Resilience models for New Zealand's alpine skiers based on people's knowledge and experience: a mixed method and multi-step fuzzy cognitive mapping approach

Artificial Neural Networks (ANN) as a tool offers opportunities for modeling the inherent complexity and uncertainty associated with socio-environmental systems. This study draws on New Zealand ski fields (multiple locations) as socio- environmental systems while considering their perceived resilience to low probability but potential high consequences catastrophic natural events (specifically earthquakes). We gathered data at several ski fields using a mixed methodology including: geomorphic assessment, qualitative interviews, and an adaptation of Ozesmi and Ozesmi’s (2003) multi-step fuzzy cognitive mapping (FCM) approach. The data gathered from FCM are qualitatively condensed, and aggregated to three different participant social groups. The social groups include ski fields users, ski industry workers, and ski field managers. Both quantitative and qualitative indices are used to analyze social cognitive maps to identify critical nodes for ANN simulations. The simulations experiment with auto-associative neural networks for developing adaptive preparation, response and recovery strategies. Moreover, simulations attempt to identify key priorities for preparation, response, and recovery for improving resilience to earthquakes in these complex and dynamic environments. The novel mixed methodology is presented as a means of linking physical and social sciences in high complexity, high uncertainty socio-environmental systems. Simulation results indicate that participants perceived that increases in Social Preparation Action, Social Preparation Resources, Social Response Action and Social Response Resources have a positive benefit in improving the resilience to earthquakes of ski fields’ stakeholders

The use of artificial neural networks to diagnose mastitis in dairy cattle

The use of milk sample categorization for diagnosing mastitis using Kohonen's self-organizing feature map (SOFM) is reported. Milk trait data of 14 weeks of milking from commercial dairy cows in New Zealand was used to train and test a SOFM network. The SOFM network was useful in discriminating data patterns into four separate mastitis categories. Several other artificial neural networks were tested to predict the missing data from the recorded milk traits. A multi-layer perceptron (MLP) network proved to be most accurate (R² = 0.84, r = 0.92) when compared to other MLP (R² = 0.83, r = 0.92), Elman (R² = 0.80, r = 0.92), Jordan (R² = 0.81, r = 0.92) or linear regression (R² = 0.72, r = 0.85) methods. It is concluded that the SOFM can be used as a decision tool for the dairy farmer to reduce the incidence of mastitis in the dairy herd

A modeling and analysis study reveals that CaMKII in synaptic plasticity Is a dominant affecter in CaM systems in a T286 phosphorylation-dependent manner

NMDAR-dependent synaptic plasticity in the hippocampus consists of two opposing forces: long-term potentiation (LTP), which strengthens synapses and long-term depression (LTD), which weakens synapses. LTP and LTD are associated with memory formation and loss, respectively. Synaptic plasticity is controlled at a molecular level by Ca²⁺-mediated protein signaling. Here, Ca²⁺ binds the protein, calmodulin (CaM), which modulates synaptic plasticity in both directions. This is because Ca²⁺-bound CaM activates both LTD-and LTP-inducing proteins. Understanding how CaM responds to Ca²⁺ signaling and how this translates into synaptic plasticity is therefore important to understanding synaptic plasticity induction. In this paper, CaM activation by Ca²⁺ and calmodulin binding to downstream proteins was mathematically modeled using differential equations. Simulations were monitored with and without theoretical knockouts and, global sensitivity analyses were performed to determine how Ca²⁺/CaM signaling occurred at various Ca²⁺ signals when CaM levels were limiting. At elevated stimulations, the total CaM pool rapidly bound to its protein binding targets which regulate both LTP and LTD. This was followed by CaM becoming redistributed from low-affinity to high-affinity binding targets. Specifically, CaM was redistributed away from LTD-inducing proteins to bind the high-affinity LTP-inducing protein, calmodulin-dependent kinase II (CaMKII). In this way, CaMKII acted as a dominant affecter and repressed activation of opposing CaM-binding protein targets. The model thereby showed a novel form of CaM signaling by which the two opposing pathways crosstalk indirectly. The model also found that CaMKII can repress cAMP production by repressing CaM-regulated proteins, which catalyze cAMP production. The model also found that at low Ca²⁺ stimulation levels, typical of LTD induction, CaM signaling was unstable and is therefore unlikely to alone be enough to induce synaptic depression. Overall, this paper demonstrates how limiting levels of CaM may be a fundamental aspect of Ca²⁺ regulated signaling which allows crosstalk among proteins without requiring directly interaction

Calcium and adenosine triphosphate control of cellular pathology: asparaginase-induced pancreatitis elicited via protease-activated receptor 2

Exocytotic secretion of digestive enzymes from pancreatic acinar cells is elicited by physiological cytosolic Ca2+ signals, occurring as repetitive short-lasting spikes largely confined to the secretory granule region, that stimulate mitochondrial adenosine triphosphate (ATP) production. By contrast, sustained global cytosolic Ca2+ elevations decrease ATP levels and cause necrosis, leading to the disease acute pancreatitis (AP). Toxic Ca2+ signals can be evoked by products of alcohol and fatty acids as well as bile acids. Here, we have investigated the mechanism by which l-asparaginase evokes AP. Asparaginase is an essential element in the successful treatment of acute lymphoblastic leukaemia, the most common type of cancer affecting children, but AP is a side-effect occurring in about 5–10% of cases. Like other pancreatitis-inducing agents, asparaginase evoked intracellular Ca2+ release followed by Ca2+ entry and also substantially reduced Ca2+ extrusion because of decreased intracellular ATP levels. The toxic Ca2+ signals caused extensive necrosis. The asparaginase-induced pathology depended on protease-activated receptor 2 and its inhibition prevented the toxic Ca2+ signals and necrosis. We tested the effects of inhibiting the Ca2+ release-activated Ca2+ entry by the Ca2+ channel inhibitor GSK-7975A. This markedly reduced asparaginase-induced Ca2+ entry and also protected effectively against the development of necrosis

Galactose protects against cell damage in mouse models of acute pancreatitis

Acute pancreatitis (AP), a human disease in which the pancreas digests itself, has substantial mortality with no specific therapy. The major causes of AP are alcohol abuse and gallstone complications, but it also occurs as an important side effect of the standard asparaginase-based therapy for childhood acute lymphoblastic leukemia. Previous investigations into the mechanisms underlying pancreatic acinar cell death induced by alcohol metabolites, bile acids, or asparaginase indicated that loss of intracellular ATP generation is an important factor. We now report that, in isolated mouse pancreatic acinar cells or cell clusters, removal of extracellular glucose had little effect on this ATP loss, suggesting that glucose metabolism was severely inhibited under these conditions. Surprisingly, we show that replacing glucose with galactose prevented or markedly reduced the loss of ATP and any subsequent necrosis. Addition of pyruvate had a similar protective effect. We also studied the effect of galactose in vivo in mouse models of AP induced either by a combination of fatty acids and ethanol or asparaginase. In both cases, galactose markedly reduced acinar necrosis and inflammation. Based on these data, we suggest that galactose feeding may be used to protect against AP

Impact of T‐cell depletion strategies on outcomes following hematopoietic stem cell transplantation for idiopathic aplastic anemia: A study on behalf of the European blood and marrow transplant severe aplastic anemia working party

We retrospectively analyzed the outcomes of 1837 adults and children with severe aplastic anemia (SAA) who underwent matched sibling donor (MSD) and matched unrelated donor (MUD) hemopoietic stem cell transplantation (HSCT) between 2000 and 2013. Patients were grouped by transplant conditioning containing either anti‐thymocyte globulin (ATG) (n = 1283), alemtuzumab (n = 261), or no serotherapy (NS) (n = 293). The risks of chronic GvHD were significantly reduced when ATG or alemtuzumab were compared with NS (P = .021 and .003, respectively). Acute GVHD was significantly reduced in favor of alemtuzumab compared with ATG (P = .012) and NS (P < .001). By multivariate analysis, when compared with ATG, alemtuzumab was associated with a lower risk of developing acute (OR 0.262; 95% CI 0.14‐0.47; P < .001) and chronic GVHD (HR 0.58; 95% CI 0.35‐0.94; P = .027). OS was significantly better in ATG and alemtuzumab patients compared with NS (P = .010 and .025). Our data shows inclusion of serotherapy in MSD and MUD HSCT for patients with SAA reduces chronic GVHD and provides a survival advantage over patients not receiving serotherapy. Notably, alemtuzumab reduced the risk of acute and chronic GvHD compared with ATG and indicates that alemtuzumab might be the serotherapy of choice for MSD and MUD transplants for SAA

Impact of conditioning regimen on outcomes for children with acute myeloid leukemia undergoing transplantation in first complete remission. An analysis on behalf of the Pediatric Disease Working Party of the European Group for Blood and Marrow Transplantation

Hematopoietic stem cell transplantation (HSCT) represents the cornerstone of treatment in pediatric high-risk and relapsed acute myeloid leukemia (AML). The aim of the present study was to compare outcomes of pediatric patients with AML undergoing HSCT using 3 different conditioning regimens: total body irradiation (TBI) and cyclophosphamide (Cy); busulfan (Bu) and Cy; or Bu, Cy, and melphalan (Mel). In this retrospective study, registry data for patients &gt; 2 and &lt;18 years age undergoing matched allogeneic HSCT for AML in first complete remission (CR1) in 204 European Group for Blood and Marrow Transplantation centers between 2000 and 2010 were analyzed. Data were available for 631 patients; 458 patients received stem cells from a matched sibling donor and 173 from a matched unrelated donor. For 440 patients, bone marrow was used as stem cell source, and 191 patients received peripheral blood stem cells. One hundred nine patients received TBICy, 389 received BuCy, and 133 received BuCyMel as their preparatory regimen. Median follow-up was 55 months. Patients receiving BuCyMel showed a lower incidence of relapse at 5 years (14.7% versus 31.5% in BuCy versus 30% in TBICy, P &lt; .01) and higher overall survival (OS) (76.6% versus 64% versus 64.5%, P = .04) and leukemia-free survival (LFS) (74.5% versus 58% versus 61.9%, P &lt; .01), with a comparable nonrelapse mortality (NRM) (10.8% versus 10.5% versus 8.1%, P = .79). Acute graft-versus-host disease (GVHD) grades III and IV but not chronic GVHD, was higher in patients receiving BuCyMel. Older age at HSCT had an adverse impact on NRM and the use of peripheral blood as stem cell source was associated with increased chronic GVHD and NRM as well as lower LFS and OS. Among pediatric patients receiving HSCT for AML in CR1, the use of BuCyMel conditioning proved superior to TBICy and BuCy in reducing relapse and improving LFS

To be an immigrant and a patient in Sweden: A study with an individualised perspective

The aim is to describe how experiences of being an immigrant can influence the situation when becoming a patient in Swedish health care. A hermeneutic approach was used. Sixteen persons born in non-Nordic countries were interviewed. The data was analysed with an empirical hermeneutical method. The findings indicate that positive experiences (i.e., establishing oneself in a new home country) enhance the possibilities of taking part in caring situations and vice versa. Hence, there is a need for individually adapted care that takes one's whole life situation into consideration. Consequently, it is suggested that the concept, “cultural competence” merely serves the purpose of illuminating caregivers' need for categorisation. It does not illuminate individual needs in a caring situation

Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells

Autologous T cells engineered to express chimeric antigen receptor against the B cell antigen CD19 (CAR19) are achieving marked leukemic remissions in early-phase trials but can be difficult to manufacture, especially in infants or heavily treated patients. We generated universal CAR19 (UCART19) T cells by lentiviral transduction of non-human leukocyte antigen-matched donor cells and simultaneous transcription activator-like effector nuclease (TALEN)-mediated gene editing of T cell receptor α chain and CD52 gene loci. Two infants with relapsed refractory CD19(+) B cell acute lymphoblastic leukemia received lymphodepleting chemotherapy and anti-CD52 serotherapy, followed by a single-dose infusion of UCART19 cells. Molecular remissions were achieved within 28 days in both infants, and UCART19 cells persisted until conditioning ahead of successful allogeneic stem cell transplantation. This bridge-to-transplantation strategy demonstrates the therapeutic potential of gene-editing technology