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1
Evans, Sarah, Katherine E. O. Todd-Brown, Kathryn Jacobson, and Peter Jacobson. "Non-rainfall Moisture: A Key Driver of Microbial Respiration from Standing Litter in Arid, Semiarid, and Mesic Grasslands." Ecosystems 23, no. 6 (December 2, 2019): 1154–69. http://dx.doi.org/10.1007/s10021-019-00461-y.
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Abstract Models assume that rainfall is the major moisture source driving decomposition. Non-rainfall moisture (NRM: high humidity, dew, and fog) can also induce standing litter decomposition, but there have been few measurements of NRM-mediated decomposition across sites and no efforts to extrapolate the contribution of NRM to larger scales to assess whether this mechanism can improve model predictions. Here, we show that NRM is an important, year-round source of moisture in grassland sites with contrasting moisture regimes using field measurements and modeling. We first characterized NRM frequency and measured NRM-mediated decomposition at two sites in the Namib Desert, Namibia (hyper-arid desert), and at one site in Iowa, USA (tallgrass prairie). NRM was frequent at all sites (85–99% of hours that litter was likely to be wet were attributed to NRM) and tended to occur in cool, high-humidity periods for several hours or more at a time. NRM also resulted in CO2 release from microbes in standing litter at all sites when litter became sufficiently wet (> 5% gravimetric moisture for fine litter and > 13% for coarse), and significantly contributed to mass loss, particularly in the western Namib site that received almost no rain. When we modeled annual mass loss induced by NRM and rain and extrapolated our characterization of NRM decomposition to a final semiarid site (Sevilleta, New Mexico), we found that models driven by rainfall alone underestimated mass loss, while including NRM resulted in estimates within the range of observed mass loss. Together these findings suggest that NRM is an important missing component in quantitative and conceptual models of litter decomposition, but there is nuance involved in modeling NRM at larger scales. Specifically, temperature and physical features of the substrate emerge as factors that affect the microbial response to litter wetting under NRM in our sites, and require further study. Hourly humidity can provide an adequate proxy of NRM frequency, but site-specific calibration with litter wetness is needed to accurately attribute decomposition to periods when NRM wets litter. Greater recognition of NRM-driven decomposition and its interaction with other processes like photodegradation is needed, especially since fog, dew, and humidity are likely to shift under future climates.
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Blomberg, Helena, and Jonas Stier. "Flashback as a Rhetorical Online Battleground: Debating the (Dis)guise of the Nordic Resistance Movement." Social Media + Society 5, no. 1 (January 2019): 205630511882333. http://dx.doi.org/10.1177/2056305118823336.
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The right-wing Swedish Nordic Resistance Movement (NRM) is increasingly active on social media. Using discursive psychology, this text explores the rhetorical organization of text and rhetorical resources used on the Swedish online forum Flashback. The aim is to reveal and problematize truth claims about NRM made by antagonists and protagonists. Questions are (1) how and what do NRM antagonists and protagonists convey in Flashback posts about NRM, and its ideology and members? (2) how do NRM antagonists and protagonists make truth claims about NRM in Flashback posts? The empirical material consisting of 1546 Flashback posts analyzed to identify typical discussions on “NMR’s true nature”; accomplished social actions stemming from the posts. Findings show that the Flashback thread can be understood as being a rhetorical battle that concerns the “truth” about NRM, where a variety of rhetorical resources are used to render statements credibility and those involved legitimacy.
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Takeda, Rui Carrie, Yasuhiko Shibasaki, Takayuki Katagiri, Kyoko Fuse, Hirohito Sone, and Masayoshi Masuko. "Easix-1yearas a Prognostic Index for Late Non-Relapse Mortality after Allogenichematopoietic Cell Transplantation." Blood 138, Supplement 1 (November 5, 2021): 4888. http://dx.doi.org/10.1182/blood-2021-147888.
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Abstract Introduction Late non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation(allo-HCT) is a problem that is yet to be solved. Moreover, no efficient markers exist to predict late NRM. Vascular endothelial damage is known to be a cause of late NRM after allo-HCT. The transplant endothelial activation and stress index (EASIX) was initially established for the diagnosis of thrombotic microangiopathy. Pre-transplant EASIX (EASIX-pre) quartiles were reported to be predictive markers for early NRM after allo-HCT, but EASIX could also potentially help in the evaluation of late NRM. Since late NRM may be affected by time dependent factors that cannot be evaluated before allo-HCT, the timing of EASIX evaluation may be important. Therefore, we focused on EASIX 1 year after allo-HCT (EASIX-1year). Aims This study aimed to clarify the usefulness of EASIX-pre and EASIX-1year as predictive markers of late NRM and overall survival (OS) after allo-HCT. Methods Among 210 patients with hematological disease who underwent a first allo-HCT between 2006 and 2019at our facility, we evaluated EASIX-1year in 102(53 males and 49 females) patients who were alive after 1 year without relapse and/or withdrawal. EASIX was calculated as LDH level (U/I) × Cre level (mg/dL) / Plt level (nL). EASIX-pre was evaluated 7-10 days before conditioning. EASIX-1year was evaluated within 1 month of 1 year after allo-HCT. Landmark analysis was used to perform statistical analysis of late NRM and OS starting 1 year after allo-HCT. Late NRM and OS assessments using EASIX-pre and EASIX-1year were performed with two risk groups based on the cutoff values from the receiver operating characteristic curve. Forty-four patients had acute myeloid leukemia, 24 had acute lymphoblastic leukemia, 14 had myelodysplastic syndrome, 8 had malignant lymphoma, and 12 had other diseases. The median age of the patients was 40 years (range: 16-66 years). Fifty-seven patients received myeloablative conditioning and the others received reduced intensity conditioning regimens. The number of patients in each HCT-comorbidity index (HCT-CI) risk group was as follows: low risk: 51, intermediate risk: 28, and high risk: 23. This study was performed in accordance with the Japanese Ethical Guidelines for Medical and Health Research Involving Humans and approved by the Ethical Committee of our facility. Results Median EASIX-pre was0.98 (0.12-24.1). The C-statistic of EASIX-pre for late NRM and OS were 0.561 (cutoff value: 0.595) and 0.591 (cutoff value: 0.766), respectively. Univariate analysis revealed that a high EASIX-pre value was not significantly associated with late NRM (5-year NRM 3.4% vs. 0%, p=0.24) and OS (5-year OS 91.3% vs. 93.5%, p=0.22). Moreover, the HCT-CI at pre-transplantation was not an indicator of late NRM (5-year NRM 10.2 % vs. 0%, p=0.29, 5-year OS 79.8% vs. 96.2%, P=0.19). Median EASIX-1year was 0.98 (0.15-21.8). The C-statistic of EASIX-1year for late NRM and OS were 0.63 (cutoff value 2.396) and 0.663 (cutoff value 1.159), respectively. Univariate analysis revealed that a high EASIX-1year value was significantly associated with late NRM (5-year NRM 10.1% vs. 1.3%, p<0.05), but was not significantly associated with OS (5-year OS 88.3% vs. 95.2%, p=0.16). By adjusting age, donor source, HCT-CI, chronic graft versus host disease, and conditioning in multivariate analysis, a high of EASIX-1year was extracted as the risk factor for late NRM (Hazard ratio 4.26, p<0.05). Conversely, neither EASIX-pre nor pre-transplant HCT-CI were extracted as risk factors for late NRM. Conclusion The present study indicated that EASIX-1year may be useful as a prognostic index for late NRM. Otherwise, pre-transplant conditions, such as EASIX-pre and pre-transplant HCT-CI, may have limited effects on late NRM. Disclosures No relevant conflicts of interest to declare.
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Ferriola, P. C., and W. Stewart. "Fibronectin expression and organization in mesothelial and mesothelioma cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 271, no. 5 (November 1, 1996): L804—L812. http://dx.doi.org/10.1152/ajplung.1996.271.5.l804.
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Mesothelial cells are believed to be the progenitor cells for malignant mesothelioma, a tumor associated with exposure to asbestos and other mineral fibers. Little is known regarding fibronectin (Fn) function in mesothelial and mesothelioma cells. Fn RNA, protein levels, and localization were assessed in secondary cultures and later passages of spontaneously immortalized rat pleural mesothelial (NRM) cells and in neoplastic cell lines derived from asbestos-induced mesotheliomas. NRM cells expressed similar levels of Fn RNA regardless of passage number or cell density, as determined by Northern blotting and ribonuclease protection assays. Western blotting showed that Fn protein was both secreted by NRM cells and associated with cell lysates. Immunofluorescent confocal laser scanning microscopy demonstrated that secondary cultures of NRM cells assembled Fn into abundant homogeneous fibrillar arrays organized primarily between cells, whereas later passages of NRM cells displayed abundant but less homogeneous Fn organization. Fn RNA and protein levels in neoplastic mesothelial cells were slightly less or similar to levels in NRM cells. Organization of Fn in neoplastic cells was heterogeneous compared with secondary cultures of NRM cells, but Fn fibril formation was still apparent. F-actin microfilaments were organized in both NRM and neoplastic cells; however, actin stress fibers were maintained in neoplastic cells, whereas NRM cells displayed dense actin peripheral bands at high density. The maintenance of organized Fn and actin in mesothelioma cells is surprising and may contribute to the localized growth and invasive properties of these tumors.
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Raimondi, Roberto, Alberto Tosetto, Rosi Oneto, Riccardo Cavazzina, Francesco Rodeghiero, Andrea Bacigalupo, Renato Fanin, Alessandro Rambaldi, and Alberto Bosi. "Validation of the Hematopoietic Cell Transplantation-Specific Comorbidity Index: a prospective, multicenter GITMO study." Blood 120, no. 6 (August 9, 2012): 1327–33. http://dx.doi.org/10.1182/blood-2012-03-414573.
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Abstract The development of tools for the prediction of nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (HSCT) would offer a major guidance in the therapeutic decision. Recently, the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) has been associated with increased NRM risk in several retrospective studies, but its clinical utility has never been demonstrated prospectively in an adequately sized cohort. To this aim, we prospectively evaluated a consecutive cohort of 1937 patients receiving HSCT in Italy over 2 years. HCT-CI was strongly correlated with both 2-year NRM (14.7%, 21.3%, and 27.3% in patients having an HCT-CI score of 0, 1-2, and ≥ 3, respectively) and overall survival (56.4%, 54.5%, and 41.3%, respectively). There was an excellent calibration between the predicted and observed 2-year NRM in patients having an HCT-CI score of 0 and 1-2, whereas in the ≥ 3 group the predicted NRM overestimated the observed NRM (41% vs 27.3%). HCT-CI alone was the strongest predictor of NRM in patients with lymphoma, myelodysplastic syndrome, and acute myeloid leukemia in first remission (c-statistics 0.66, 064, and 0.59, respectively). We confirm the clinical utility of the HCT-CI score that could also identify patients at low NRM risk possibly benefiting from an HSCT-based treatment strategy.
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Kurosawa, Saiko, Kimikazu Yakushijin, Takuhiro Yamaguchi, Yoshiko Atsuta, Tokiko Nagamura-Inoue, Hideki Akiyama, Shuichi Taniguchi, et al. "Changes In Incidence and Causes of Non-Relapse Mortality (NRM) After Allogeneic Hematopoietic Cell Transplantation (allo-HCT): Are Transplants Improving?" Blood 116, no. 21 (November 19, 2010): 901. http://dx.doi.org/10.1182/blood.v116.21.901.901.
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Abstract Abstract 901 Background: Many changes have been made to reduce NRM after allo-HCT. While an improvement in NRM has been demonstrated in younger patients who are in remission, NRM has not been examined in other settings, such as in older patients or allo-HCT in non-remission. Therefore, we retrospectively assessed changes in the incidence and causes of NRM over the last 12 years in allo-HCT patients. Methods: We analyzed a nationwide registry database to estimate the incidence of NRM and overall survival (OS) in patients aged 16 years or older who had acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) or myelodysplastic syndrome (MDS) and received the first allo-HCT from 1997 to 2008. We compared the NRM incidence after allo-HCT in three consecutive four-year periods (1997-2000, 2001–2004, and 2005–2008) for younger patients (16-49 years), and in the later two periods for older patients (≥50 years). Analyses were separately performed for standard-risk and high-risk patients. The standard-risk group included patients with acute leukemia/MDS in remission or untreated low-risk MDS (RA/RARS), and the high-risk group included those who were not in remission at allo-HCT. Subgroup analyses were performed based on patient age and donor source: HLA-matched/1-Ag mismatched related donor (related donor) versus unrelated bone marrow (BM) or cord blood (CB) donor (alternative donor). Results: A total of 10003 patients with a median age of 42 years were analyzed and the median follow-up of surviving patients was 37 months (0-154). The proportion of AML, ALL, and MDS patients was 53%, 28%, and 19%, respectively. A total of 2003, 3424, and 4576 allo-HCT were performed in 1997–2000, 2001–2004, and 2005–2008, respectively. The number and proportion of patients aged 50 years or older (n=227, 11%; n=1061, 31%; n=1907, 42%), the use of a reduced-intensity conditioning regimen (n=34, 2%; n=697, 20%; n=1244, 27%) and allo-HCT from an unrelated CB donor (n=42, 2%; n=582, 17%; n=990, 22%) increased over the three periods. An analysis of standard-risk patients (n=6280) showed that the incidence of NRM was 23% at 3 years after allo-HCT. Older patients had a significantly higher NRM than younger patients (31% vs 20%, p<0.001). The donor source significantly affected the incidence of NRM, and unrelated CB had the highest risk of NRM (related, 17%; unrelated BM, 26%; unrelated CB, 32%, p<0.001). The highest incidence of NRM was seen in 2001–2004 (25%) and the lowest incidence was seen in the most recent period, 2005–2008 (22%). A subgroup analysis of younger patients who received allo-HCT from a related donor showed that there was no significant improvement in NRM, and this was 12–15%. In younger patients who received allo-HCT from an alternative donor, the NRM incidence significantly decreased over the three periods (30%, 24%, and 22%, p<0.001) mainly due to a reduced risk of death associated with GVHD, organ failure and lung complications, and OS also significantly improved (58%, 59%, and 64%, p=0.008). In older patients who received allo-HCT from a related donor, NRM significantly improved in 2005–2008 compared to 2001–2004 (29% vs 18%, p<0.001). However, due to the increase in the incidence of relapse in 2005–2008, this decreased NRM did not lead to an improvement of OS (51% vs 55%, p=0.21). In older patients who received allo-HCT from an alternative donor, NRM and OS significantly improved in 2005–2008 compared to 2001–2004 (NRM, 43% vs 31%, p<0.001; OS, 40% vs 51%, p<0.001). The reduction in NRM was mainly due to a significant decrease in death associated with GVHD and infection. In the analysis of high-risk patients (n=3723), the incidence of NRM was generally higher than that in the standard-risk group (34% vs 23% at 3 years, p<0.001). High-risk patients who received allo-HCT from an alternative donor had a significantly lower NRM in the later periods, which led to an improvement in OS. Multivariate analysis indicated that the period of 2005–2008, younger age, and the application of a related donor were independently associated with a lower risk of NRM in both the standard- and high-risk groups. Conclusions: NRM and OS have recently improved, especially for allo-HCT from unrelated BM or CB donors. These advances were observed not only in younger patients but also in older patients. Although allo-HCT in non-remission was generally associated with a higher risk of NRM, we observed a similar trend regarding the improvement of NRM and OS. Disclosures: No relevant conflicts of interest to declare.
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Lambert, GA, KL Hoskin, and AS Zagami. "Cortico-NRM Influences on Trigeminal Neuronal Sensation." Cephalalgia 28, no. 6 (June 2008): 640–52. http://dx.doi.org/10.1111/j.1468-2982.2008.01572.x.
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We tested the idea that migraine triggers cause cortical activation, which disinhibits craniovascular sensation through the nucleus raphe magnus (NRM) and thus produces the headache of migraine. Stimulation of the dura mater and facial skin activated neurons in the NRM and the trigeminal nucleus. Stimulation of the NRM caused suppression of responses of trigeminal neurons to electrical and mechanical stimulation of the dura mater, but not of the skin. This suppression was antagonized by the iontophoretic application of the 5-HT1B/1D receptor antagonist GR127935 to trigeminal neurons. Migraine trigger factors were simulated by cortical spreading depression (CSD) and light flash. Activity of neurons in the NRM was inhibited by these stimuli. Multiple waves of CSD antagonized the inhibitory effect of NRM stimulation on responses of trigeminal neurons to dural mechanical stimulation but not to skin mechanical stimulation. The cortico-NRM-trigeminal neuraxis might provide a target for a more universally effective migraine prophylactic treatment.
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Schaffrath, Judith, Tanja Diederichs, Susanne Unverzagt, Maxi Wass, Ulrike Gläser, Thomas Weber, Mascha Binder, Carsten Müller-Tidow, and Lutz P. Müller. "Correlation of nutrition-associated parameters with non-relapse mortality in allogeneic hematopoietic stem cell transplantation." Annals of Hematology 101, no. 3 (December 21, 2021): 681–91. http://dx.doi.org/10.1007/s00277-021-04736-0.
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AbstractOutcome of allogeneic stem cell transplantation (alloSCT) is hampered by substantial non-relapse mortality (NRM). Given its impact on organ function and immune response, the nutritional status has been suggested as relevant for NRM. We aimed to evaluate the association of NRM with nutritional status prior to alloSCT and in the post-SCT course. In a retrospective single-center study, we analyzed 128 alloSCTs. Besides standard characteristics, nutrition-associated parameters BMI, serum total protein, and serum albumin were recorded before conditioning and at various time points after alloSCT. Association with NRM was evaluated by univariate and multivariate survival analysis. The cohort comprised patients with a median BMI of 26 kg/m2 (16.7–46.9 kg/m2), median serum total protein of 59 g/l (41–77 g/l), and serum albumin of 36 g/l (22–46 g/l) before SCT. NRM at d+100 was 14.8% and at 1 year 26.6%. Prior to SCT, only serum albumin deficiency was associated with increased NRM (p = .010) in multivariate analysis. After SCT (d+30 and d+100), all nutrition-associated parameters decreased (p < .002), but no association of deteriorating nutritional status with NRM was found. In multivariate analysis, serum albumin (p = .03) and severe albumin deficiency (p = .02) correlated with NRM at d+30 and d+100, while BMI and serum total protein did not. In our study, albumin deficiency, particularly prior to alloSCT, shows a strong correlation with NRM. This finding may add to monitoring, risk evaluation, and counseling of patients and serve as a rational for interventions to improve the nutritional status in patients undergoing SCT.
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Newell, Laura F., Todd E. DeFor, Corey S. Cutler, Michael R. Verneris, Bruce R. Blazar, Joseph H. Antin, Alan Howard, et al. "Follistatin and Endoglin: Potential Biomarkers of Endothelial Damage and Non-Relapse Mortality after Myeloablative Allogeneic Hematopoietic Cell Transplantation in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0402." Blood 128, no. 22 (December 2, 2016): 63. http://dx.doi.org/10.1182/blood.v128.22.63.63.
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Abstract Introduction: Inflammation and angiogenesis are linked biologic processes influencing the onset and recovery of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT). In aGVHD, angiogenic factors (AF) contributing to tissue healing/repair (e.g. epidermal growth factor [EGF]) versus AF associated with tissue damage/inflammation (e.g. follistatin [FS]) exist in a dysregulated balance. Whether these AF are associated with, or predictive of, non-relapse mortality (NRM) in the absence of aGVHD, is not understood. Given that regimen-related tissue injury plays a role in NRM, we hypothesized that elevated levels of inflammation-associated AF early after HCT would be associated with NRM even in patients without aGVHD. Methods: We studied plasma samples from patients enrolled on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) aGVHD prophylaxis study 0402, a randomized trial of tacrolimus/methotrexate vs tacrolimus/sirolimus after matched sibling peripheral blood stem cell transplantation with myeloablative conditioning. Levels of AF (angiopoietin-2 [Ang2], EGF, FS, vascular endothelial growth factor [VEGF]-A and -B, endoglin [sEng], placental growth factor [PlGF], and soluble VEGF receptor [sVEGFR]-1 and -2) were quantified by MILLIPLEX magnetic bead panels. We analyzed factors associated with NRM in univariate analysis and used multivariate analysis to develop composite AF scores to predict NRM. In calculating the composite scores, we extrapolated the individual probabilities of NRM based upon regression models, and sorted the individual probabilities into 3 composite scores based on: 1) estimated probability of NRM <10%, 2) probability of NRM between 10-19%, 3) probability of NRM >20%. Results: 221 patients from BMT CTN 0402 had pre-transplant plasma samples and samples at day +28 available for analysis. Univariate analysis showed associations of raw levels of Ang2, FS, sEng, and sVEGFR1 on day +28 with NRM. Of these, only higher levels of log-transformed FS (p=0.01) and of sEng (p=0.04) showed a correlation with NRM; these two AF were selected for the final model. In multivariate analysis, patients with the highest levels of day +28 FS and sEng (score 3, n=32, Figure) had a 4.6-fold higher relative risk (RR) of NRM (95% confidence interval 1.7-12.3, p<0.01, Table). The prognostic value of the composite score was stronger than either individual factor alone (RR log[FS]=2.1, p=0.03, and RR log[sEng]=2.3, p=0.07). Grade III-IV aGVHD and patient age>50 years were also independently associated with 1-year NRM. There was no effect of patient gender, disease status, CMV serostatus, or type of GVHD prophylaxis (tacrolimus/methotrexate versus tacrolimus/sirolimus) on NRM. There was no significant effect of the composite score, grade III-IV aGVHD, or age on the competing risk of relapse. FS and sEng measured before HCT were not associated with 1-year NRM (p=0.91 and p=0.62, respectively). There was only a weak correlation between the day 0 and day 28 FS and sEng (Spearman's rho 0.36 and 0.38, respectively). Among the 221 cohort patients, there were 25 deaths due to NRM, including 5 deaths occurring prior to day 56. Death was more likely to be from organ toxicity in patients with composite score 3 (5/9, 56%) vs those with a composite score of 1 (1/8, 12%) or 2 (3/8, 37%). Conclusions: A composite score using day 28 plasma levels of FS and sEng predicts the risk of 1-year NRM after HCT, providing further evidence that endothelial dysfunction is a relevant biological problem in HCT. Pre-HCT measurements of FS and sEng were not associated with NRM, suggesting that elevations in these factors may reflect susceptibility to regimen-related toxicity. We have previously shown that elevated levels of FS and sEng at the onset of aGVHD are associated with poor survival. Here, we show that these factors are predictive of NRM independent of aGVHD. Follistatin modulates inflammatory responses following tissue injury via interaction with the transforming growth factor β superfamily and may reflect endothelial cell damage. sEng is upregulated in proliferating endothelial cells, in inflammation and tissue ischemia, and can influence leukocyte adhesion and endothelial transmigration. Measurement of these predictive AF may highlight prospective opportunities to intervene and prevent subsequent complications thereby limiting NRM after allogeneic HCT. Disclosures No relevant conflicts of interest to declare.
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Cobbinah, Patrick Brandful. "Local attitudes towards natural resources management in rural Ghana." Management of Environmental Quality: An International Journal 26, no. 3 (April 13, 2015): 423–36. http://dx.doi.org/10.1108/meq-04-2014-0061.
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Purpose – Local support is fundamental in natural resources management (NRM). However, recent studies indicate that NRM in protected areas in developing countries is often faced with local resistance due to its impacts on livelihoods. The purpose of this paper is to examine local attitudes – positive and negative responses – towards NRM in protected areas and implications of NRM benefits on local support for conservation of protected areas. Design/methodology/approach – A quantitative research method was used for this study. Structured questionnaire survey was administered to 310 respondents across four case study communities – Abrafo, Mesomagor, Adadientem and Nuamakrom – around the Kakum Conservation Area (KCA), Ghana. χ2 test and logistic regression were used to analyse the data with the aid of Statistical Package for Social Sciences (SPSS) software. Findings – Findings showed positive attitudes towards NRM in protected areas (85.9 per cent) and high support for conservation of KCA (86.5 per cent). Respondents recognised the importance of the KCA in managing natural resources especially forest and water resources. Positive attitudes towards conservation of KCA were largely influenced by receipt of socio-economic benefits from the KCA, in terms of employment, income and involvement in KCA management. However, those excluded from socio-economic benefits from the KCA also expressed positive attitudes towards conservation, suggesting that support for NRM transcends socio-economic benefits. On the other hand, local people recognised the challenges associated with NRM in protected areas such as increased farm raids by wildlife, loss of access to timber and non-timber forest products. Originality/value – This paper has revealed that although socio-economic benefits from NRM in protected areas influence local people’s support for conservation, local knowledge of the environmental benefits is equally important. The depth of local knowledge of NRM in the KCA is dependent on educational status and level of involvement of respondents in the KCA in terms of employment, and the effectiveness of educational campaigns by the park officials. Therefore, in the absence of clear development programmes from government and park officials to educate and involve local people in NRM, it appears the conservation objective upon which NRM in protected areas are designed may not be realised.
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Kadri, Yasmine, Michelle Phan, Nadia Bambace, Léa Bernard, Sandra Cohen, Jean-Sébastien Delisle, Thomas Kiss, et al. "Donor Age and Non-Relapse Mortality: Study of Their Association after HLA-Matched Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome." Current Oncology 29, no. 8 (August 22, 2022): 5955–62. http://dx.doi.org/10.3390/curroncol29080470.
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The purpose of this retrospective study was to study the correlation between donor age (DA) and non-relapse mortality (NRM) and relapse incidence (RI) among patients treated with allogeneic hematopoietic cell transplantation (aHCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in a single Canadian center. Data from 125 consecutive patients transplanted with a matched related or unrelated donor between 2015 and 2020 were analyzed using multivariable models. After a median follow-up of 2.8 years, the cumulative incidences of NRM and relapse were 19% and 35% at 5 years. Despite being independently associated with NRM and relapse-free survival (RFS), DA was not associated with RI. The independent determinants of NRM in addition to DA were patient age and hematopoietic cell transplantation comorbidity index (HCT-CI), independently of donor kinship. The effect of DA on NRM was found to be significantly increased over the age of 50 years. DA was not associated with incidence of acute graft-versus-host disease (aGVHD) but showed an association with the occurrence of chronic GVHD (cGVHD). In conclusion, younger donors should be favored to limit NRM and increase RFS in HLA-matched aHCT. The etiological mechanisms behind the association of DA with higher NRM remain to be elucidated.
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Chiang, C. Y., J. W. Hu, and B. J. Sessle. "Parabrachial area and nucleus raphe magnus-induced modulation of nociceptive and nonnociceptive trigeminal subnucleus caudalis neurons activated by cutaneous or deep inputs." Journal of Neurophysiology 71, no. 6 (June 1, 1994): 2430–45. http://dx.doi.org/10.1152/jn.1994.71.6.2430.
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1. The aim of this study was to test whether parabrachial area (PBA) stimulation exerts inhibitory influences on the spontaneous activity and responses evoked by skin and deep afferent inputs in trigeminal subnucleus caudalis (Vc) neurons, and to compare these effects with those of nucleus raphe magnus (NRM) stimulation. A total of 92 nonnociceptive and nociceptive Vc neurons was recorded in urethan/alpha-chloralose-anesthetized rats. Each neuron was functionally classified as low-threshold mechanoceptive (LTM), wide dynamic range (WDR), nociceptive-specific (NS), nociceptive convergent with both skin and deep inputs (S+D), or deep nociceptive (D); the LTM neurons could be subdivided as rapidly adapting (RA) or slowly adapting (SA). Conditioning stimulation was applied to histologically verified sites in PBA and NRM. 2. The spontaneous or evoked activity of all classes of neurons could be inhibited by PBA as well as by NRM stimulation, but generally the incidence and magnitude of inhibition were lower for the LTM neurons. Occasionally, facilitation of neuronal activity was also produced by PBA and NRM stimulation. 3. The spontaneous activity of 11 LTM neurons (6 RA, 5 SA), 13 nociceptive neurons (6 WDR, 7 NS), and 5 D neurons was tested with stimulation of PBA or NRM or both. LTM spontaneous activity was more significantly inhibited by NRM stimulation than by PBA stimulation, whereas both NRM and PBA stimulation had similar and significant inhibitory effects on NS, WDR, and D neurons. 4. The evoked nonnociceptive responses of 28 LTM neurons (16 RA, 12 SA) and of 6 WDR neurons were also tested with stimulation of PBA or NRM or both. The magnitudes of inhibition of the responses produced by PBA conditioning stimulation were statistically significantly less than those induced by NRM conditioning stimulation. 5. The cutaneous and deep nociceptive responses of cutaneous nociceptive neurons (9 NS, 19 WDR) and seven D neurons, respectively, were also tested with PBA and NRM stimulation. There was a significant difference in potency between PBA- and NRM-induced inhibition, but no difference in the magnitude of inhibitory effects among NS, WDR, and D neurons. For both PBA and NRM conditioning stimulation, graded increases in intensities of stimulation produced linear increases in inhibitory effects on nociceptive responses; an increase in stimulation frequency from 5 to 400 Hz also produced increases in inhibition of the nociceptive responses. 6. In five S+D nociceptive convergent neurons, the responses elicited by deep inputs were more powerfully inhibited by PBA stimulation than those elicited by cutaneous inputs.(ABSTRACT TRUNCATED AT 400 WORDS)
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Commodore, Sarah, Andrew Metcalf, Christopher Post, Kevin Watts, Scott Reynolds, and John Pearce. "A Statistical Calibration Framework for Improving Non-Reference Method Particulate Matter Reporting: A Focus on Community Air Monitoring Settings." Atmosphere 11, no. 8 (July 30, 2020): 807. http://dx.doi.org/10.3390/atmos11080807.
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Recent advancement in lower-cost air monitoring technology has resulted in an increased interest in community-based air quality studies. However, non-reference monitoring (NRM; e.g., low-cost sensors) is imperfect and approaches that improve data quality are highly desired. Herein, we illustrate a framework for adjusting continuous NRM measures of particulate matter (PM) with field-based comparisons and non-linear statistical modeling as an example of instrument evaluation prior to exposure assessment. First, we collected continuous measurements of PM with a NRM technology collocated with a US EPA federal equivalent method (FEM). Next, we fit a generalized additive model (GAM) to establish a non-linear calibration curve that defines the relationship between the NRM and FEM data. Then, we used our fitted model to generate calibrated NRM PM data. Evaluation of raw NRM PM2.5 data revealed strong correlation with FEM (R = 0.9) but an average bias (AB) of −2.84 µg/m3 and a root mean square error (RMSE) of 2.85 µg/m3, with 406 h of data. Fitting of our GAM revealed that the correlation structure was maintained (r = 0.9) and that average bias (AB = 0) and error (RMSE = 0) were minimized. We conclude that field-based statistical calibration models can be used to reduce bias and improve NRM data used for community air monitoring studies.
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Beitz, A. J. "Relationship of glutamate and aspartate to the periaqueductal gray-raphe magnus projection: analysis using immunocytochemistry and microdialysis." Journal of Histochemistry & Cytochemistry 38, no. 12 (December 1990): 1755–65. http://dx.doi.org/10.1177/38.12.1701457.
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This study tested the hypothesis that the excitatory amino acid transmitters glutamate and/or aspartate are associated with the periaqueductal gray (PAG)-raphe magnus (NRM) projection. Retrograde neuroanatomical tracing procedures utilizing the tracers WGA-HRP or D-[3H]-aspartate were combined with immunocytochemical localization of glutamate or aspartate to determine if glutamate and/or aspartate immunostained neurons projected to the NRM. Both glutamate- and aspartate-immunoreactive cells in the PAG were found to project to the NRM. Double labeling immunocytochemichemical procedures indicated that glutamate and aspartate are co-localized in many PAG neurons, suggesting the following possibilities: (a) one of these two amino acids may serve as a precursor to the other; (b) both amino acids may be co-released from the same PAG neuron; or (c) both amino acids are present in high levels in the perikarya for metabolic purposes. At the EM level, both glutamate- and aspartate-immunoreactive terminals were identified in the NRM, strengthening the concept that both amino acids participate in synaptic transmission in this medullary nucleus. To determine if glutamate and aspartate are in fact released from PAG-NRM axons, the PAG was stimulated chemically with homocysteic acid (HCA) and amino acids were collected from the NRM using a microdialysis probe. Microinjection of HCA, but not vehicle, into the PAG resulted in the release of both glutamate and aspartate in the nucleus raphe magnus. These data suggest that both glutamate and aspartate are released from PAG fibers terminating in the NRM and provide strong support for the hypothesis that excitatory amino acids play a neurotransmitter role in the PAG-NRM pathway.
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Mamdani, Mahmood. "Uganda in transition: Two years of the NRA/NRM." Third World Quarterly 10, no. 3 (July 1988): 1155–81. http://dx.doi.org/10.1080/01436598808420103.
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NKONYA, EPHRAIM, JOHN PENDER, and EDWARD KATO. "Who knows, who cares? The determinants of enactment, awareness, and compliance with community Natural Resource Management regulations in Uganda." Environment and Development Economics 13, no. 1 (February 2008): 79–101. http://dx.doi.org/10.1017/s1355770x0700407x.
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ABSTRACTAt the community level, bylaws and other regulations are commonly used to manage natural resources. However, there is limited research on how communities enact these regulations and what determines awareness and compliance with these regulations. A survey of 273 communities was conducted in Uganda with an objective of analyzing the determinants of enactment, awareness and compliance with community Natural Resource Management (NRM) regulations. Presence in the community of programs and organizations with focus on agriculture and the environment increases the probability to enact and to be aware of NRM regulations. The probability to comply with regulations enacted by village councils was greater than the case with such regulations passed by higher legislative bodies, suggesting the important role played by decentralization in NRM. Poverty is associated with lower compliance with NRM regulations. This supports the poverty-natural resource degradation trap hypothesis, and suggests that measures to reduce poverty can also improve NRM.
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Ming Christie, Lai. "Contested Country: Local and Regional Natural Resources Management in Australia." Pacific Conservation Biology 16, no. 4 (2010): 292. http://dx.doi.org/10.1071/pc110291.
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I was attracted by the book title at first glance. "Contested Coumry" is such powerful description to one of the major challenges in the field of natural resources management (NRM) where conflicts emerge between stakeholders over the valuation and utilization of natural resources. In fact, this is also the site where asymmetrical power relations are embedded. Although this volume focuses mainly on the Australian context, its significance has great implications for both local and international practice of NRM policy implementation. As the editors point out in the introduction, it is open to question whether the current regional NRM approach is realistic in addressing the environmental crisis and achieving biodiversity conservation. Therefore, this book is very ambitious in its effort to critically ancllyse the efficiency of the regional and community-approach of NRM which has been largely implemented since the mid-1990s. Apart from this, what the future holds for NRM is another key theme tackled in this volume by contributors.
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Penack, Olaf, Christophe Peczynski, Mohamad Mohty, Ibrahim Yakoub-Agha, Rafael de la Camara, Bertram Glass, Rafael F. Duarte, et al. "Association of pre-existing comorbidities with outcome of allogeneic hematopoietic cell transplantation. A retrospective analysis from the EBMT." Bone Marrow Transplantation 57, no. 2 (October 30, 2021): 183–90. http://dx.doi.org/10.1038/s41409-021-01502-8.
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AbstractRisk assessment of allogeneic hematopoietic cell transplantation (allo-HCT) is hindered by the lack of current data on comorbidities and outcome. The EBMT identified 38,760 allo-HCT recipients with hematologic malignancies transplanted between 2010 and 2018 from matched sibling and unrelated donors with a full data set of pre-existing comorbidities. Multivariate analyses using the Cox proportional-hazards model including known risk factors for non-relapse mortality (NRM) were performed. We found that pre-existing renal comorbidity had the strongest association with NRM (hazard ratio [HR] 1.85 [95% CI 1.55–2.19]). In addition, the association of multiple pre-existing comorbidities with NRM was significant, including diabetes, infections, cardiac comorbidity, and pulmonary comorbidity. However, the HR of the association of these comorbidities with NRM was relatively low and did not exceed 1.24. Consequently, the risk of NRM was only moderately increased in patients with a high hematopoietic cell transplantation comorbidity index (HCT-CI) ≥ 3 (HR 1.34 [1.26–1.42]). In the current EBMT population, pre-existing non-renal comorbidities determined NRM after allo-HCT to a much lesser extent as compared with the underlying HCT-CI data. Improvements in management and supportive care as well as higher awareness based on the use of HCT-CI may have contributed to this favorable development.
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Stotler, Christy, Lisa Rybicki, Matt Kalaycio, Robert Dean, Edward A. Copelan, Ronald Sobecks, Brad Pohlman, et al. "Non-Relapse Mortality (NRM) after Autologous Stem Cell Transplant (ASCT) Is Reduced with Stringent Follow-up Post-Transplant." Blood 112, no. 11 (November 16, 2008): 2155. http://dx.doi.org/10.1182/blood.v112.11.2155.2155.
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Abstract Advances in supportive care have reduced early treatment related mortality with ASCT to approximately 1%. ASCT is so well tolerated that it is commonly thought that patients (pts) either relapse or are cured from their disease. However, registry data continues to show that NRM accounts for 25% of treatment failures following ASCT. NRM in this setting is poorly studied and represents a possible area of intervention. We previously reported on NRM at the Cleveland Clinic (ASH 2007: Abstract 1671) in which we reviewed 1573 consecutive autologous transplants performed between 1/92 and 12/05. This analysis included only adult pts receiving peripheral stem cells, single transplants, busulfan based preparative regimens, diagnoses of HL, NHL and MM (n=856). Relapse was the most common cause of death in 303 (79%) pts with NRM occurring in 82 pts (21% of deaths). The most common cause of NRM was pulmonary toxicity in 26 pts, followed by secondary malignancy (19 pts), infection (12 pts), cardiac toxicity (7 pts), other organ failure (7pts) and other causes (11 pts). The majority of NRM from pulmonary toxicity, other organ failure and infection occurred within one year of transplant. Forty-seven patients died within 100 days of transplant – 30 from relapse and 17 from NRM. In an effort to reduce NRM, we targeted pulmonary toxicity as a point of intervention. To identify pts at higher risk for pulmonary toxicity we prospectively followed 137 consecutive pts from 4/05 to 4/06 with monthly phone calls from the BMT nurses using a questionnaire focused to identify pts with symptoms of pulmonary toxicity, and obtained PFTs 1 and 6 months post-ASCT. 12/137 pts had a decrease in DLCO with 7 (58%) of events occurring within one month of transplant, an additional 4 (33%) events within 6 months and one event (9%) at 11 months. HL was the underlying diagnosis in 41% of pts, and prior radiation therapy (XRT) was also identified as a risk factor. Based on this analysis high risk pts were then defined as pts with a decline in DLCO >25% at one month post-ASCT, pts with HL and those with history of prior XRT. High risk pts received 4 and 8 months post-ASCT PFTs. Increased vigilance for the low risk group included phone calls at 3, 6 and 12 months to check for symptoms of pulmonary dysfunction. Patients experiencing a drop in DLCO of >25% at any point in time received a course of steroids and repeat PFT testing. The patient’s local oncologist also received a letter which included a copy of CDC vaccination guidelines with recommendations for re-immunization at one year post-ASCT, and a list of signs and symptoms of delayed pulmonary toxicity. To evaluate if changes made to our follow-up protocol impacted on rates of NRM, we identified 149 pts undergoing ASCT from 5/06 to 12/07 (using the same inclusion criteria as the original cohort). Data regarding the original 856 patients was also updated. For the 5/06 to 12/07 study group 127 pts (85%) are alive and 22 pts (15%) have died. Twenty pts (90.9 %) died from relapse and 2 pts (9.1%) died from NRM, both due to pulmonary toxicity. Only two patients died within 100 days of transplant, both due to relapse. There was no NRM within 100 days of transplant. On multivariable analysis of risk factors for NRM for all patients, year of transplant (1/92 to 12/05) emerged as a risk factor for NRM (HR 5.24, P=0.026). Age at transplant (HR 1.26, P=.013), number of prior chemotherapy regimens (HR 1.24, P=.019), prior radiation (HR 1.81, P=.006) and time to platelet engraftment (HR 0.24, P=.001) also emerged as risk factors for NRM. We have adopted more stringent post-ASCT surveillance protocols and while follow-up is short, results suggest that it may be possible to reduce NRM after ASCT.
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Schaumberg, Debra A. "Reply to NRM Buist." American Journal of Clinical Nutrition 75, no. 1 (January 1, 2002): 162. http://dx.doi.org/10.1093/ajcn/75.1.162a.
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Fomin, Egor V. "Sociological analysis of doctrine and social organization of new religious movements in Russia." Izvestiya of Saratov University. Sociology. Politology 22, no. 3 (August 24, 2022): 298–304. http://dx.doi.org/10.18500/1818-9601-2022-22-3-298-304.
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This article describes and analyzes the dogma and social organization of new religious movements (NRM) according to the author’s classification. The classification was created on the basis of such criteria as the NRM interaction with society and traditional religions, geography, dogma and legal status. The final analysis characterizes the movements which activities are prohibited or restricted in Russia. As a result, it is believed that Jehovah’s Witnesses is a neo-Christian old foreign (incorporated) alternative NRM of the first wave, opposite to the social order. The Church of Scientology is a syncretic (eclectic) foreign (incorporated) reformation NRM of the second wave, adapted to the social environment, the Church of the Last Testament is a syncretic (eclectic) domestic alternative NRM of the Christian type of the first wave. The history, dogma, rituals and practices, social organization, hierarchy, the number of members, current state, relationship with the social environment and legal status are considered. In conclusion, it is noted that the problem of describing the characteristics of NRMs is still widely discussed due to the confessional affiliation of researchers and the variety of NRMs.
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Schenberg, L. C., and T. A. Lovick. "Attenuation of the midbrain-evoked defense reaction by selective stimulation of medullary raphe neurons in rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 269, no. 6 (December 1, 1995): R1378—R1389. http://dx.doi.org/10.1152/ajpregu.1995.269.6.r1378.
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In rats anesthetized with alfaxalone/alfadolone, electrical stimulation in the dorsal periaqueductal gray matter (PAG) evoked a cardiovascular defense reaction with increases in blood pressure, heart rate, femoral conductance, and respiratory activity but a decrease in renal conductance. These responses were attenuated significantly after microinjection of 200 nl 0.1 M DL-homocysteic acid (DLH) into nucleus raphe magnus (NRM, n = 12) or nucleus raphe obscurus (NRO, n = 22). The maximum reduction in the pressor response was similar after stimulation in NRM (-36.3%) and NRO (-37.3%). The reduction of the tachycardia, however, was greater after stimulation in NRM (-78.1%) compared with NRO (-34.6%). The maximum reduction in the PAG-evoked vasodilation of the hindlimb averaged -55.7% and -55.3% after stimulation of NRM and NRO, respectively, whereas the renal vasoconstriction was reduced by -66.4% and -79.0%. The PAG-evoked increase in respiratory amplitude was attenuated only after stimulation of NRO. It is concluded that neurons in NRM and NRO may be involved in modulating the level of excitability of neurons in the midbrain defense area and/or in its efferent pathway.
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Bacigalupo, Andrea, Anna Maria Raiola, Alida Dominietto, Carmen Di Grazia, Francesca Gualandi, Teresa Lamparelli, Stefania Bregante, et al. "DONOR LYMPHOCYTE INFUSIONS (DLI): Risk Factors for Non Relapse Mortality (NRM) In 287 Patients Receiving DLI." Blood 116, no. 21 (November 19, 2010): 2333. http://dx.doi.org/10.1182/blood.v116.21.2333.2333.
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Abstract Abstract 2333 Introduction. Donor lymphocyte infusions (DLI) have been now used for 20 years in patients undergoing allogeneic hemopoietic stem cells transplants (HSCT). Initially DLI were only used in patients with chronic myeloid leukemia (CML) for the treatment of relapse. Subsequently DLI have been used in other disorders, and for different reasons, such as molecular relapse, mixed chimerism and also in prophylaxis programs. DLI are associate with a risk of Graft versus Host Disease (GvHD) and non relapse mortality (NRM). We have been using escalating doses of DLI for many years, and wanted to assess risk factors for GvHD and NRM. Patients. We analyzed 287 patients who received a total of 1288 DLI, for different reasons and at different intervals from transplant. The median number of DLI was 4 (1-15) the median interval between transplant and DLi was 282 dasy (1-4480), the median number of infused CD3 cells /kg of recipients body weight was 1×10^7 (1×10^3- 5×10^7). The diagnoses were chronic myeloid leukemia (n=78), acute leukemia (n=100), myelofibrosis (n=21), myelodisplastic syndrome (n=14), lymphoma (n= 35), other diagnosis (n=38). Median patients age was 40 (12-68). Statistical analysis. Factors studied for an association with GvHD and NRM were donor type (siblings/alternative donors), diagbnosis (CML others), year of DLI (</> 2001), maximum dose of DLI (</> 1×10^7), recipient age (<=/>40 years), donor age (<=/> 40 years), number of DLI (</> 4), interval transplant-DLI (</> 282 days), phase of the disease at transplant (early/advanced), and gender (donor recipient). Results GvHD. Seventy patients (24%) developed acute GvHD grade II-IV. In univariate analysis we coujld only identify the year of transplant as a predictor: GvHD II-IV developed in 29% of patients grafted before 2001 and in 19% of patients grafted later (p=0.04). In multivariate analysis this result was confirmed. Results NRM. With a median follow up for surviving patients of 2346 days (125-7194) 158 patients survive (55%). The primary cause of death was relapse of the original disease in 100 patients (35%), whereas 29 died of NRM (10%). Factors predicting NRM in univariate analysis were interval diagnosis-DLI, donor type and patient age. In multivariate COX analysis, the strongest predictor for NRM was the interval between transplant and DLI (p=00001) with a RR of 6.6 of NMR for patients receiving DLI before the median intgerval (282 days). Other predictors were donor type (siblings had a risk of 0.43, p=0.04), patients age (with a risk of 2.3 for patients over the age of 40) and advanced disease at the time of transplant (p=0.01) Conclusions. In this relatively large series of consecutive DLI, the risk of acute GvHD was relatively low, and we could not identify significant predictors. NRM was strongly associated with the interval between transplant and DLI, and this may be a warning for strategies aimed at improving GvL in patients with advanced leukemia, with very early administration of DLI. Disclosures: No relevant conflicts of interest to declare.
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Martin, Paul J., David M. Levine, Barry E. Storer, Sarah C. Nelson, Xinyuan Dong, and John A. Hansen. "Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation." Blood Advances 4, no. 14 (July 20, 2020): 3224–33. http://dx.doi.org/10.1182/bloodadvances.2020001927.
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Abstract Many studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.
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Follett, K. A., and G. F. Gebhart. "Modulation of cortical evoked potentials by stimulation of nucleus raphe magnus in rats." Journal of Neurophysiology 67, no. 4 (April 1, 1992): 820–28. http://dx.doi.org/10.1152/jn.1992.67.4.820.
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1. In pentobarbital sodium-anesthetized rats, we evaluated changes in cortical evoked potentials (EPs) associated with electrical and chemical stimulation of nucleus raphe magnus (NRM). A condition-test (C-T) paradigm was used. Cortical EPs were produced by test stimuli delivered to a hindpaw or the thalamic ventral posterior lateral nucleus (VPL; electrical stimulation), or by photic stimulation of the eyes or electrical stimulation of contralateral homotopical cortex (transcallosal EPs). These test stimuli were then preceded by electrical or chemical conditioning stimulation (CS) delivered to NRM through a stereotaxically implanted electrode or injection cannula, respectively. Effects of CS on EPs produced by the test stimuli were characterized. 2. Electrical CS preceding a test stimulus delivered to the foot reduced the amplitude of EPs at thresholds as low as 10-25 microA. The magnitude of EP reduction was dependent on CS intensity, frequency, and the C-T interval. Optimal parameters were trains of 10 pulses (400 Hz) delivered at a C-T interval of 5-10 ms. Injection of glutamate and lidocaine into NRM demonstrated that these effects were due to activation of NRM neurons and not to current spread to medial lemniscus (ML). NRM CS also reduced cortical EPs produced by test stimulation in VPL but did not alter EPs from visual stimulation or from electrical stimulation of contralateral homotopical cortex. 3. These findings suggest that NRM CS attenuates EPs by inhibiting thalamic or thalamocortical afferent activity. Because NRM CS affected all components of the cortical EPs, the effect appears to involve alteration of general sensory activity and is not nociception specific.(ABSTRACT TRUNCATED AT 250 WORDS)
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Rachakonda, Sivaramakrishna P., Hao Dai, Olaf Penack, Olga Blau, Igor Wolfgang Blau, Aleksandar Radujkovic, Carsten Müller-Tidow, Rajiv Kumar, Peter Dreger, and Thomas Luft. "Single Nucleotide Polymorphisms in CD40L Predict Endothelial Complications and Mortality After Allogeneic Stem-Cell Transplantation." Journal of Clinical Oncology 36, no. 8 (March 10, 2018): 789–800. http://dx.doi.org/10.1200/jco.2017.76.4662.
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Purpose Endothelial vulnerability is a potential risk factor for complications after allogeneic stem-cell transplantation (alloSCT). The CD40/CD40 ligand (CD40L) axis contributes to inflammatory diseases and is upregulated in endothelial cells upon activation, suggesting a role in alloSCT biology. Here, we studied single nucleotide polymorphisms (SNPs) in the CD40L gene in recipients of alloSCT. Patients and Methods Three CD40L SNPs (rs3092920, rs3092952, rs3092936) were analyzed for association with transplant-associated thrombotic microangiopathy, overall nonrelapse mortality (NRM), and NRM after acute graft-versus-host disease in 294 recipients of alloSCT without statin-based endothelial prophylaxis (SEP). The significant genotype was then put into perspective with established thrombomodulin ( THBD) gene polymorphisms. Findings were validated in an independent cohort without SEP and in an additional 344 patients who received SEP. Results The rs3092936 CC/CT genotype was associated with an increased risk of transplant-associated thrombotic microangiopathy ( P = .001), overall NRM ( P = .03), and NRM after acute graft-versus-host disease ( P = .01). The rs3092936 CC/CT genotype was largely mutually exclusive of high-risk THBD SNPs. Both CD40L and THBD SNPs predicted adverse overall survival (OS) and overall NRM to a similar extent in training cohort (OS, P = .04; NRM, P < .001) and validation cohort (OS, P = .01; NRM, P = .001) without SEP. In contrast, SEP completely abolished the influence of the high-risk CD40L and THBD SNPs ( P = .40). Conclusion An increased risk of endothelial complications can be predicted before alloSCT by genetic markers in the recipient’s genome. The normalization of mortality risks in patients treated with SEP suggests a way of overcoming the negative effect of high-risk genotypes and warrants further clinical validation.
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Yeon, Sang Hoon, Myung-Won Lee, Thi Thuy Duong, Sora Kang, Sungju Jee, So-Young Ahn, Hyewon Ryu, et al. "Cardiopulmonary Exercise Test With Comorbidity Index Before Allogeneic Hematopoietic Stem Cell Transplantation." Integrative Cancer Therapies 21 (January 2022): 153473542211342. http://dx.doi.org/10.1177/15347354221134249.
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Purpose: To evaluate the role of the cardiopulmonary exercise test (CPET) with comorbidity index as a predictor of overall survival (OS) and non-relapse mortality (NRM) in patients with hematological malignancies who undergo allogeneic hematopoietic stem cell transplantation (HSCT). Methods: We retrospectively analyzed consecutive adult patients with hematological malignancies who underwent HLA-matched donor-HSCT at Chungnam National University Hospital (Daejeon, South Korea) between January 2014 and December 2020. Maximal oxygen consumption (VO2max) was classified using the recommendations of the Mayo Clinic database. Results: Of 72 patients, 38 (52.8%) had VO2max values lower than the 25th percentile (VO2max ≤ 25th) of an age- and sex-matched normal population. Patients with VO2max ≤ 25th had no significant differences both OS and NRM (30 month OS 29.8% vs 41%, P = .328; and 30 month NRM 16% vs 3.3%, P = .222), compared with other patients. VO2max ≤ 25th was assigned a weight of 1 when added to the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) to form a composite comorbidity/CPET index (HCT-CI/CPET). Patients with HCT-CI/CPET scores of 0 to 1 demonstrated significantly better OS and NRM than did patients with HCT-CI/CPET scores ≥2 [median OS not reached vs 6 months, P < .001 and 30 month NRM 7.4% vs 33.3%, P = .006]. An HCT-CI/CPET score ≥2 was the only adverse risk factor for NRM on multivariate analysis [hazard ratio (HR) of NRM 10.36 (95% CI 1.486-2.25, P = .018)]. Conclusion: The composite HCT-CI/CPET score can predict the survival and mortality of patients with hematological malignancies who undergo allogeneic HSCT.
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Jones, S. L., and G. F. Gebhart. "Spinal pathways mediating tonic, coeruleospinal, and raphe-spinal descending inhibition in the rat." Journal of Neurophysiology 58, no. 1 (July 1, 1987): 138–59. http://dx.doi.org/10.1152/jn.1987.58.1.138.
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1. The contribution of midline medullary bulbospinal neurons to descending inhibition from the locus coeruleus (LC) and the funicular trajectories of coeruleo- and raphe-spinal fibers mediating inhibition of spinal nociceptive transmission were examined in different experiments. Extracellular recordings of lumbar dorsal horn neurons were made in deeply pentobarbital-anesthetized, paralyzed rats. All units studied responded to electrical stimulation of the ipsilateral tibial nerve at intensities supramaximal to activate A-alpha-delta- and C-fibers and to mechanical and heat (50 degrees C) stimuli of the glabrous skin of the ipsilateral hind foot. Parallel studies were done in lightly pentobarbital-anesthetized rats utilizing the nociceptive tail-flick (TF) reflex. 2. To examine the contribution of bulbospinal neurons in the nucleus raphe magnus (NRM) to descending coeruleospinal inhibition, lidocaine microinjections were made into the NRM to produce a time-limited, reversible block. Lidocaine microinjections into the NRM effectively blocked NRM stimulation-produced inhibition of the TF reflex (prelidocaine stimulation thresholds were increased two to three times), but did not affect stimulation-produced inhibition from the LC. 3. In parallel electrophysiological studies, stimulation in the NRM inhibited heat-evoked dorsal horn unit activity to 31% of control, whereas stimulation in the LC/SC inhibited heat-evoked activity of the same units to 30% of control. Following NRM lidocaine microinjections, stimulation at the same intensity in the NRM no longer inhibited heat-evoked activity (93% of control), confirming the efficacy of the lidocaine block. LC stimulation-produced inhibition, however, was not affected by blockage of the NRM; heat-evoked unit activity was inhibited by LC stimulation to 39% of control. 4. The effects of ipsilateral and bilateral ventrolateral funiculus (VLF) lidocaine microinjections on spontaneous and heat-evoked unit activity were examined in other experiments. Spontaneous activity increased following ipsilateral VLF lidocaine microinjections for 13/18 units; decreases and no change in spontaneous activity were observed for three and two units, respectively. Heat-evoked unit activity was increased significantly following ipsilateral VLF lidocaine microinjections.(ABSTRACT TRUNCATED AT 400 WORDS)
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Stotler, Christy, Matt Kalaycio, Robert M. Dean, Ronald Sobecks, Edward A. Copelan, Steven Andresen, Brad Pohlman, et al. "Non-Relapse Mortality Associated with Autologous Stem Cell Transplant (ASCT)." Blood 110, no. 11 (November 16, 2007): 1671. http://dx.doi.org/10.1182/blood.v110.11.1671.1671.
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Abstract Advances in supportive care have reduced early treatment related mortality with ASCT to approximately 1%. Registry data has shown that relapse is the cause of treatment failure in approximately 80% of patients. However, non-relapse mortality (NRM), over time, affects 20% of transplant recipients. Delayed NRM is poorly studied. To characterize the factors associated with NRM, we reviewed 1573 consecutive autologous transplants performed at the Cleveland Clinic from 1/1992 through 12/2005. This analysis included only adult patients (pts) receiving peripheral stem cells, busulfan based preparative regimens, single transplants, and diagnoses of NHL, HD and MM (n = 856). The median age was 49, 62% were male, and 30% received prior radiation therapy. The most common number of prior chemotherapy regimens was 2 (48%); the primary diagnosis was NHL (67%), HD (18%), MM (15%); and 90% had sensitive disease at the time of transplant. 471 (55%) are alive and 385 (45%) have died. Relapse was the most common cause of death, occurring in 303 (79%) patients. Non-relapse mortality occurred in 82 patients (21% of deaths). The most common cause of NRM was pulmonary toxicity, occurring in 26 patients, followed by secondary malignancy in 19 pts, infection (12 pts), cardiac toxicity (7 pts), other organ failure (7 pts), and other causes (11 pts). Patients who died from secondary malignancy were significantly more likely to have received prior radiation therapy (p = 0.004), to require more days of pheresis to collect stem cells (p<0.001) and had a longer time to platelet engraftment than did other patients (p<0.001). 16/19 deaths due to secondary malignancy were from hematologic malignancies. Causes of death in the “other” category included accidents (n=3), homicide (n=1) and suicide (n=1). Liver toxicity was the most common organ affected in the “other organ failure” category. 46% of patients with NRM due to pulmonary toxicity had a prior exposure to radiation therapy, as did 43% of those with cardiac toxicity. The time to development of NRM is shown below: Figure Figure The substantial majority of NRM due to pulmonary toxicity, other organ failure or infection occurs within one year post-transplant. This suggests a need for more intensive surveillance of recipients of autologous transplantation for 12 months, possibly with regular visits to the transplanting institution. We have adopted more stringent follow up with promising early results at reducing 1 year NRM. The median time of NRM from secondary malignancy is 3.5 years, which suggests that surveillance of blood counts should continue well beyond one year post-transplant. Whether more aggressive surveillance will reduce NRM associated with ASCT requires further study.
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Robin, Marie, Raphael Porcher, Renato de Castro, Gustavo Fisher, Regis Peffault de Latour, Patricia Ribaud, Agnes Devergie, Vanderson Rocha, Jean Yves Mary, and Gerard Socie. "Initial Liver Involvement in Acute Graft-Versus-Host Disease (GVHD) Predicts a Severe Acute Gvhd and Poor Long-Term Survival." Blood 112, no. 11 (November 16, 2008): 1164. http://dx.doi.org/10.1182/blood.v112.11.1164.1164.
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Abstract Objectives: Current grading systems in acute GVHD can not effectively identify patients with poor prognosis at time of GVHD diagnosis. The aim of this study was to evaluate clinical or biological parameters at the onset of GVHD associated with poor prognosis of acute GVHD. Methods: Among 257 patients (pts) who received an allogeneic stem cell transplant (SCT) after a myeloablative conditioning regimen between 1993 and 1999, 146 pts developed acute GVHD. One hundred-day cumulative incidence of acute GVHD was 57.3% (95%CI 51.1–63.4) whereas 100-day cumulative incidence of death non related to GVHD was 5.3% (95%CI 2.5–8.1). Patients with acute GVHD were analyzed for risk factors associated with non-relapse-mortality (NRM) using proportional cause-specific hazards models. Characteristics of patients: Median age was 32 years (from 4 to 60 years). Sex ratio men/women was 1,4. Disease was defined as low risk (n=43) (acute leukemia in first remission, aplastic anemia without more than 20 blood transfusions before transplantation and chronic myeloid leukemia in first chronic phase) and high risk (n=99, all other diagnosis). Source of stem cell was bone marrow in 106, peripheral blood stem cells in 23 and cord blood in 13 pts. 87 patients received SCT from a sibling donor and 55 patients from an unrelated donor. 85 patients were HLA identical with their donor. Median follow-up was 76 months. Results: At time of diagnosis, GVHD involved a single organ in the majority of the patients (109 pts, 78%): skin for 63, gut for 35, liver for 11 pts. 37 patients had multiple organs affected by GVHD: 34 patients had 2 organs and 3 had 3 organs (liver, skin and gut). The Table 1 shows acute GVHD grade from diagnosis to maximal grade. Table 1 Maximal grade Initial grade No GVH 1 2 3 4 Total No GVH 111 - - - - 111 (43%) 1 - 31 16 3 10 60 (23%) 2 - 0 56 13 14 83 (32%) 3 - 0 0 2 1 3 (1%) Total 111 (43%) 31 (12%) 72 (28%) 18 (7%) 25 (10%) 257 Overall 1-year NRM was 54.9% (95%CI 46.6–63.2). 57 patients experienced a failure to corticosteroid treatment and were considered as “non-responders”. Covariates tested for NRM predictive factors were gender, CMV status, conditioning regimen, source of SCT, HLA match, hematological disease, initial characteristics of GVHD and response to treatment after 7 days. Significant (p < 0.05) risk factors for NRM were non sibling donor (NRM: 64.5% [51.5–77.5]), absence of methotrexate in GVHD prophylaxis (NRM: 67.3 [50.2–84.5]), initial liver involvement (NRM: 80.2% [62.2 to 98.2]) and acute GVHD resistant to corticosteroids (NRM: 78.9 % [68.1–89.8]). Patients who were responder to corticosteroids had same NRM than patients who did not develop any GVHD. Albumin level (alb) was associated with NRM in patients with initial gut involvement (NRM 21.4% [0.0–44.0] in pts with alb > or = 35 and 61.1% [37.4–84.8] in pts with alb < 35 gr/L, p=0.035). Initial grade was not significantly associated with NRM: 1-year cumulative incidence was 52.4% (39.3–65.6), 56.3% (45.3–67.4) and 66.7% (0.0–00) in patients with initial grade I, II and III, resp. as compared to 26.2% (17.4–5.0) in patients without GVHD. In multivariate analysis, initial liver involvement (HR: 2.45 (1.46 to 4.12), p=0.0007) and non sibling donor (HR: 1.58 (1.02 to 2.43, p= 0.0039) were both associated with NRM. Conclusion: In this study, classification of GVHD at time of diagnosis was not predictive for NRM. Initial liver involvement was the most important clinical predictor and may be considered in clinical management and need prospective clinical trials.
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Cyriac, Sunu, Auro Viswabandya, Jeffrey H. Lipton, Dennis Dong Hwan Kim, Rajat Kumar, Wilson Lam, Arjun Law, Zeyad Al-Shaibani, Jonas Mattsson, and Fotios V. Michelis. "Impact of Hematopoeitic Cell Transplantation-Co-Morbidity Index (HCT-CI) and Its Individual Components on Allogeneic Transplant Outcomes." Blood 134, Supplement_1 (November 13, 2019): 5722. http://dx.doi.org/10.1182/blood-2019-127654.
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Background Allogeneic Stem Cell Transplantation (SCT) is potentially curative for many hematological diseases, however carries a high risk of mortality and morbidity. Multiple scoring systems has been developed to predict SCT outcomes and one of the more popular one id the Hematopoeitic Cell Transplantation - Co-Morbidity Index (HCT-CI). This study evaluates the value of HCT-CI score in predicting the outcomes of patients undergoing SCT at Princess Margaret Cancer Centre (PMCC). We also looked at the impact of the individual elements of HCT-CI in predicting SCT outcomes. Methods Two experienced physicians prospectively calculated the HCT-CI score for all patients transplanted at our center. Prospective calculation was performed during the patient's pre-transplant assessment before transplant admission using a pre-prepared form. All other patient and transplant characteristics were retrospectively collected from the EPR. Non-Relapse Mortality (NRM) and Overall survival (OS) were calculated to assess the prognostic power of the scores. This was correlated with the major SCT outcomes of Non-relapse mortality (NRM) and Overall survival (OS). Separately the impact of each components of HCT-CI was assessed in Univariate and multivariable analysis for NRM and OS. Results From August 2014 to April 2017, 299 patients underwent allogeneic HCT at the Princess Margaret Cancer Centre (PMCC), Toronto. Base line characteristics of the patients are shown in Table 1. HCT-CI scores were grouped as 0-2 as group 1 and ≥3 as group 2. Nearly two thirds belonged to group 1. (Table 1) The 2 year OS for the whole cohort was 51% (45%-56%) and NRM at 2 years was 25.1% (20%-31%). For the HCT-CI scores 0-2 vs ≥3, 2-year OS was 53% vs 46% respectively (p=0.29). The NRM at 2 years was 34% (29%-39%) for the whole cohort. For the HCT-CI scores 0-2 vs ≥3, 2-year NRM was 33% vs 35% respectively (p=0.75). (Figure 1) Univariate analysis of the impact of the independent components of HCT-CI score on OS and NRM was done. A p value of 0.2 was taken as cut off for selection for multivariable analysis. For NRM, cardiac co-morbidity, Diabetes and cerebrovascular accident were considered for multivariable analysis, where as cardiac co-morbidity, diabetes, severe pulmonary comorbidity, arrythmia and cerebrovascular accident were considered for OS multivariable analysis. On multivariable analysis, diabetes was the only factor found independently impacting both NRM [HR 2.2 (95%CI 1.4-3.4), p=0.0005] and OS [HR 1.6 (95%CI 1.1-2.4), p=0.025]. Conclusion HCT-CI was not found to predict OS or NRM accurately in our cohort of patients. Among the components of HCT-CI, diabetes was the only co-morbidity that significantly impacted both OS and NRM. Future prognostic scorings should incorporate only significant elements of comorbidities along with other transplant and disease related elements while developing prognostic scores. Disclosures Mattsson: Therakos: Honoraria; Celgene: Honoraria; Gilead: Honoraria. Michelis:CSL Behring: Other: Financial Support.
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Zu, Jiyun, and Patrick C. Kyllonen. "Nominal Response Model Is Useful for Scoring Multiple-Choice Situational Judgment Tests." Organizational Research Methods 23, no. 2 (November 25, 2018): 342–66. http://dx.doi.org/10.1177/1094428118812669.
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We evaluated the use of the nominal response model (NRM) to score multiple-choice (also known as “select the best option”) situational judgment tests (SJTs). Using data from two large studies, we compared the reliability and correlations of NRM scores with those from various classical and item response theory (IRT) scoring methods. The SJTs measured emotional management (Study 1) and teamwork and collaboration (Study 2). In Study 1 the NRM scoring method was shown to be superior in reliability and in yielding higher correlations with external measures to three classical test theory–based and four other IRT-based methods. In Study 2, only slight differences between scoring methods were observed. An explanation for the discrepancy in findings is that in cases where item keys are ambiguous (as in Study 1), the NRM accommodates that ambiguity, but in cases where item keys are clear (as in Study 2), different methods provide interchangeable scores. We characterize ambiguous and clear keys using category response curves based on parameter estimates of the NRM and discuss the relationships between our findings and those from the wisdom-of-the-crowd literature.
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Gibb, Ryan. "The Elections in Uganda, February 2016." Africa Spectrum 51, no. 2 (August 2016): 93–101. http://dx.doi.org/10.1177/000203971605100206.
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On 18 February, Uganda conducted presidential and parliamentary elections. Incumbent president Yoweri Museveni of the National Resistance Movement (NRM) won the multiparty contest for a third consecutive time. If his reign as the NRM leader during Uganda's stint as a one-party state is counted, the February elections marked the beginning of Museveni's fifth overall term as president. The NRM continues to dominate parliament, having won a super-majority of the contested seats. Opposition members who competed for both the presidential seat and a seat in parliament contested the results of the election, and the primary opposition candidate Kizza Besigye was placed under house arrest. International observers questioned the integrity of the results, specifically in rural areas that were poorly monitored, and opposition strongholds in urban centres suffered logistical problems. The elections reconfirmed the strength of the NRM following years of political infighting.
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Levine, John E., Andrew C. Harris, Austin Taylor, Thomas M. Braun, John Magenau, and James L. M. Ferrara. "A Biomarker-Based Grading System At Onset Of GvHD Predicts NRM Better Than The Modified Glucksberg Grading System." Blood 122, no. 21 (November 15, 2013): 145. http://dx.doi.org/10.1182/blood.v122.21.145.145.
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Abstract Maximum grades of the commonly used modified Glucksberg staging system for acute graft versus host disease (GVHD) correlate with non-relapse mortality (NRM), but cannot guide treatment at diagnosis. All patients with GVHD grade II-IV are standardly treated with high dose steroids, and no further treatment decisions are based on GVHD severity at onset. In contrast, treatment for GVHD grade I varies so that some patients receive systemic steroid therapy while others are observed. We wished to devise a grading system that predicted eventual mortality and that could therefore guide treatment at diagnosis. We have previously shown that plasma concentrations of GVHD biomarkers (TNFR1, IL2Rα, elafin, REG3α, ST2) have prognostic significance (Paczesny, Blood, 2009, Paczesny, Sci Trans Med, 2010, Ferrara Blood, 2011, Vander Lugt, NEJM, 2013). We identified 360 University of Michigan allogeneic hematopoietic cell recipients with acute GVHD (median age 48y, range 0-70y) who had plasma samples taken at the time of diagnosis [median day 28, range: 5-174] and stored in our repository: grade I (n =130, 36%), grade II (n = 151, 42%), or grade III/IV (n = 79, 22%). Biopsy confirmation was available for >80% of cases. Progression from Glucksberg I to Glucksberg ≥ II occurred in 84 (64%) patients at a median of 6 days from onset, whether systemic therapy for grade I was initiated (N=80; 70%) or not (N=50; 56%, p=0.12). We chose 6 month NRM as the key endpoint as it encompasses treatment failures due to nonresponse, loss of treatment response, and complications of treatment; 93% of 6 m NRM was due to GVHD. The 6 m NRM for patients presenting with Glucksberg I (15%) and Glucksberg II (24%) was not significantly different [as also shown by others: MacMillan, Blood, 2010]; their combined NRM was 20% (n=281, Panel A). Patients who presented with Glucksberg III/IV had significantly worse 6 m NRM than Glucksberg I/II (56%, N=79, p<0.001, Panel C). We measured the plasma concentrations of the 5 prognostic biomarkers above and used logistic regression to develop Ann Arbor GVHD grades such that 6 m NRM for Ann Arbor I would be ∼10% (as in patients with Glucksberg I whose GVHD never progressed) and >50% for Ann Arbor III (similar to the 6 m NRM for Glucksberg III/IV). We treated relapse after development of GVHD as a competing risk and developed separate regression models according to the clinical severity at presentation, i.e. Glucksberg I/II and III/IV. Panel B shows the 6 m NRM of patients who presented with Glucksberg I/II according to Ann Arbor I (thin), II (medium), and III (thick). Patients with Ann Arbor III (n=29/281, 10%) experienced far worse 6 m NRM (59%) than either Ann Arbor I (11%) or Ann Arbor II (17%) [p<0.001 for each]. Likewise, Panel D shows that biomarkers reclassify significant numbers of patients with Glucksberg III/IV at onset to Ann Arbor I and II (n=21/79, 27%). These reclassified patients experienced much lower NRM (0% and 21%, respectively) than patients with Ann Arbor III (71%, p<0.001). Results are summarized in Panels E (combined Glucksberg NRM) and F (combined Ann Arbor NRM). NRM for Ann Arbor grade III remained significantly worse compared to Ann Arbor grade I and II (p<0.001 for both comparisons). Of note, the difference between Ann Arbor grade I and II (10% vs 18%, p=0.08) approaches statistical significance. Comparison of the models by the Akaike Information Criterion indicated that Ann Arbor grades predict NRM better than Glucksberg grades. Patients with Ann Arbor grade III GVHD experienced worse NRM (67%) than those with Glucksberg III/IV (56%), while patients with Ann Arbor grade I (10%) have better NRM than those with Glucksberg I/II (20%). As expected, patients with Ann Arbor grade I were most likely to respond to treatment by day 28 and those with Ann Arbor III GVHD were least likely (p=0.01 and p=0.03, respectively). In conclusion, we have developed a new acute GVHD grading system using biomarkers at onset of disease that reclassifies significant numbers of patients and produces more accurate risk groups than Glucksberg grades. If validated in patients from other centers, this system may be able to guide therapy: patients with Ann Arbor Grade III who experience high rates of treatment failure with standard approaches would benefit from experimental therapies as primary treatment. Likewise, patients with Ann Arbor grade I might require low dose/no systemic steroids. Disclosures: Levine: University of Michigan: Patent for GVHD biomarkers, Patent for GVHD biomarkers Patents & Royalties. Braun:University of Michigan: Patent for GVHD Biomarkers, Patent for GVHD Biomarkers Patents & Royalties. Ferrara:University of Michigan: Patent for GVHD Biomarkers, Patent for GVHD Biomarkers Patents & Royalties.
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Kalaycio, Matt, Brad Pohlman, Ronald Sobecks, Steven Andresen, Kristie Summers, Brian J. Bolwell, Lisa Rybicki, and Elizabeth Kuckowski. "Increased Risk of Non-Relapse Mortality within One Year after Autologous Stem Cell Transplant in Older Adults with Lymphoma." Blood 104, no. 11 (November 16, 2004): 5111. http://dx.doi.org/10.1182/blood.v104.11.5111.5111.
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Abstract The risk of early mortality after high-dose chemotherapy followed by autologous stem cell transplant (ASCT) is generally less than 5%. However, this mortality rate is often determined by deaths that occur while hospitalized or within 60–100 days of ASCT. We queried our long-term follow-up database to determine non-relapse mortality (NRM) for patients with lymphoma within 1 year of ASCT. From 1/1/99 to 3/30/04 we treated 317 evaluable lymphoma patients with busulfan 14mg/kg, VP-16 60 mg/kg, and cyclophosphamide 120 mg/kg followed by ASCT. Of these 317 patients, 21 (6.6%) had NRM within 1 year of ASCT. There were no significant differences between the 296 patients who did not die of NRM and the 21 who did with regard to diagnosis of non-Hodgkin versus Hodgkin lymphoma, exposure to radiation therapy, exposure to rituximab, stage, and disease status at the time of ASCT. However, the median age of the 21 patients who died of NRM was 56 years compared to 49 years in the 296 who did not (p = 0.003). Of the 21 patients who died of NRM, 13 (62%) died of pulmonary complications. Adult respiratory distress syndrome (ARDS) was listed as the cause of death (COD) in 5 patients, but nearly all patients died at other institutions limiting our ability to confirm COD. Pneumonia was the COD in 5 patients and pulmonary toxicity was the COD in 2 patients. We routinely screen patients with pulmonary function tests including DLCO before and approximately 42 days after ASCT. There was no significant decrease in the median pre-ASCT and the post-ASCT DLCO in either the whole cohort of patients dying of NRM or the 13 patients dying of pulmonary complications. The 8 patients with NRM, but not pulmonary complications, died of various causes including cardiac tamponade, sepsis/multi-system organ failure, cirrhosis, renal failure, and secondary malignancy. The median time from ASCT to NRM was 146 days (range 45 to 287 days). Thus, lymphoma patients remain at risk for NRM for several months after ASCT. Older patients are at particular risk. The most common COD is pulmonary failure that cannot be predicted by screening pulmonary function tests. The cause of the pulmonary failure is uncertain. Busulfan may cause pulmonary toxicity, but the dose in this series of patients is relatively low and we have not seen similar pulmonary complications in 95 patients (median age 52 years) with myeloma treated with the combination of busulfan 16 mg/kg and cyclophosphamide 120mg/kg.
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Levine, John E., Thomas M. Braun, Andrew C. Harris, Ernst Holler, Austin Taylor, Holly K. Miller, John M. Magenau, et al. "A Biomarker Algorithm Defines Onset Grades of Acute Graft-Vs-Host Disease with Distinct Non-Relapse Mortality." Blood 124, no. 21 (December 6, 2014): 661. http://dx.doi.org/10.1182/blood.v124.21.661.661.
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Abstract The severity of symptoms at the onset of graft versus host disease (GVHD) does not accurately define risk, and thus most patients (pts) are treated alike with high dose systemic steroids. We hypothesized that concentrations of one or more plasma biomarkers at the time of GVHD diagnosis could define distinct non-relapse mortality (NRM) risk grades that could guide treatment in a multicenter setting. We first analyzed plasma that was prospectively collected at acute GVHD onset from 492 HCT pts from 2 centers, which we randomly divided into training (n=328) and validation (n=164) sets; 300 HCT pts who enrolled on multicenter BMT CTN primary GVHD therapy clinical trials provided a second validation set. We measured the concentrations of 3 prognostic biomarkers (TNFR1, REG3α, and ST2) and used competing risks regression to create an algorithm from the training set to compute a predicted probability (p) of 6 mo NRM from GVHD diagnosis where log[-log(1-p)] = -9.169 + 0.598(log2TNFR1) - 0.028(log2REG3α) + 0.189(log2ST2). We then rank ordered p from lowest to highest and identified thresholds that met predetermined criteria for 3 GVHD grades so that NRM would increase 15% on average with each grade. A range of thresholds in the training set met these criteria, and we chose one near each median to demarcate each grade. In the resulting grades, risk of NRM significantly increased with each grade after the onset of GVHD in both the training and validation sets (FIG 1A,B). Most (80%) NRM was due to steroid-refractory GI GVHD, even though surprisingly only half of these pts presented with GI symptoms. We next applied the biomarker algorithm and thresholds to the second multicenter validation set (n=300) and observed similarly significant differences in NRM (FIG 1C). Relapse, which was treated as a competing risk for NRM, did not differ among the three GVHD grades (Figure 1D-F). The differences in NRM thus translated into significantly different overall survival for each GVHD grade (Figure 1G-I). These differences in survival are explained by primary therapy response at day 28, which was highly statistically different for each of Ann Arbor grade (grade 1, 81%; grade 2, 68%; grade 3, 46%; p<0.001 for all comparisons). We performed additional analyses on the multicenter validation set of pts that developed GVHD after treatment with a wide spectrum of supportive care, conditioning and GVHD prophylaxis practices. As expected, the Glucksberg grade at GVHD onset did not correlate with NRM (data not shown). Despite small sample sizes, the same biomarker algorithm and thresholds defined three distinct risk strata for NRM within each Glucksberg grade (FIG 2A-C). Pts with the higher Ann Arbor grades were usually less likely to respond to treatment. Unexpectedly, approximately the same proportion of pts were assigned to each Ann Arbor grade (~25% grade 1, ~55% grade 2, ~20% grade 3) regardless of the Glucksberg grade (FIG 2D-F). Several clinical risk factors, such as donor type, age, conditioning, and HLA-match, can predict treatment response and survival in patients with GVHD. Using Ann Arbor grade 2 as a reference, we found that Ann Arbor grade 1 predicted a lower risk of NRM (range 0.16-0.32) and grade 3 a higher risk of NRM (range 1.4-2.9), whether or not any of these clinical risk factors were present. To directly compare Ann Arbor grades to Glucksberg grades, we fit a multivariate model with simultaneous adjustment for both grades. FIG 3 shows that Ann Arbor grade 3 pts had significantly higher risk for NRM (p=0.005) and Ann Arbor grade 1 pts had significantly less risk for NRM (p=0.002) than pts with Ann Arbor grade 2. By contrast, the confidence intervals for the HRs of the Glucksberg grades encompassed 1.0, demonstrating a lack of statistical significance between grades. In conclusion, we have developed and validated an algorithm of plasma biomarkers that define three grades of GVHD with distinct risks of NRM and treatment failure despite differences in clinical severity at presentation. The biomarkers at GVHD onset appear to reflect GI tract disease activity that does not correlate with GI symptom severity at the time. This algorithm may be useful in clinical trial design. For example, it can exclude pts who are likely to respond to standard therapy despite severe clinical presentations, thus limiting the exposure of low risk pts to investigational agents while also identifying the high risk pts most likely to benefit from investigational approaches. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Levine: University of Michigan: GVHD biomarker patent Patents & Royalties. Braun:University of Michigan: GVHD biomarker patent Patents & Royalties. Ferrara:University of Michigan: GVHD biomarker patent Patents & Royalties.
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Martínez-Cava, A., R. Morán-Navarro, and J. García Pallarés. "Análisis de la validez de las ecuaciones de estimación del 1RM con técnica de parada: una nueva propuesta." SPORT TK-Revista EuroAmericana de Ciencias del Deporte 6, no. 2 (July 24, 2017): 101. http://dx.doi.org/10.6018/300441.
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<p>El objetivo de esta investigación es validar nuevas ecuaciones de regresión para estimar el valor de fuerza dinámica máxima absoluta (1RM) mediante test de máximo número de repeticiones hasta el fallo muscular (nRM) ejecutados con técnica de parada o stop. Igualmente, se estudian los niveles de validez que presentan las ecuaciones que ya se encuentran actualmente definidas en la literatura internacional para estimar la magnitud de la carga (%1RM) y el valor de 1RM a partir de un test nRM en ejecuciones con técnica de parada. Los resultados indican que las nuevas ecuaciones propuestas en esta investigación [1RM en Press Banca = masa desplazada en kg (-0,01841*nRM)+0,981; 1RM en Sentadilla Completa = masa desplazada en kg (-0,01176*nRM)+0,975] muestran indicadores sustancialmente mejores de validez(ET = 1,8-2,2 kg; R<sup>2</sup> = 0,956-0,988), y por lo tanto de mayor capacidad predictiva, que el resto de ecuaciones definidas en la literatura internacional hasta la fecha.</p>
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Radujkovic, Aleksandar, Dietrich W. Beelen, Christian Kasperk, Anthony D. Ho, Peter Dreger, and Thomas Luft. "Low Pre-Transplant Testosterone Levels in Male Patients Are Associated with Endothelial Vulnerability and Non-Relapse Mortality after Allogeneic Stem Cell Transplantation." Blood 128, no. 22 (December 2, 2016): 4587. http://dx.doi.org/10.1182/blood.v128.22.4587.4587.
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Abstract Introduction: Low testosterone has been demonstrated to be an independent determinant of endothelial (dys)function in men. Graft-versus-host disease (GVHD) is a major contributor to non-relapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). Vulnerability of the recipients' endothelial cell system is a novel concept to explain why a proportion of patients with acute GVHD fail to respond to escalating immunosuppressive therapy and ultimately succumb to GVHD and related complications. This retrospective study investigated the prognostic impact of pre-transplant testosterone levels on NRM after alloSCT in male patients. Patients and methods: Between 2002 and 2014, a total of 277 male patients undergoing alloSCT at Heidelberg University (median age 55 years) provided informed consent to participate in this observational study (training cohort). 71 patients (26%) received transplants from related donors (RD). Diagnoses were acute myeloid leukemia (AML) in 108 patients (48%), myelodysplastic syndrome (MDS) in 66 patients (29%), lymphoid malignancies (lymphoma, chronic and acute lymphoid leukemia) in 75 patients (33%), and multiple myeloma in 28 patients (12%). A total of 176 patients (78%) received statin treatment post alloSCT as per institutional standard policy. For validation, an independent patient cohort of 205 men allografted for AML and MDS (median age 57 years, 18% RD, no statin treatment) at Essen University was analysed. Pre-transplant serum samples for testosterone measurements were collected between 0 and 2 months before alloSCT and cryopreserved at -80°C. Testosterone concentrations were measured by radioimmunoassay. Pre-transplant levels of suppressor of tumorigenicity-2 (ST2) were determined by ELISA. Overall survival (OS), incidence of relapse and NRM and were calculated from date of alloSCT to the appropriate endpoint using Cox regression analysis with cause specific hazard models for NRM and relapse. As confounding prognostic factors we included testosterone levels, age, donor type, graft type, donor sex, conditioning intensity, and disease type and stage prior to alloSCT. Results: Median pre-transplant testosterone level in the training and validation cohort was 13.6 nmol/L (range 0.3-41.7 nmol/L) and 16.0 nmol/L (0.8-38.1 nmol/L), respectively. In the training cohort, lower pre-transplant testosterone as continuous variable was associated with shorter OS (p=0.009). Lower testosterone levels showed a trend towards higher NRM (p=0.09) and a significant association with NRM after onset of acute GVHD (p=0.02). Multivariate analysis confirmed that lower pre-transplant testosterone levels were a significant predictor of an increased NRM risk after GVHD onset (p=0.03). In the subgroup of patients not receiving statins post-transplant, lower testosterone levels were associated with increased incidence of transplant-associated microangiopathy (p=0.01). In addition, lower pre-transplant testosterone levels correlated with higher pre-transplant ST2 levels indicating endothelial vulnerability. In the validation cohort, similar results with regard to OS (p=0.02), NRM (p=0.04), NRM after acute GVHD onset (p=0.03) in univariate analysis, and to NRM after GVHD onset (p=0.02) in multivariable analysis could be observed. The association of pre-transplant testosterone levels (in quartiles) and incidence of NRM after GVHD onset in the training and validation cohort is depicted in Figure 1A and 1B, respectively. Conclusion: Our study suggests that low pre-transplant testosterone is associated with serological and clinical evidence for endothelial damage and is an independent risk factor for a fatal outcome of GVHD. Prospective studies in the alloSCT setting investigating testosterone and testosterone supplementation in deficient patients are highly warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Gjærde, Lars Klingen, Sisse Rye Ostrowski, Niels Smedegaard Andersen, Lone Smidstrup Friis, Brian Kornblit, Søren Lykke Petersen, Ida Schjødt, and Henrik Sengeløv. "Pre-Transplantation ST2 Levels and Non-Relapse Mortality after Myeloablative Allogeneic Hematopoietic Cell Transplantation." Blood 136, Supplement 1 (November 5, 2020): 30–31. http://dx.doi.org/10.1182/blood-2020-133876.
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Introduction: Suppression of tumorigenicity 2 (ST2) is a prognostic plasma marker of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT) when measured at day +14 [Vander Lugt MT et al., N Engl J Med, 2013] and at day +7 in combination with regenerating islet-derived 3α (REG3α) [Hartwell MJ et al., JCI Insight, 2017]. We hypothesized that also pre-transplantation ST2 levels would be associated with NRM in the first 6 months after allo-HCT. Methods: We studied 112 adult patients who underwent allo-HCT with myeloablative conditioning at Rigshospitalet between July 2015 and August 2018 (Table 1). ST2 levels were measured by enzyme-linked immunosorbent assays using stored EDTA plasma samples obtained at the patients' scheduled pre-transplantation visit around day -23 (±11 days) and post-transplantation at days +7 and +14 (±3 days, n = 76 and 66). Univariable linear models and Spearman's ρ were used to evaluate associations and correlations between pre-transplantation ST2 levels and patient characteristics and other prognostic markers, respectively. Cause-specific Cox regression models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for NRM in the first 6 months after allo-HCT (relapse as competing risk) and grade II-IV acute graft-versus-host disease (GvHD) in the first 100 days after allo-HCT (NRM and relapse as competing risks) according to pre-transplantation ST2 levels. Gray's test was used to test differences in the cumulative incidence of NRM in the first 6 months after allo-HCT according to quartiles of pre-transplantation ST2 levels. Results: The median pre-transplantation plasma ST2 level was 19.9 ng/mL (inter-quartile range: 14.6-25.7 ng/mL, Figure Panel A); levels were higher in males (β = 8.7 ng/mL, p < 0.01), but did not differ by age (p = 0.81) or by being transplanted for acute leukemia (p = 0.89). ST2 was correlated with C-reactive protein (ρ = 0.24, p = 0.01), the endothelial activation and stress index (EASIX, calculated as creatinine x lactate dehydrogenase/thrombocytes, ρ = 0.27, p < 0.01) and ferritin (ρ = 0.28, p < 0.01). Longitudinally, pre-transplantation ST2 levels were strongly correlated with ST2 levels on day +7 (ρ = 0.57, p < 0.01) and day +14 (ρ = 0.48, p < 0.01). The cumulative incidence of NRM at 6 months was 11% (n = 12); causes of death were organ failure (75%), acute graft-versus-host disease (GvHD, 17%) and infection (8%). Higher pre-transplantation ST2 levels were associated with increased hazard of NRM in the first 6 months after allo-HCT (HR 1.73 per 10 ng/mL increase, 95% CI: 1.28-2.33, p < 0.01, area under the receiver operating characteristics curve = 0.61). Despite a significantly higher NRM in patients with pre-transplantation ST2 levels in the highest quartile (cumulative incidence at 6 months: 21% vs. 7% in patients with levels in the three lower quartiles, p = 0.03), there was no overall significant difference in NRM according to quartiles of pre-transplantation ST2 levels (p = 0.15, Figure Panel B). No significant association was found between pre-transplantation ST2 levels and grade II-IV acute GvHD (HR 0.88, 95% CI: 0.61-1.26, p = 0.48). Conclusion: Pre-transplantation ST2 levels were associated with increased NRM in the first 6 months after myeloablative allo-HCT, mainly driven by higher NRM in patients with pre-transplantation ST2 levels in the highest quartile. Larger studies are warranted to validate pre-transplantation ST2 levels as a prognostic marker of NRM after allo-HCT, which potentially could be used to support the choice of conditioning intensity. Disclosures No relevant conflicts of interest to declare.
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Mackay, Moragh, Catherine Allan, Ross Colliver, and Jonathon Howard. "Systems Approaches Enable Improved Collaboration in Two Regional Australian Natural Resource Governance Situations." International Journal of Systems and Society 1, no. 2 (July 2014): 1–21. http://dx.doi.org/10.4018/ijss.2014070101.
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Natural Resource Management (NRM) in Australia is socially and ecologically complex, uncertain and contested. Government and non-government stakeholders act and collaborate in regionally-based, multi-scale NRM governance situations, but imbalances in power and breakdowns in trust constrain transparency and equity. Here, we report on an action research project exploring the potential of social learning to contribute to systemic change in multi-governance situations. We sought to understand practices and institutional arrangements in two regional NRM governance case studies in southern Victoria, Australia. Drawing on this research, we explore how social learning, with its foundation of systems thinking, has enabled improved collaborative processes and adaptive governance to emerge.
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Gutierrez, Antonio, Leyre Bento, Silvana Novelli, Alejandro Martin, Gonzalo Gutierrez, Maria Queralt Salas, Mariana Bastos-Oreiro, et al. "Allogeneic Stem Cell Transplantation in Mantle Cell Lymphoma; Insights into Its Potential Role in the Era of New Immunotherapeutic and Targeted Therapies: The GETH/GELTAMO Experience." Cancers 14, no. 11 (May 27, 2022): 2673. http://dx.doi.org/10.3390/cancers14112673.
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Allo-SCT is a curative option for selected patients with relapsed/refractory (R/R) MCL, but with significant NRM. We present the long-term results of patients receiving allo-SCT in Spain from March 1995 to February 2020. The primary endpoints were EFS, OS, and cumulative incidence (CI) of NRM, relapse, and GVHD. We included 135 patients, most (85%) receiving RIC. After a median follow-up of 68 months, 5-year EFS and OS were 47 and 50%, respectively. Overall and CR rates were 86 and 80%. The CI of relapse at 1 and 3 years were 7 and 12%. NRM at day 100 and 1 year were 17 and 32%. Previous ASCT and Grade 3–4 aGVHD were associated with a higher NRM. Grade 3–4 aGVHD, donor type (mismatch non-related), and the time-period 2006–2020 were independently related to worse EFS. Patients from 1995–2005 were younger, most from HLA-identical sibling donors, and were pretreated less. Our data confirmed that allo-SCT may be a curative option in R/R MCL with low a CI of relapse, although NRM is still high, being mainly secondary to aGVHD. The arrival of new, highly effective and low toxic immunotherapeutic or targeted therapies inevitably will relegate allo-SCT to those fit patients who fail these therapies, far away from the optimal timing of treatment.
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Imus, Philip H., Hua-Ling Tsai, Leo Luznik, Ephraim J. Fuchs, Carol Ann Huff, Douglas E. Gladstone, Patrick Lowery, et al. "Haploidentical transplantation using posttransplant cyclophosphamide as GVHD prophylaxis in patients over age 70." Blood Advances 3, no. 17 (September 6, 2019): 2608–16. http://dx.doi.org/10.1182/bloodadvances.2019000155.
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Abstract Hematologic malignancies in older people are unlikely to be cured with chemotherapy alone. Advances in allogeneic blood or marrow transplantation (alloBMT), especially nonmyeloablative (NMA) conditioning and the use of haploidentical donors, now make this therapy available to older people; however, long-term outcomes and predictors of success are unclear. We reviewed the outcomes of 93 consecutive patients aged 70 and older (median, 72; range, 70-78), who underwent haploidentical BMT at Johns Hopkins Hospital between 1 September 2009 and 1 April 2018. All patients received NMA conditioning and posttransplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis. The 2-year overall survival was 53%, and 2-year event-free survival was 43%. The 180-day cumulative incidence (CuI) of nonrelapse mortality (NRM) was 14%, and the 2-year CuI was 27%. The 2-year CuI of relapse was 30%. Of 78 patients who were alive and had their weight recorded on day 180, weight loss predicted subsequent NRM (subdistribution hazard ratio, 1.0; 95% CI, 1-1.13; P = .048). In conclusion, haploidentical BMT with PTCy is feasible and relatively safe in septuagenarians. Although early, 6-month NRM was relatively low at 14%, but overall NRM continued to climb to 27% at 2 years, at least in part because of late deaths that appeared to be somewhat age related. Further studies to elucidate predictors of NRM are warranted.
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Diaconescu, Razvan, Christopher R. Flowers, Barry Storer, Mohamed L. Sorror, Michael B. Maris, David G. Maloney, Brenda M. Sandmaier, and Rainer Storb. "Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors." Blood 104, no. 5 (September 1, 2004): 1550–58. http://dx.doi.org/10.1182/blood-2004-03-0804.
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Abstract Nonmyeloablative regimens for allogeneic hematopoietic cell transplantation (HCT) have been developed for patients ineligible for myeloablative conditioning. We compared regimen-related toxicities (RRTs) and nonrelapse mortality (NRM) in 73 nonmyeloablative and 73 myeloablative recipients of HLA-matched related donor HCT, using the National Cancer Institute (NCI) Common Toxicity Criteria. Nonmyeloablative regimens were 2 Gy total body irradiation (TBI), either alone (n = 40) or combined with fludarabine, 30 mg/m2/d for 3 days (n = 33). Posttransplantation immunosuppression included mycophenolate mofetil and cyclosporine. Myeloablative regimens consisted mostly of cyclophosphamide + TBI or busulfan + cyclophosphamide, followed by posttransplantation methotrexate and cyclosporine. Nonmyeloablative patients were at higher risk than ablative patients because of greater age, longer time from diagnosis to HCT, more frequent preceding high-dose HCT, and higher pretransplantation Charlson comorbidity scores. Nevertheless, they experienced significantly less severe toxicities in 7 organs/systems: hematologic, gastrointestinal, hepatic, hemorrhage, infection, metabolic, and pulmonary. This translated into less NRM at day 100 (3% versus 23%, P = 10-4) and 1 year (16% versus 30%, P = .04). In multivariate analysis, the strongest factor predicting lessened RRT and NRM was nonmyeloablative conditioning, whereas high pretransplantation comorbidity scores predicted higher NRM. In conclusion, nonmyeloablative regimens had lower RRT and NRM and could be considered for comparative studies, including younger patients with more favorable Charlson comorbidity scores.
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Cisowski, S. M., J. R. Dunn, M. Fuller, and P. J. Wasilewski. "NRM: IRM(s) demagnetization plots of intrusive rocks and the origin of their NRM." Tectonophysics 184, no. 1 (November 1990): 35–54. http://dx.doi.org/10.1016/0040-1951(90)90119-s.
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Robertson, Michael, Andrew Bathgate, Andrew Moore, Roger Lawes, and Julianne Lilley. "Seeking simultaneous improvements in farm profit and natural resource indicators: a modelling analysis." Animal Production Science 49, no. 10 (2009): 826. http://dx.doi.org/10.1071/an09008.
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Natural resource indicators are used by catchment management organisations as targets for land use management. However, the nature of the trade-off function between natural resource management (NRM) outcomes and whole-farm profit is ill-defined, and varies between regions and according to the particular NRM indicator considered. Defining this function will assist catchment management organisations and farmers to evaluate the achievability of particular targets, and help determine the size of economic incentives required to offset any expected loss in farm profit associated with meeting targets. We addressed this issue by modelling representative farm businesses in two mixed farming regions (southern New South Wales and the central wheatbelt of Western Australia). The Agricultural Production Systems Simulator (APSIM) and GRAZPLAN farming systems models were linked and used to generate values of four NRM indicators (water leakage, nitrate leaching, groundcover and soil organic carbon change) for a wide range of crop–pasture rotations. The NRM indicator values were then incorporated into the Model of an Integrated Dryland System (MIDAS) whole-farm economic model to define the relationship with farm profit and farm cropping percentage. For some circumstances and indicators, the resulting trade-off functions were relatively flat; a wide range of enterprise mixes can lead to the same NRM outcomes but significant gains in the indicators may not be possible using current rotation options. For others, significant improvements could be achieved but at a substantial loss in whole-farm profit (through the selection of less profitable rotations). There were also examples where simultaneous gains in indicators and farm profit were possible. This analysis demonstrates an approach by which biophysical simulation models of the farming system can be linked to linear-programming representations of farming enterprises, and provides a method for deriving relationships between NRM targets and economic performance.
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HARWOOD, R. R., A. H. KASSAM, H. M. GREGERSEN, and E. FERERES. "NATURAL RESOURCES MANAGEMENT RESEARCH IN THE CGIAR: THE ROLE OF THE TECHNICAL ADVISORY COMMITTEE." Experimental Agriculture 41, no. 1 (January 2005): 1–19. http://dx.doi.org/10.1017/s0014479704002315.
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Judicious management of our natural resources is a major pillar of sustainable agriculture, broadly defined. It is, therefore, unfortunate that, until now, research in natural resources management (NRM) has not received sufficient support, or the recognition that other agricultural research topics have had. The Consultative Group on International Agricultural Research (CGIAR) recognized, early on, the complementarities and synergies between NRM research and other themes, notably genetic improvement, and its research Centres have pursued some vigorous programmes for many years. The Technical Advisory Committee (TAC) to the CGIAR was supportive of such programmes from the start and provided advice to the CGIAR System on NRM research strategies. Highlights of such advice over the last 20 years are discussed, including the ecoregional approach, the 1996 study of Priorities and Strategies for Soil and Water Research, and the CGIAR Vision and Strategy of 2000. Recent developments at the Centres leading to the promotion of integrated approaches to NRM (INRM) are described, and a set of priority areas in INRM research for future CGIAR activities is presented.
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Burns, Ethan, Kartik Anand, Jason R. Westin, Sai Ravi Kiran Pingali, Joe Ensor, Dahlia Sano, Loretta J. Nastoupil, et al. "Comparative Review of 30 Day Non-Relapse Mortality (NRM) in B-Cell Lymphomas Associated with Anti-CD19 Chimeric Antigen Receptor T-Cells (CAR-T) from FDA Database, Clinical Studies, and MD Anderson." Blood 134, Supplement_1 (November 13, 2019): 1931. http://dx.doi.org/10.1182/blood-2019-131077.
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Introduction CAR-T cells targeting CD19 positive B-cells have improved outcomes and remission rates in relapsed/refractory non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (B-ALL). Although toxicities contributing to non-progression related mortality (NRM) have been reported in the pivotal trials, its incidence in the standard of care setting post-approval is unknown. The following data includes toxicity profiles implicated in events leading to NRM obtained from the FDA adverse event reporting system (FAERS) with comparison to MD Anderson (MDACC-L) CAR-T Lymphoma cohort and to the pivotal CAR-T trials. Methods We retrospectively queried FAERS for all adverse events (AE) associated with tisagenlecleucel (T) and axicabtagene ciloleucel (AC) reported from January 1, 2013-June 30, 2019. FAERS contains AEs from clinical trials and healthcare providers and is standardized according to the Medical Dictionary for Regulatory Activities (MedDRA), a clinically validated AE classification dictionary for pharmacovigilance monitoring. All cases with the outcome of death as reported by FAERS were queried. Cases in which the time to event with NRM was greater than 30 days or unknown were excluded. Total events recorded with NRM and disease progression were categorized according to the MedDRA coding system and compared using the chi-squared and a two-sided Fisher's exact test (statistical significance: p<0.05). NRM was compared between FAERS, MDACC-L, and the ZUMA-1, JULIET and ELIANA trials. Median days to NRM was measured. In the MDACC-L, a competing risk analysis using cumulative incidence function (CIF) between NRM and disease progression was calculated with Fine & Gray competing risk model. Results On FAERS, there were a total of 1184 reported cases, 669 with AC and 515 with T. Five cases were excluded because the reported event occurred 30 days after initiation of T (4) or AC (1), and 96 deaths were excluded because of missing start or event dates. As a result, there were 1,083 cases, 633 with AC and 450 with T. There were 101 (9.3%) deaths; 59 (13.1%) with T and 42 (6.6%) with AC. Seventy-six (7.0%) deaths were attributed to NRM; 39 (8.7%) with T and 37 (5.8%) with AC (Table 1) (Figure 1). AC had a significantly greater proportion of cytokine release syndrome (CRS) (p=0.027) and neurologic events (0.038) compared to T. The median number of days to the reported event was 4 (R: 0-27) for AC and 6 (R: 0-28) for T. There was no significant difference amongst cardiac, vascular, respiratory, or infectious events. There were 112 patients in the MDACC-L (108 received A and 4 received T), with 3 cases excluded due to non-availability of cause of death. There were 7 deaths for competing risk analysis between progression and NRM. At 30 days, the competing risk analysis for MDACC-L using the CIF for NRM was 2.74% (0.8-8.9%) when progression was used as a competing event. In comparison, the proportion of 30 day NRM with ZUMA-1 was 3%, JULIET was 0%, while ELIANA was 1.3%. Conclusions NRM, an important outcome measure in stem cell transplantation, needs to be clearly defined in CAR-T therapies. We present NRM events based on the largest dataset available, FAERS. This analysis highlights the major toxicities associated with NRM, time to event occurrence, and indicates potential opportunities for mortality reducing interventions. Competing risk analysis suggests NRM is 2.74% following axicabtagene ciloleucel treatment for lymphoma. The comparative data highlights the differences in the reporting, and the need for close monitoring of CAR-T specific AEs. It also reflects the limitation of FAERS such as missing data that may change the actual NRM, inability to differentiate the grade of a reported AE, and inability to determine the exact date of death. We plan to present this data with a profile of NRM events at the upcoming ASH meeting in Orlando. Disclosures Westin: Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding. Nastoupil:Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bayer: Honoraria. Nieto:Novartis: Research Funding; Affimed: Consultancy; Astra-Zeneca: Research Funding; Affimed: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; BioInvent: Consultancy, Research Funding; Loxo Oncology: Research Funding; BeiGene: Research Funding; Aviara: Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Dava Oncology: Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Pulse Biosciences: Consultancy; Kite Pharma: Consultancy, Research Funding; VelosBio: Research Funding; Juno Therapeutics: Research Funding. Hawkins:Novartis Pharmaceuticals: Other: advisory panels. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Neelapu:Celgene: Consultancy, Research Funding; Acerta: Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Precision Biosciences: Consultancy; Allogene: Consultancy; Incyte: Consultancy; BMS: Research Funding; Cellectis: Research Funding; Karus: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Cell Medica: Consultancy; Poseida: Research Funding. Iyer:Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding.
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Pivkova Veljanovska, Aleksandra, Sonja Genco Genadieva-Stavrik, Zlate Stojanoski, Lazar Chadievski, Irina Panovska Stavridis, Sanja Aleksandar Trajkova, Lidija Cevreska, and Borce Georgievski. "Outcome after autologous transplantation in the terms of comorbidity for patients with lymphoproliferative diseases: Single center experience." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e19502-e19502. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e19502.
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e19502 Background: Autologous stem cell transplantation (ASCT) improves survival in patients with myeloma and lymphoma but is associated with morbidity and nonrelapse mortality (NRM). Hematopoietic cell transplant comorbidity index (HCT-CI) was shown to predict risk of NRM and survival after allogeneic transplantation. We tested the utility of HCT-CI as a predictor of NRM and overall survival (OS) in patients undergoing ASCT. Methods: We analyzed outcomes of 220 patients after high-dose melphalan and high –dose anti lymphoma chemotherapy during year 2000 to 2015. Individual comorbidities were prospectively collected at the time of ASCT. The impact of HCT-CI and other potential prognostic factors, including Karnofsky performance score (KPS), on NRM and survival were studied in multivariate Cox regression models. Results: HCT-CI score was 0, 1, 2, 3, and >3 in 42%, 18%, 13%, 13%, and 14% of the study cohort, respectively. Subjects were stratified into 3 risk groups: HCT-CI score of 0 (42%) versus HCT-CI score of 1 to 2 (32%) versus HCT-CI score > 2 (26%). Higher HCT-CI was associated with lower KPS < 90 (33% of subject’s score of 0 versus 50% in HCT-CI score > 2). HCT-CI score > 2 was associated with melphalan dose reduction (22% versus 10% in score 0 cohorts). One-year NRM was low at 2% (95% confidence interval, 1% to 4%). On multivariate analysis, overall survival was inferior in groups with HCT-CI score of 1 to 2 (relative risk, 1.37, [95% confidence interval, 1.01 to 1.87], P = .04) and HCT-CI score > 2 (relative risk, 1.5 [95% confidence interval, 1.09 to 2.08], P = .01). Factors that affect OS in the autologous recipients among lymphoma and myeloma patients were: HCT-CI, Karnofsky score, number of CD34+ cells/kg and time from diagnosis until transplant (p<0.05). Factors that affect TRM/NRM were HCT-CI, ECOG, Karnofsky score and number of hospital days and body weight.(p<0.05). Conclusions: ASCT for MM and lymphoma is associated with low NRM, and death is predominantly related to disease progression. Comorbidity evaluation during autologous transplantation for lymphoproliferative diseases can be a useful tool in predicting transplant outcome.
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Sharma, Manish, Rima M. Saliba, Muzaffar H. Qazilbash, Grace-Julia Okoroji, Uday Popat, Marcos de Lima, Richard Champlin, and Chitra Hosing. "Poor FEV1 or DLco on Pre-Transplant PFT Does Not Compromise Outcomes In Patients Undergoing a Reduced-Intensity Allogeneic Progenitor Cell Transplant." Blood 116, no. 21 (November 19, 2010): 1322. http://dx.doi.org/10.1182/blood.v116.21.1322.1322.
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Abstract Abstract 1322 Background: Pre-transplant work-up prior to an allogeneic stem cell transplant (allo-SCT) generally includes pulmonary functions tests (PFT) with assessment of FEV1 and DLco. It has been previously published that patients with a DLco or FEV1 less than 60% of predicted have higher non-relapse mortality (NRM) when undergoing a myeloablative allo-SCT. However, the PFT criteria for selecting candidates for a reduced intensity (RI) allogeneic transplant allo-SCT remains poorly investigated. We performed a retrospective analysis to assess the impact of low FEV1 or DLco on NRM and overall survival (OS) in patients undergoing a RI allo-SCT. Methods: All patients who underwent a RI allo-SCT for hematological malignancies at MD Anderson Cancer Center from Jan 2000 to April 2009 were included. Using Cox's proportional hazards regression, we compared the rate of NRM and OS between patients who had a pre-transplant FEV1 or DLco > 50% (control group) prior to a RI allo-SCT and those with FEV1 and DLco < 50% (study group). The cumulative incidence of NRM was estimated considering disease progression as a competing risk. Actuarial OS was estimated by the Kaplan-Meier method. Results: Patient characteristics are presented in Table 1. There were no statistically significant differences between the study and control groups except for age and sex. A significantly higher proportion of patients were > 50 years in the control group (65%) compared with the low PFT group (45%, P=0.02) and there were more males in the control group (P=.001). The median FEV1 and DLco in the study group was 55% (28-111) and 47% (33-98) of predicted, respectively. On univariate analysis abnormal PFTs did not impact OS at 30 months (HR 1.1, 95% CI 0.7–1.8, P=0.7) or NRM at 1 year (HR 1.3, (95% CI 0.6–2.7, P=0.4). Active disease at SCT, and a diagnosis of CLL, NHL or HL were associated with significantly worse OS and NRM, whereas age >50 years was only associated with worse OS. Low PFT had no significant impact on OS and NRM when evaluated separately in patients older or younger than 50 years old. Conclusion: Our experience suggests that a low (<50% of predicted) FEV1 or a DLco on pre-transplant evaluation does not adversely impact NRM and OS after RI allo-SCT. These findings need to be validated in a multivariate analysis. Disclosures: No relevant conflicts of interest to declare.
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DeFor, Todd E., Navneet S. Majhail, Claudio Brunstein, Daniel J. Weisdorf, and Chap T. Le. "Comparative Assessment of Weighting Comorbidities in the Hematopoietic Cell Transplantation (HCT) Specific Comorbidity Index (HCT-CI)." Blood 112, no. 11 (November 16, 2008): 798. http://dx.doi.org/10.1182/blood.v112.11.798.798.
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Abstract An increasing number of HCT recipients have pre-existing comorbidities at the time of transplantation. Sorror et al (Blood 2005) have proposed the HCT-CI, which evaluates various comorbidities as a combined categorical weighted score that independently predicts non-relapse mortality (NRM) and overall survival (OS) after HCT. In a recent study that included 373 adult allogeneic HCT recipients at our center, we have shown that the sensitivity and generalizability of the HCT-CI needs to be improved further prior to its routine universal use (Majhail et al, Biology of Blood and Marrow Transplantation 2008). The median age of the original cohort was 47 (range, 18–69) years and included 150 myeloablative and 223 non-myeloablative HCT recipients. The HCT-CI score was zero (low-risk) in 16%, 1–2 (intermediate-risk) in 32%, and ≥3 (high-risk) in 52% patients. We hypothesized that the HCT-CI loses some power in the early and unnecessary step of converting the adjusted hazard ratios (HR) of the comorbidities for NRM to the categorical weights of 0 to 3 prior to summation of the final score. We propose a revised HCT-CI based on a pure multiplicative model that assigns weights to comorbidities more efficiently and increases the discriminating and predictive power of the original HCT-CI for NRM and OS. In our analysis, which included the same study cohort (N=373), we calculated the HR for each comorbidity from a regression analysis on NRM after adjusting for all other comorbidities as well as age, donor type, disease risk and conditioning regimen intensity. Instead of converting the adjusted HR to categorical weights and then summing these weights, we directly calculated a risk index (multiplicative HCT-CI [MHCT-CI]) by exponentiating the sum of all parameter coefficients from the regression analysis. The revised index score is: MHCT-CI = exponent [0.82*(binary indicator (bi) for cardiac disorders) + 0.20*(bi for peptic ulcer) + 0.60*(bi for diabetes) – 0.43*(bi for obesity) + 0.30*(bi for psychiatric disturbance) + 0.34*(bi for Moderate/Severe hepatic function) + 0.63*(bi for infection) + 0.73*(bi for renal insufficiency) + 0.63*(bi for moderate pulmonary abnormalities) + 0.90*(bi for severe pulmonary abnormalities) + 0.22*(bi for prior solid tumor)]. Comorbidities not appearing did not have influence on NRM. The distribution of the MHCT-CI score was ≤1 (low-risk) in 20%, 1–2.5 (intermediate-risk) in 41% and ≥2.5 (high-risk) in 40% patients. MHCT-CI was more predictive for both NRM and OS compared to the original HCT-CI. The HR for intermediate and high risk categories increased (>43% for NRM and >19% for OS). The adjusted likelihood ratio, showing model fit, increased from 13.2 to 22.1 for NRM and increased from 18.8 to 34.1 for OS after substituting MHCT-CI for HCT-CI. There are no statistical tests for this statistic but an increase shows better prediction of the endpoint. The c statistic, which is the proportion of all pairs of patients in the study in which the patient with the higher index score has a worse outcome, increased from 0.641 to 0.752 for NRM (P=0.03) and increased from 0.611 to 0.713 for OS (P=0.01). In conclusion, the MHCT-CI showed higher discriminating and predictive power for post-HCT NRM and OS among our study population. Given that an increasing number of HCT recipients are being transplanted with pre-existing comorbidities, the greater discrimination of assigning patient comorbidity will better inform future studies among HCT recipients by better adjusting for these important risk factors.