacetabular Impingement." Orthopaedic Journal of Sports Medicine 8, no. 10 (October 1, 2020): 232596712095914. http://dx.doi.org/10.1177/2325967120959140.
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Background: The use of hip arthroscopic surgery in the treatment of femoroacetabular impingement (FAI) is increasing, but it is universally known as a technically demanding procedure with a “steep” learning curve. There are limited data investigating the correlation between surgeon experience and patient-reported outcomes (PROs) as well as procedure and traction times. Purpose: To prospectively evaluate the relationship between surgeon experience and PROs after hip arthroscopic surgery for the treatment of FAI. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 190 patients undergoing primary hip arthroscopic surgery for FAI were prospectively enrolled during a sports medicine fellowship–trained surgeon’s first 36 months of practice. A radiographic evaluation as well as PRO surveys including the 12-Item Short Form Health Survey (SF-12), the modified Harris Hip Score (mHHS), and the Hip disability and Osteoarthritis Outcome Score (HOOS) were administered preoperatively and at 2 years postoperatively. Logistic regression as well as analysis of variance was performed to evaluate for correlations between surgical experience and PROs, procedure time, and traction time. Results: Of the 190 patients, 168 (88%; mean age, 35.3 ± 9.6 years; mean body mass index, 25.07 ± 3.98) completed a 2-year follow-up and were included for analysis. The mean procedure time was 91.5 ± 23.9 minutes, and the mean traction time was 54.0 ± 17.7 minutes. Patients demonstrated significant improvements at 2 years after surgery for all PRO scores (mHHS, HOOS, and SF-12 physical component summary; P < .001), except the SF-12 mental component summary, which had no change ( P = .43). The procedure time significantly decreased after 70 cases, while the traction time continued to decrease until 110 cases ( R 2 = 0.99; P < .0001). There was no correlation between increasing case volume and 2-year PRO scores ( P > .2 for mHHS, HOOS, and SF-12). There was also no difference with increasing case volume and amount of improvement from preoperative to 2-year postoperative PRO scores for the SF-12 and HOOS. Case volume did not affect the complication rate, as this cohort experienced 4 minor cases of neurapraxia. Conclusion: Surgical efficiency in hip arthroscopic surgery for the treatment of FAI was maximized after 110 cases in this cohort. However, significant PRO improvements can be achieved early in a surgeon’s practice prior to maximizing surgical efficiency.
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Flores, Sergio E., Kristina R. Borak, and Alan L. Zhang. "Hip Arthroscopic Surgery for Femoroacetabular Impingement: A Prospective Analysis of the Relationship Between Surgeon Experience and Patient Outcomes." Orthopaedic Journal of Sports Medicine 6, no. 2 (February 1, 2018): 232596711875504. http://dx.doi.org/10.1177/2325967118755048.
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Background: Hip arthroscopic surgery is a rapidly growing procedure, but it may be associated with a steep learning curve. Few studies have used patient-reported outcome (PRO) surveys to investigate the relationship between surgeon experience and patient outcomes after the arthroscopic treatment of femoroacetabular impingement (FAI). Hypothesis: Patients undergoing hip arthroscopic surgery for the treatment of FAI in the early stages of a surgeon’s career will have significantly worse outcomes and longer procedure times compared with patients treated after the surgeon has gained experience. Study Design: Cohort study; Level of evidence, 2. Methods: Patients undergoing hip arthroscopic surgery for FAI and labral injuries were prospectively enrolled during a sports medicine fellowship–trained surgeon’s first 15 months of practice. Patients were stratified into an early group, consisting of the first 30 consecutive cases performed by the surgeon, and a late group, consisting of the second 30 consecutive cases. Radiographic and physical examinations were performed preoperatively and postoperatively. PRO surveys, including the 12-item Short Form Health Survey (SF-12), the modified Harris Hip Score (mHHS), and the Hip disability and Osteoarthritis Outcome Score (HOOS), were administered preoperatively and at a minimum of 1 year postoperatively. Results: There was no difference between the early and late groups for patient age (37.2 ± 11.5 vs 35.3 ± 10.8 years, respectively; P = .489), body mass index (25.6 ± 4.0 vs 25.1 ± 4.5 kg/m2, respectively; P = .615), or sex ( P = .465). There was a significantly increased procedure time (119.3 ± 21.0 vs 99.0 ± 28.6 minutes, respectively; P = .002) and traction time (72.7 ± 21.4 vs 59.0 ± 16.7 minutes, respectively; P = .007) in the early group compared with the late group. Mean postoperative PRO scores significantly improved in both groups compared with preoperative values for all surveys except for the SF-12 mental component summary. No differences were found in PRO score improvements or complication rates between the early and late groups. Conclusion: The total procedure time and traction time decrease after a surgeon’s first 30 hip arthroscopic surgery cases for FAI and labral tears, but patient outcomes can similarly improve regardless of surgeon experience in the early part of his or her career.
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Salhotra, Amandeep, Shicheng Yang, Alexander Wendling, Xiao Huang, James G. Farmar, Harun El Masri, and Mary J. Laughlin. "Role of NFAT1 (NFATc2) in Proliferation and Differentiation of Human CD34+ Hematopoietic Stem Cells." Blood 118, no. 21 (November 18, 2011): 4833. http://dx.doi.org/10.1182/blood.v118.21.4833.4833.
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Abstract Abstract 4833 Background: NFAT1 (NFATc2) transcription factor is known to modulate allogeneic T-cell mediated immune responses in the post transplant setting by affecting release of bioactive cytokines such as IFN- γ and IL-2 from donor CD4+T-Cells. Cyclosporine-A (CSA) inhibits NFAT1 activation via the phosphatase-Calcineurin and has been shown to be effective in prophylaxis and treatment of graft versus host disease (GVHD). However, little is known of the role of NFAT1 transcription factor and its inhibition, in affecting differentiation and proliferation of CD34+ Hematopoietic Stem Cells. Methods: Mononuclear cells (MNC) were prepared using Ficoll Paque density gradient method from human cord blood (Umbilical Cord blood Units kindly provided by Dr. Pablo Rubinstein, MD, New York Blood Center). These MNC's were enriched for CD34+ HSC using magnetic bead separation (Auto Macs, Miltenyi). The resulting purity of HSC routinely exceeded >90%. This CD 34 + cell population was seeded at a density of 60,000 cells/ml in 12 well plates in CellGenix (serum free media) supplanted by the following cytokines: IL-3 (5ng/ml), FLT-3L (100 ng/ml), SCF (50 ng/ml), G-CSF (30 ng/ml) and GM-CSF (5ng/ml). Cells were cultured under normoxic conditions for 7 days at 37.0C with 5% CO2 either in the presence or absence of CSA at concentration 2μM. We examined cell proliferation and differentiation by the following cell surface markers- CD34/CD33/HLA-DR/CD71/ and CD14. Cell counts were enumerated (Coulter) at baseline, day 2, 5, 7 and multiplied by FACS proportions to calculate absolute numbers of specified cell populations. Experiments were conducted with and without CSA in culture media, a known inhibitor of NFAT1 dephosphorylation. Cells were harvested on Day 0, 2, 5 and 7. Results: Flow cytometry analysis of CD 34 + cells grown in absence of CSA showed progressive decline of CD34 expression over days 2, 5 and 7 and progressive increased in CD33 and HLA-DR surface expression. In the presence of CSA however, we saw a rapid rise of CD33 (41.0% versus 28.1%), HLA-DR (44.4% versus 29.1%) and CD 71 (24.4% versus 12.7%) cell fractions on Day 7, compared to culture conditions when CSA was absent., No difference was noted in total cell count in CSA treated (701,666.6 ± 7637 (Mean and SD))and untreated (643,333 ± 5166 cells) conditions in culture by Day 7. Discussion: The above results suggest that inhibition of NFAT1 signaling in CD34+ HSC using CSA results in more rapid differentiation towards the myelomonocytic and erythrocytic lineages as seen by flow cytometry. This data suggests that NFAT1 may participate in hematopoietic differentiation of CD34 progenitors in these cytokine conditions, and further that loss of NFAT1 signaling may allow enhanced kinetics of differentiation of CD34 + HSC towards myelomonocytic and erythroid lineages. Further understanding of NFAT1 regulation of normal HSC may have implications for routine CSA administration in patients undergoing allogeneic transplantation as well as potential role in myeloid malignancies resulting from NFAT1 dysregulation. Acknowledgment: Farrow Fellowship Award Disclosures: No relevant conflicts of interest to declare.
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Wong, Ivan H., John Paul King, Gordon Boyd, Michael Mitchell, and Catherine Coady. "Radiographic Analysis of Glenoid Size and Shape After Arthroscopic Coracoid Autograft Versus Distal Tibial Allograft in the Treatment of Anterior Shoulder Instability." American Journal of Sports Medicine 46, no. 11 (August 10, 2018): 2717–24. http://dx.doi.org/10.1177/0363546518789348.
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Background: The Latarjet procedure for autograft transposition of the coracoid to the anterior rim of the glenoid remains the most common procedure for reconstruction of the glenoid after shoulder instability. The anatomic glenoid reconstruction using distal tibial allograft has gained popularity and is suggested to better match the normal glenoid size and shape. However, concerns about decreased healing and increased resorption arise when an allograft bone is used. Purpose: To use radiological findings to evaluate the arthroscopic reconstruction of the glenoid with respect to the size, shape, healing, and resorption of coracoid autograft versus distal tibial allograft. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review was performed of 48 consecutive patients who had an arthroscopic bony reconstruction of the glenoid (12 coracoid autograft, 36 distal tibial allograft), diagnosed anterior shoulder instability, and computed tomography (CT)–confirmed glenoid bone loss more than 20%. Coracoid autograft was performed only when tibial allograft was not accessible from a bone bank. Two fellowship-trained musculoskeletal radiologists reviewed pre- and postoperative CT scans at a minimum follow-up of 6 months for the following: graft position, glenoid concavity, cross-sectional area, width, version, total area, osseous union, and graft resorption. Clinical outcome was noted in terms of instability, subluxation, and dislocation at a minimum follow-up of 2 years. Simple logistic regression, 2-tailed independent-sample t tests, paired t tests, and Fisher exact tests were performed. Results: Graft union was seen in 9 of the 12 patients (75%) who had coracoid autograft and 34 of the 36 patients (94%) who had tibial allograft (odds ratio, 5.66; 95% CI, 0.81-39.20; P = .08). The odds ratio comparing allograft to coracoid for overall resorption was 7.00 (95% CI, 1.65-29.66; P = .008). Graft resorption ≥50% was seen in 3 (8%) of the patients who had tibial allograft and none of the patients who had coracoid autograft. Graft resorption less than 50% was seen in the majority of patients in both groups: 27 (73%) patients with tibial allograft and 5 (42%) patients with coracoid autograft. No statistically significant difference was found between the 2 procedures regarding anteroposterior diameter of graft ( P = .81) or graft cross-sectional area ( P = .93). However, a significant difference was observed in step formation between the 2 procedures ( P < .001). Two patients experienced subluxations in the coracoid group (16%) as well as 2 patients in the tibial allograft group (6%) with a P value of .25. Conclusion: Arthroscopic anatomic glenoid reconstruction via distal tibial allograft showed similar bony union but higher resorption compared with coracoid autograft. Even so, no statistically significant difference was found between the 2 procedures regarding final graft surface area, the size of grafts, and the anteroposterior dimensions of the reconstructed glenoids. These short-term results suggest that distal tibial allografts can be used as an alternative to coracoid autograft in the recreation of glenoid bony morphologic features.
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Orgueira, Hernan A., Alessandra Bartolozzi, Peter Schell, and Peter H. Seeberger. "Conformational Locking of the Glycosyl Acceptor for Stereocontrol in the Key Step in the Synthesis of Heparin Financial support from the National Institutes of Health (HL-64799 and HL-62598), The Research Corporation (Research Innovation Award to P.H.S.), CaP CURE (Research Awards to P.H.S.), FOMEC (Postdoctoral Fellowship for H.A.O.), CNRI (Italian National Research Center, Postdoctoral Fellowship for A.B.), and the DAAD (German Academic Exchange Service, Postdoctoral Fellowship for P.S.) is gratefully acknowledged. Funding for the MIT-DCIF Varian 500 MHz NMR was provided by NSF (Award CHE-9808061). Funding for the MIT-DCIF Bruker 400 MHz NMR was provided by NIH (Award 1S10RR13886-01). Funding for the MIT-DCIF Varian 300 MHz was provided by NSF (Award DBI-9729592)." Angewandte Chemie International Edition 41, no. 12 (June 17, 2002): 2128. http://dx.doi.org/10.1002/1521-3773(20020617)41:12<2128::aid-anie2128>3.0.co;2-v.
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Orgueira, Hernan A., Alessandra Bartolozzi, Peter Schell, and Peter H. Seeberger. "Conformational Locking of the Glycosyl Acceptor for Stereocontrol in the Key Step in the Synthesis of Heparin Financial support from the National Institutes of Health (HL-64799 and HL-62598), The Research Corporation (Research Innovation Award to P.H.S.), CaP CURE (Research Awards to P.H.S.), FOMEC (Postdoctoral Fellowship for H.A.O.), CNRI (Italian National Research Center, Postdoctoral Fellowship for A.B.), and the DAAD (German Academic Exchange Service, Postdoctoral Fellowship for P.S.) is gratefully acknowledged. Funding for the MIT-DCIF Varian 500 MHz NMR was provided by NSF (Award CHE-9808061). Funding for the MIT-DCIF Bruker 400 MHz NMR was provided by NIH (Award 1S10RR13886-01). Funding for the MIT-DCIF Varian 300 MHz was provided by NSF (Award DBI-9729592)." Angewandte Chemie 114, no. 12 (June 17, 2002): 2232. http://dx.doi.org/10.1002/1521-3757(20020617)114:12<2232::aid-ange2232>3.0.co;2-m.
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Bruni, C., S. Heidenreich, A. Duenas, A. M. Hoffmann-Vold, A. Gabrielli, Y. Allanore, E. Chatelus, et al. "POS0855 PATIENT PREFERENCES, TRADE-OFFS AND ACCEPTABLE RISKS IN THE TREATMENT OF SYSTEMIC SCLEROSIS-ASSOCIATED INTERSTITIAL LUNG DISEASE: A STEP TOWARDS SHARED DECISION-MAKING." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 681.3–682. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2112.
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Background:Current treatments for systemic sclerosis-associated interstitial lung disease (SSc-ILD) are characterised by different attributes such as mode of administration, adverse events (AE) and efficacy. Physicians and patients often have different perspectives on treatments, thus shared decision-making between patients and physicians is essential. An understanding of patients’ decision processes when weighing treatment attributes and the trade-offs they are willing to make is important for shared decision-making.Objectives:The study aimed to 1) identify relevant treatment attributes, 2) elicit patient preferences for these attributes and 3) quantify preference as relative attribute importance (RAI; a higher RAI indicates that more of the variability in patients’ responses may be explained by changes in the attribute); and maximum acceptable risk (MAR) of diarrhoea, nausea and/or vomiting (MAR is a trade-off measure that evaluates attributes in risk-equivalences as a unit of measurement).Methods:A discrete choice experiment (DCE) was created, based on a literature review, a patient advisory board, qualitative patient interviews, and a workshop involving SSc-ILD expert physicians. Seven SSc-ILD treatment attributes were identified: 1) mode of administration; 2) shortness of breath; 3) skin tightness; 4) cough; 5) tiredness; 6) risk of gastrointestinal tract (GIT) AEs; and 7) risk of serious and non-serious infections. The levels of AE risk were informed by frequencies observed in clinical trials and patient input during the interviews. The DCE was integrated into an online survey, which asked patients to make repeated choices between two alternatives described by varying levels of included attributes. Patients with SSc-ILD were recruited by physician referral from Switzerland, Norway, France, Germany and the USA. DCE data were analysed using a logit model, and RAI and MAR measures were calculated.Results:A total of 231 patients with physician-confirmed SSc-ILD (mean age 52.6±13.2 years; 54% diagnosed for >5 years) completed the survey. Patients with SSc-ILD mostly preferred twice-daily oral treatments (p<0.001) and infusion every 6–12 months (p<0.001) over monthly infusions. Patients’ choices were mostly affected by the risk of GIT AEs (RAI=25%; 95% CI 22–28%) and risk of infections (RAI=20%; 95% CI 16–24%). Improvements in shortness of breath and type and severity of cough were jointly more important than improvement in skin tightness (p<0.001).Patients accepted an additional 21% risk (95% CI 13–29%) of GIT AEs if they could reduce the frequency of infusions from monthly to 6–12 monthly, or accepted an extra 15% (95% CI 7–23%) increase in risk if changing to an oral treatment twice daily. Among symptoms, an additional 28% (95% CI 20–36%) risk of GIT AEs was considered acceptable if the severity of patients’ persistent cough was reduced to a level that was easier to tolerate, even if it remained persistent. Similarly, a 37% (95% CI 28–46%) increase in the risk of GIT AEs was acceptable if it resulted in breathlessness during routine activities rather than breathlessness at rest. Finally, patients were willing to accept an additional 36% risk (95% CI 27–45%) of GIT AEs if it reduced their risk of non-serious infections from 30% to 15% and of serious infections from 10% to 5%.Conclusion:This is the first study to quantitatively elicit patients’ preferences for attributes of SSc-ILD treatments. Preferences were driven by safety, efficacy and technical considerations. Patients showed willingness to make trade-offs, providing a firm basis for shared decision-making in routine clinical practice.Disclosure of Interests:Cosimo Bruni Speakers bureau: Actelion, Consultant of: Eli Lilly, Grant/research support from: Gruppo Italiano Lotta alla Scleroderma (GILS), Fondazione Italiana per la Ricerca sull’Artrite (FIRA), New Horizon Fellowship, European Scleroderma Trial and Research (EUSTAR), Foundation for Research in Rheumatology (FOREUM)., Sebastian Heidenreich Consultant of: Sebastian Heidenreich, PhD is employed by Evidera Inc, a business unit of PPD. Evidera is a CRO that offers paid research services to pharmaceutical companies., Ashley Duenas Consultant of: Yes. I am an employee of Evidera which received funding from Boehringer Ingelheim for work related to this study., Anna-Maria Hoffmann-Vold Speakers bureau: Boehringer Ingelheim, Actelion, Roche, Merck Sharp & Dohme, Lilly, Consultant of: Actelion, Boehringer Ingelheim, Roche, Bayer, Merck Sharp & Dohme, ARXX, Lilly and Medscape, Grant/research support from: Boehringer Ingelheim, Armando Gabrielli Grant/research support from: Pfizer Bhering, Yannick Allanore Consultant of: Honorarium received from Boehringer, Medsenic,Sanofi, Menarini, Grant/research support from: Grants received from Alpine, Ose Immunogenetics, Emmanuel Chatelus: None declared, Jörg H.W. Distler Shareholder of: JHWD is stock owner of 4D Science, Consultant of: JHWD has consultancy relationships with Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: JHWD has received research funding from Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, Eric Hachulla: None declared, Vivian Hsu Speakers bureau: I am a speaker for Boehringer Ingelheim Pharmaceuticals, Consultant of: with Boehringer Ingelheim Pharmaceuticals, Grant/research support from: Principal Investigator for several clinical trials, currently with Genentech, Corbus Pharmaceutical, and EICOS, Nicolas Hunzelmann Speakers bureau: Boehringer, Roche, Sanofi, Dinesh Khanna Shareholder of: Eicos Sciences, Inc (less than 5%), Consultant of: Paid Consultant for: Acceleron, Actelion, Abbvie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GSK, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis, and United Therapeutics, Grant/research support from: Research Grant support from: Immune Tolerance Network, Bayer, BMS, Horizon, Pfizer, Employee of: Leadership/Equity position – Chief Medical Officer, CiviBioPharma/Eicos Sciences, Inc – recieves a stipend for role as Chief Medical Officer, which would technically qualify as emplyoment., Marie-Elise Truchetet Speakers bureau: Abbvie, Lilly, Sobi, Boehringer, Paid instructor for: Lilly, Consultant of: UCB, Sobi, Abbvie, Grant/research support from: UCB, Gilead, Ulrich Walker Shareholder of: Bayer, NASDAQ, MSCI-World ETF’s, Speakers bureau: All companies producing pharmaceuticals used in AIDS, Paid instructor for: Roche, Abbvie, Novartis, Consultant of: All companies producing pharmaceuticals used in AIDS, Grant/research support from: Gilead, Abbvie, (in the last two years). Other companies in previous years., Margarida Alves Employee of: Boehringer Ingelheim, Nils Schoof Employee of: Employee of Boehringer Ingelheim International GmbH, Lesley Ann Saketkoo Speakers bureau: Boehringer Ingelheim, Actelion, Janssen, Mallinckrodt, United Therapeutics, Consultant of: Actelion, Boehringer Ingelheim, Bayer, Bristol Meyer Squibb, Corbus, EICOS, Janssen, Horizon, United Therapeutics, Inc, Grant/research support from: Mallinckrodt, United Therapeutics, Oliver Distler Speakers bureau: Boehringer Ingelheim, Medscape, IQone, Roche, Consultant of: OD has/had consultancy relationship and/or has received research funding in the area of potential treatments for systemic sclerosis and its complications from (last three years):Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143)., Grant/research support from: Kymera Therapeutics, Mitsubishi Tanabe
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Yui, Jennifer, Farzana Sayani, and Marilyn Schapira. "Hematologist Experiences and Perceptions of Outpatient Management of Adult Patients with Sickle Cell Disease." Blood 134, Supplement_1 (November 13, 2019): 4710. http://dx.doi.org/10.1182/blood-2019-131611.
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BACKGROUND: Improvements in care have extended the life expectancy of patients with sickle cell disease (SCD) well into adulthood, increasing the need for hematologists who have clinical expertise in managing adult patients with SCD. Despite widely-cited shortage of clinicians and resources dedicated to this purpose, we lack data to support these needs. We sought to 1) quantify hematologists' experience in outpatient management of SCD and their comfort with treatments and complications, and 2) assess the need for and perceived importance of resources to care for these patients. METHODS: We performed an electronic survey of hematologists/oncologists from four states (Mississippi, Louisiana, Georgia, and Maryland) and the District of Columbia, with sites chosen that had 30% or higher of African American residents. 694 surveys were sent. Results from the initial 50 survey respondents are reported here. Outcomes were measured on a five-point Likert scale with comfort level ranging from very uncomfortable to very comfortable, importance ranging from not important to extremely important, and availability from no available resources to highly resourced (Figures 1, 2). RESULTS: Sixty percent (60%) of respondents identified as a general hematologist/oncologist, with the rest further specialized, and 4% identifying as a benign hematologist. Thirty-nine percent (39%) of respondents have treated no patients with SCD in the last three years of their current practice, with 12% of respondents not treating any patients with SCD in their current practice or during fellowship. Fifty-two percent (52%) of respondents felt comfortable ("somewhat comfortable" or "very comfortable") with the overall management of SCD in the outpatient setting (Figure 1), while 25% reported discomfort ("somewhat uncomfortable" or "very uncomfortable"). Discomfort with treatments ranged from 8% for folic acid to 50% for hematopoietic stem cell transplantation. Discomfort with managing complications was >30% for renal, neurologic, and ophthalmologic complications, and sexual/reproductive health. When choosing from a list of eight pre-identified resources (Figure 2), 40% of the respondents chose social work/case management as the most important resource for improving management. Eighty-nine percent (89%) of respondents rated both social work/case management and pain management expertise to be very important or extremely important. However, 27% and 16% of respondents noted they had no available resources or were poorly resourced in these areas, respectively. Further, 72% and 73% rated infrastructure for transitions from pediatric care and community organizations to be very or extremely Important, but over 50% stated they had no available resources or were poorly resourced in these domains. CONCLUSIONS: Existing efforts focused on improving knowledge through clinical updates have increased provider comfort in managing SCD, but 25% of hematologists surveyed report being uncomfortable with the outpatient management of SCD. Respondents identified social work/case management and pain management as the most important resources needed in caring for patients with SCD. They also identified poor availability of resources, particularly for infrastructure for transitions from pediatric care, and for community organizations. These findings can help inform policy and procedures aimed at improving outpatient management of patients with SCD. Disclosures No relevant conflicts of interest to declare.
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Simonetti, Giorgia, Samantha Bruno, Carmine Onofrillo, Cristina Papayannidis, Giovanni Marconi, Michele Cavo, Lorenzo Montanaro, and Giovanni Martinelli. "Alternative Overexpression of NRF2 or MYC Defines a Subgroup of Poor Prognosis Acute Myeloid Leukemia and Suggests a Novel Therapeutic Strategy By Combined Bromodomain Inhibition and Forced NRF2 Pathway Activation." Blood 132, Supplement 1 (November 29, 2018): 2639. http://dx.doi.org/10.1182/blood-2018-99-117429.
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Abstract Introduction. Inhibition of Bromodomain and extraterminal (BET) proteins was effective against different acute myeloid leukemia (AML) subtypes in preclinical studies (Dawson et al. Nature 2011; Zuber et al. Nature 2011; Dawson et al. Leukemia 2013; Chen et al. Cancer Cell 2014; Gröschel et al. Cell 2014; Zhao et al. Cell Reports 2016). However, the drug had limited clinical activity, suggesting the need of ad hoc combination therapies able to target leukemia stem cells (LSCs) in their microenvironment. Hypoxia is an integral component of the bone marrow microenvironment and plays a crucial role in survival and chemoresistance of LSCs. Aims. The study aims to elucidate the consequences of BETi treatment in AML under hypoxic conditions and identify novel potential combination strategies. Methods. AML cell lines (OCI-AML3: NPM1- and DNMT3A-mutated, Kasumi-1: t(8;21), HL60: MYC-amplified, MOLM-13, NOMO-1: MLL-driven, KG-1: TP53-mutated) were treated with the BET inhibitor (i) GSK1215101A (250/500 nM, 48h) or the NRF2 activator omaveloxolone (NRF2a, 0.2-1 mM, 48h) and with the drug combination (72h) at 1% or 20% O2 concentration. Cell viability, apoptosis and cell cycle were evaluated by trypan blue dye exclusion assay, AnnexinV and PI staining, respectively. Gene expression profiling (HTA2.0, Affymetrix) was carried out on actively translated mRNAs isolated by polysome profiling after 16h of BETi treatment and on 61 primary AML. The TCGA AML dataset was analyzed on the cBioPortal. Gene expression correlation and enrichment analysis were performed by Pearson coefficient and GSEA, respectively. Kaplan-Meier survival curves were compared by Logrank test. Glutathione was quantified by mass spectrometry (Metabolon). Results. BETi induced a dose-dependent reduction of cell viability in AML cells lines under hypoxia (25%-65% decrease at 500 nM) except for HL-60. Under the same conditions, the treatment caused a significant arrest in the G0/G1 phase of the cell cycle in OCI-AML3, Kasumi-1, HL-60 and KG-1 models (p<0.05) and induction of apoptosis in NOMO-1 and Kasumi-1 (40% and 50% AnnexinV+ cells, respectively, p<0.05). BETi reduced the translational rate of Kasumi-1 and OCI-AML3 cells, as determined by a decrease of disome-polysome peaks height. The treatment exacerbated hypoxia-mediated MYC suppression and associated with downregulation of a MYC signature at translational level. Moreover, it induced upregulation of the NRF2 regulator ARNT (p=0.02) and the NRF2 targets CAT, EPHX1, FTH1, GSTM1, MGST1, PRDX1 (p<0.05) under normoxia and/or hypoxia, with reduced KEAP1 mRNA and protein specifically at 1% O2 (p=0.01). These results suggest stabilization of NRF2 protein and activation of the pathway, as strengthened by increased levels of reduced and oxidized glutathione in OCI-AML3 cells (p<0.01). Based on this alternative activation of MYC and NRF2 pathway in AML, we analyzed gene expression and mutation in non-M3 AML from an internal cohort and the TCGA dataset. Upregulation of NRF2 expression and deregulation of MYC (overexpression/driver mutation) occurred in 4% and 9% of cases, respectively (independent of genomic amplification), with mutual exclusivity and an inverse correlation (p=0.03). MYC or NRF2 alterations defined a subgroup of patients with poor overall survival (10 vs. 18.1 months, p=0.04) and progression-free survival (7.2 vs. 17 months, p=0.0006). We then asked whether antioxidant gene expression was a defense response under BETi pressure. However, pharmacological inhibition of NRF2 or glutathione biosynthesis failed to potentiate the anti-leukemic effects of BETi. Conversely, activation of NRF2 pathway, which is effective as single agent on AML cells, potentiates the effects of BETi treatment in non-M3 AML, with reduced cell viability and increased apoptosis. Conclusions. BET protein activity drives alternative NRF2 or MYC overexpression in AML, which defines a subgroup of patients with poor prognosis. NRF2 activation is finely tuned in AML, as both inhibition and activation of the pathway induce cell death. However, NRF2 activation specifically potentiates BETi treatment under hypoxia and normoxia, suggesting a novel combination therapy against AML LSCs. Supported by: EHA Non-Clinical Junior Research Fellowship, ELN, AIL, AIRC, project Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project, Fondazione del Monte BO e RA project. Figure. Figure. Disclosures Cavo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Martinelli:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Speakers Bureau; Abbvie: Consultancy; Roche: Consultancy; Ariad/Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy; Janssen: Consultancy; Novartis: Speakers Bureau.
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Vederhus, John-Kåre, Christine Timko, Øistein Kristensen, and Thomas Clausen. "The courage to change: Patient perceptions of 12-Step fellowships." BMC Health Services Research 11, no. 1 (December 2011). http://dx.doi.org/10.1186/1472-6963-11-339.
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Velasco, Richard Carlos L., Rebecca Hite, and Jeff Milbourne. "Exploring Advocacy Self-efficacy Among K-12 STEM Teacher Leaders." International Journal of Science and Mathematics Education, April 3, 2021. http://dx.doi.org/10.1007/s10763-021-10176-z.
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AbstractAdvocacy is an emergent dimension of teacher leadership, given its growing importance in shaping policy and facilitating reform efforts in American K-12 education. In 2014, the National Academies called for advancing advocacy-based activities and leadership among K-12 science, technology, engineering, and mathematics (STEM) teachers, who are presently understudied. The purpose of this embedded single-case case study was to explore STEM teachers’ development of self-efficacy in advocacy for STEM education. Contextualizing the case, participants consisted of 11 STEM teacher leaders who were part of the STEM Teacher Ambassadors (STA) program, a year-long advocacy-focused leadership development fellowship program, jointly sponsored by the National Science Teaching Association and National Council of Teachers of Mathematics. Employing case study research methodology, primary data were collected using semi-structured interviews, while secondary data were sourced via focus group interview and documents to triangulate interview data. Utterances (i.e., participant statements, groups of statements, or segments of statements) from transcribed data were coded a priori and analyzed via four constructs of self-efficacy theory: enactive master experiences, vicarious experiences, verbal persuasion, and emotional arousal. Results revealed 157 utterances coded to self-efficacy building within STEM education advocacy. Findings suggest that STEM teacher leaders’ participation in professional development programs that specifically focus on development of policy knowledge and advocacy activities help to develop and sustain STEM teacher leaders’ advocacy self-efficacy, given that participating teachers have numerous opportunities to fully engage in mastery experiences in STEM education advocacy. Implications and recommendations for policy and suggestions for further studies are discussed.
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"Thomas Nelson Marsham, 10 November 1923 - 12 October 1989." Biographical Memoirs of Fellows of the Royal Society 38 (November 1992): 229–46. http://dx.doi.org/10.1098/rsbm.1992.0012.
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Thomas Nelson Marsham was one of that band of distinguished men of strong intellect and strong personality who laid the foundations of a programme of nuclear power generation in this country on a sound technical basis. He joined the new atomic energy enterprise when it was still the responsibility of the Ministry of Supply, transferring to the United Kingdom Atomic Energy Authority on its formation, and eventually retired from the UKAEA as a main board member in 1988. After war-time service in the Merchant Navy, he was trained as a physicist and did his doctoral research in nuclear physics. This training enabled him to master rapidly the basic neutron physics underlying the operation of nuclear reactors but, as his career advanced in the UKAEA, he showed also an excellent grasp of engineering principles. Significantly he was elected to the Fellowship of Engineering in the same year as he was elected to the Royal Society. He attained managerial rank and responsibilities in the expanding AEA at a relatively early age, so his career inevitably mirrors the changing tasks and responsibilities of the Authority itself. However, he will be remembered mainly for two outstanding contributions. The first is to the development of gas-cooled reactors in this country. He played a major role in the successful commissioning of the first generation of gas-cooled reactors at Calder Hall and Chapelcross, and later in the introduction of the more efficient advanced gas-cooled reactors, for which he was a persuasive advocate. His second main interest was the development of the fast-neutron fission reactor, a technology in which he became a national and international authority. He saw the introduction of fast reactors as an essential step towards achieving the long-term gains to the national economy from nuclear power that he believed to be both possible and essential.
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Georgiou, Helen, and Manjula Sharma. "Engaging science academics with evidence based practices: Use of concept inventories in chemistry and physics across eight universities." International Journal of Innovation in Science and Mathematics Education 28, no. 4 (March 10, 2021). http://dx.doi.org/10.30722/ijisme.28.04.003.
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There is ongoing research on how to improve student engagement and attainment in STEM in higher education, with active learning recognised as a feasible approach for several decades now. However, the uptake of active learning, and other evidence-based approaches, is inconsistent. This paper reports on one aspect of an Australian Government funded Fellowship; the specific scholarly practice of the use of concept inventories, widely associated with active learning, to engage academics in evidence-based practices in STEM disciplines. The ultimate aim was to equip lecturers with the tools to measure student attainment. In close collaboration with academics, pre- and post-tests were administered to students in a total of 12 different courses, constituting over 3000 individual student questionnaires collected across eight Australian Universities. We report on the implementation focusing on; engaging staff, the types of concept survey results made visible to staff not generally accustomed to seeing such results, and tentatively offer the possibility of national data on learning gains. Results show that the majority of lecturers engaged and continued the use of concept inventories. Our study demonstrates that concerted use of concept inventories might lead to increased uptake of evidence-based approaches with potential for improved teaching and learning in STEM disciplines.
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Herum, K. M., G. Gilles, A. Romaine, A. O. Melleby, G. Christensen, A. D. McCulloch, and C. H. Brakebusch. "Cardiac fibroblasts acquire properties of matrifibrocytes in vitro and in mice with pressure overload-induced congestive heart failure." European Heart Journal 41, Supplement_2 (November 1, 2020). http://dx.doi.org/10.1093/ehjci/ehaa946.3741.
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Abstract Introduction Activation of cardiac fibroblasts (CFB) is a key step in development of fibrosis in the heart. It was recently shown that, in addition to the well-studied myofibroblast (myoFB) phenotype, activated cardiac fibroblasts can adopt a newly defined matrifibrocyte phenotype, characterized by expression of extracellular matrix (ECM) genes associated with bone, cartilage and tendon development. However, it is unknown whether matrifibrocytes exists in the pressure-overloaded fibrotic and failing heart, and whether substrate stiffness drives differentiation. Hypothesis Matrifibrocyte differentiation occurs in vitro during culturing of primary cardiac fibroblasts, and in vivo in response to left ventricular pressure overload. Methods Left ventricular pressure overload induced by o-ring aortic banding (ORAB) induced cardiac phenotypes of concentric hypertrophic remodelling and congestive heart failure. Primary CFB from adult mice were cultured on plastic or soft polyacrylamide hydrogels (4.5 kPa) for various times. mRNA expression of phenotypic markers were measured by RT-PCR. Presence of smooth muscle α-actin (SMA) fibers was determined by immunocytochemistry. Results ECM genes normally expressed in bone and cartilage (COMP, CILP-2, OPG and SCX) were upregulated in hypertrophic left ventricles of mice with congestive heart failure. The myoFB marker acta2 was increased 2 weeks after ORAB, returned to baseline at 4 weeks and increased again at 20 weeks when the left ventricle was dilating and failing, indicating that the myoFB phenotype is not permanent. In vitro, primary CFB upregulated bone/cartilage-associated ECM genes after 12 days of culturing on plastic. Acta2 mRNA and SMA protein levels peaked after 9 days in culture whereafter they declined, indicating a shift in phenotype. Culturing primary CFB on soft (4.5 kPa) hydrogels delayed, but did not prevent, myoFB differentiation while expression of bone/cartilage ECM genes was absent or low, indicating that high stiffness is a driver of the matrifibrocyte phenotype. Blockers of mechanotransduction, SB431542 (TGFβRI inhibitor), Y27623 (ROCK inhibitor) and cyclosporine A (calcineurin inhibitor), completely inhibited myoFB differentiation but upregulated several matrifibrocyte markers, indicating that distinct signaling pathways regulate myoFB and matrifibrocyte differentiation. Removing inhibitors re-induced myofibroblast markers in cells on plastic but not on soft gels consistent with high stiffness promoting myofibroblast differentiation. Conclusion Primary cardiac fibroblasts acquire characteristics of matrifibrocytes in vitro when cultured for long time on plastic and in vivo in left ventricles of mice with pressure overload-induced congestive heart failure. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): Marie Sklodowska-Curie Individual Fellowship