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This article proposes a predictive end-effector control method for manipulators operating on mobile platforms subjected to unwanted base motion. Time series is used to forecast the base motion using historical state information. Then, a trajectory specified in the inertial frame is transformed to a predicted trajectory with respect to the manipulator. By tracking this transformed trajectory, the manipulator negates the base motion. A model-predictive control problem is formulated via quadratic programming (QP) to track said trajectory over the prediction horizon. Only the first control action in the control sequence is constrained by kinematic feasibility. In this manner, QP can be swiftly solved with linear inequality constraints. It is shown that the actual joint trajectory executed by the manipulator is always kinematically feasible. Moreover, tracking error can still be reduced despite future predicted control actions being infeasible. The method is validated through both simulation and experiment. The proposed method can reduce pose error by over 60% compared to a proportional-integral feedback controller.

Virtual links and virtual joints can be appended to the kinematic chain of a robot arm to assist in modelling and control of certain tasks. Activities such as spray painting, sand blasting, or scanning with a laser or camera can be enhanced by modelling the fluid stream, light beam, or field of view using a virtual link. Virtual joints can be used to allow movement in semi-redundant degrees of freedom of the task space. This can can be exploited to optimize the control of the real robot. A prudent choice is to minimize the effort required by the manipulator to execute the task. This often requires the inversion of the inertia matrix. However, virtual links have no inertia so the inverse does not exist. This paper first explores methods of adding virtual mass or modifying the inertia matrix to allow inversion and the consequences. Then an optimal control problem is proposed that minimizes kinetic energy in the real manipulator and maximizes use of the virtual joints. In doing so, we only need the real inertia matrix which is always invertible. The method is validated in a case study for high pressure water blasting. It is shown to reduce the dynamic torque norm compared to a minimum velocity controller.

INTRODUCTION Simulation is becoming a popular educational modality for physician continuing professional development (CPD). This study sought to characterize how simulation-based CPD (SBCPD) is being used in Canada and what academic emergency physicians (AEPs) desire in an SBCPD program. METHODS Two national surveys were conducted from March to June 2018. First, the SBCPD Needs Assessment Survey was administered online to all full-time AEPs across 9 Canadian academic emergency medicine (EM) sites. Second, the SBCPD Status Survey was administered by telephone to the department representatives (DRs)-simulation directors or equivalent-at 20 Canadian academic EM sites. RESULTS Response rates for the SBCPD Needs Assessment and the SBCPD Status Survey were 40% (252/635) and 100% (20/20) respectively. Sixty percent of Canadian academic EM sites reported using SBCPD, although only 30% reported dedicated funding support. Academic emergency physician responses demonstrated a median annual SBCPD of 3 hours. Reported incentivization for SBCPD participation varied with AEPs reporting less incentivization than DRs. Academic emergency physicians identified time commitments outside of shift, lack of opportunities, and lack of departmental funding as their top barriers to participation, whereas DRs thought AEPs fear of peer judgment and inexperience with simulation were substantial barriers. Content areas of interest for SBCPD were as follows: rare procedures, pediatric resuscitation, and neonatal resuscitation. Lastly, interprofessional involvement in SBCPD was valued by both DRs and AEPs. CONCLUSIONS Simulation-based CPD programs are becoming common in Canadian academic EM sites. Our findings will guide program coordinators in addressing barriers to participation, selecting content, and determining the frequency of SBCPD events.

Comparative outcomes of allogeneic hematopoietic cell transplantation (HCT) for BCR-ABL1− myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) vs de novo acute myeloid leukemia (AML), and AML with prior myelodysplastic syndromes (MDSs; post-MDS AML), are unknown. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared HCT outcomes in 177 MPN-BP patients with 4749 patients with de novo AML, and 1104 patients with post-MDS AML, using multivariate regression analysis in 2 separate comparisons. In a multivariate Cox model, no difference in overall survival (OS) or relapse was observed in patients with MPN-BP vs de novo AML with active leukemia at HCT. Patients with MPN-BP in remission had inferior OS in comparison with de novo AML in remission (hazard ratio [HR], 1.40 [95% confidence interval [CI], 1.12-1.76]) due to higher relapse rate (HR, 2.18 [95% CI, 1.69-2.80]). MPN-BP patients had inferior OS (HR, 1.19 [95% CI, 1.00-1.43]) and increased relapse (HR, 1.60 [95% CI, 1.31-1.96]) compared with post-MDS AML. Poor-risk cytogenetics were associated with increased relapse in both comparisons. Peripheral blood grafts were associated with decreased relapse in MPN-BP and post-MDS AML (HR, 0.70 [95% CI, 0.57-0.86]). Nonrelapse mortality (NRM) was similar between MPN-BP vs de novo AML, and MPN-BP vs post-MDS AML. Total-body irradiation–based myeloablative conditioning was associated with higher NRM in both comparisons. Survival of MPN-BP after HCT is inferior to de novo AML in remission and post-MDS AML due to increased relapse. Relapse-prevention strategies are required to optimize HCT outcomes in MPN-BP.

Allogeneic hematopoietic cell transplant (HCT) is often the only curative therapy for patients with nonmalignant diseases; however, many patients do not have an HLA-matched donor. Historically, poor survival has been seen after HLA-haploidentical HCT because of poor immune reconstitution, increased infections, graft-versus-host disease (GVHD), and graft failure. Encouraging results have been reported using a nonmyeloablative T cell–replete HLA-haploidentical transplant approach in patients with hematologic malignancies. Here we report the outcomes of 23 patients with various nonmalignant diseases using a similar approach. Patients received HLA-haploidentical bone marrow (n = 17) or granulocyte colony-stimulating factor–mobilized peripheral blood stem cell (n = 6) grafts after conditioning with cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, and 2 or 4 Gy total body irradiation. Postgrafting immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, tacrolimus, ± sirolimus. Median patient age at HCT was 10.8 years. Day 100 transplant-related mortality (TRM) was 0%. Two patients died at later time points, 1 from intracranial hemorrhage/disseminated fungal infection in the setting of graft failure and 1 from infection/GVHD. The estimated probabilities of grades II to IV and III to IV acute GVHD at day 100 and 2-year National Institutes of Health consensus chronic GVHD were 78%, 26%, and 42%, respectively. With a median follow-up of 2.5 years, the 2-year overall and event-free rates of survival were 91% and 78%, respectively. These results are encouraging and demonstrate favorable disease-specific lineage engraftment with low TRM in patients with nonmalignant diseases using nonmyeloablative conditioning followed by T cell–replete HLA-haploidentical grafts. However, additional strategies are needed for GVHD prevention to make this a viable treatment approach for patients with nonmalignant diseases.

The objective of introducing robotic manipulators into human-centric domains is to improve the efficacy of tasks in a safe and practical manner. The shift toward collaborative manipulator platforms has facilitated physical human-robot interaction (pHRI) in such environments. Often, these platforms are kinematically redundant and possess more degrees of freedom (DOF) than needed to complete a desired task. When no additional task is defined, it is possible for the manipulator to converge upon joint configurations that are unfavourable for the collaborative task. Consequently, there is potential for the posture of the manipulator to affect the interaction experienced. This paper investigates an inertia-based optimization control method for redundant manipulators interacting with an active agent. The inertia-based reconfiguration is evaluated through simulations and quantified with real-life experiments conducted with a robot-robot dyad. It was found that resolving redundancy to reconfigure the Cartesian inertia reduced the energy expenditure of the active agent during the interaction.

Allogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.

Summary Background Acute graft-versus-host-disease (GVHD) after non-myeloablative human leucocyte antigen (HLA)-matched, unrelated donor, allogeneic haemopoietic stem cell transplantation (HSCT) is associated with considerable morbidity and mortality. This trial aimed to evaluate the efficacy of adding sirolimus to the standard cyclosporine and mycophenolate mofetil prophylaxis therapy for preventing acute GVHD in this setting. Methods This multicentre, randomised, phase 3 trial took place at nine HSCT centres based in the USA, Denmark, and Germany. Eligible patients were diagnosed with advanced haematological malignancies treatable by allogeneic HSCT, had a Karnofsky score greater than or equal to 60, were aged older than 50 years, or if they were aged 50 years or younger, were considered at high risk of regimen-related toxicity associated with a high-dose pre-transplantation conditioning regimen. Patients were randomly allocated by an adaptive randomisation scheme stratified by transplantation centre to receive either the standard GVHD prophylaxis regimen (cyclosporine and mycophenolate mofetil) or the triple-drug combination regimen (cyclosporine, mycophenolate mofetil, and sirolimus). Patients and physicians were not masked to treatment. All patients were prepared for HSCT with fludarabine (30 mg/m2 per day) 4, 3, and 2 days before receiving 2 or 3 Gy total body irradiation on the day of HSCT (day 0). In both study groups, 5·0 mg/kg of cyclosporine was administered orally twice daily starting 3 days before HSCT, and (in the absence of GVHD) tapered from day 96 through to day 150. In the standard GVHD prophylaxis group, 15 mg/kg of mycophenolate mofetil was given orally three times daily from day 0 until day 30, then twice daily until day 150, and (in the absence of GVHD) tapered off by day 180. In the triple-drug group, mycophenolate mofetil doses were the same as in the standard group, but the drug was discontinued on day 40. Sirolimus was started 3 days before HSCT, taken orally at 2 mg once daily and adjusted to maintain trough concentrations between 3–12 ng/mL through to day 150, and (in the absence of GVHD) tapered off by day 180. The primary endpoint was the cumulative incidence of grade 2–4 acute GVHD at day 100 post-transplantation. Secondary endpoints were non-relapse mortality, overall survival, progression-free survival, cumulative incidence of grade 3–4 acute GVHD, and cumulative incidence of chronic GVHD. Efficacy and safety analyses were per protocol, including all patients who received conditioning treatment and underwent transplantation. Toxic effects were measured according to the Common Terminology Criteria for Adverse Events (CTCAE). The current study was closed prematurely by recommendation of the Data and Safety Monitoring Board on July 27, 2016, after 168 patients received the allocated intervention, based on the results of a prespecified interim analysis for futility. This study is registered with ClinicalTrials.gov , number NCT01231412 . Findings Participants were recruited between Nov 1, 2010, and July 27, 2016. Of 180 patients enrolled in the study, 167 received the complete study intervention and were included in safety and efficacy analyses: 77 patients in the standard GVHD prophylaxis group and 90 in the triple-drug group. At the time of analysis, median follow-up was 48 months (IQR 31–60). The cumulative incidence of grade 2–4 acute GVHD at day 100 was lower in the triple-drug group compared with the standard GVHD prophylaxis group (26% [95% CI 17–35] in the triple-drug group vs 52% [41–63] in the standard group; HR 0·45 [95% CI 0·28–0·73]; p=0·0013). After 1 and 4 years, non-relapse mortality increased to 4% (95% CI 0–9) and 16% (8–24) in the triple-drug group and 16% (8–24) and 32% (21–43) in the standard group (HR 0·48 [0·26–0·90]; p=0·021). Overall survival at 1 year was 86% (95% CI 78–93) in the triple-drug group and 70% in the standard group (60–80) and at 4 years it was 64% in the triple-drug group (54–75) and 46% in the standard group (34–57%; HR 0·62 [0·40–0·97]; p=0·035). Progression-free survival at 1 year was 77% (95% CI 68–85) in the triple-drug group and 64% (53–74) in the standard drug group, and at 4 years it was 59% in the triple-drug group (49–70) and 41% in the standard group (30–53%; HR 0·64 [0·42–0·99]; p=0·045). We observed no difference in the cumulative incidence of grade 3–4 acute GVHD (2% [0–5] in the triple-drug group vs 8% [2–14] in the standard group; HR 0·55 [0·16–1·96]; p=0·36) and chronic GVHD (49% [39–59] in triple-drug group vs 50% [39–61] in the standard group; HR 0·94 [0·62–1·40]; p=0·74). In both groups the most common CTCAE grade 4 or higher toxic effects were pulmonary. Interpretation Adding sirolimus to cyclosporine and mycophenolate mofetil resulted in a significantly lower proportion of patients developing acute GVHD compared with patients treated with cyclosporine and mycophenolate mofetil alone. Based on these results, the combination of cyclosporine, mycophenolate mofetil, and sirolimus has become the new standard GVHD prophylaxis regimen for patients treated with non-myeloablative conditioning and HLA-matched unrelated HSCT at the Fred Hutchinson Cancer Research Center. Funding National Institutes of Health.

The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) was developed and validated to weigh the burden of pretransplantation comorbidities and estimate their impact on post-transplantation risks of nonrelapse mortality (NRM). Recently, the HCT-CI was augmented by the addition of both age and the values of 3 markers: ferritin, albumin, and platelet count. So far, research involving The HCT-CI has been limited almost exclusively to recipients of allogeneic hematopoietic cell transplantation (HCT) from HLA-matched grafts. To this end, we sought to investigate the discriminative capacity of an augmented comorbidity/age index among 724 recipients of allogeneic HCT from HLA-mismatched (n = 345), haploidentical (n = 117), and umbilical cord blood (UCB; n = 262) grafts between 2000 and 2013. In the overall cohort, the augmented comorbidity/age index had a higher c-statistic estimate for prediction of NRM compared with the original HCT-CI (.63 versus .59). Findings were similar for recipients of HLA-mismatched (.62 versus .59), haploidentical (.60 versus .54), or UCB grafts (.65 versus .61). Compared with patients with an HCT-CI score ≥4, those with a score4 had a higher survival rate among recipients of HLA-mismatched (55% versus 39%; P.0008), HLA-haploidentical (58% versus 38%; P = .01), or UCB (67% versus 48%; P = .004) grafts. Our results demonstrate the utility of the augmented comorbidity/age index as a valid prognostic tool among recipients of allogeneic HCT from alternative graft sources.

Despite improvements, mortality after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases remains a significant problem. We evaluated whether pre-HCT conditions defined by the HCT Comorbidity Index (HCT-CI) predict probability of posttransplant survival. Using the Center for International Blood and Marrow Transplant Research database, we identified 4083 patients with nonmalignant diseases transplanted between 2007 and 2014. Primary outcome was overall survival (OS) using the Kaplan-Meier method. Hazard ratios (HRs) were estimated by multivariable Cox regression models. Increasing HCT-CI scores translated to decreased 2-year OS of 82.7%, 80.3%, 74%, and 55.8% for patients with HCT-CI scores of 0, 1 to 2, 3 to 4, and ≥5, respectively, regardless of conditioning intensity. HCT-CI scores of 1 to 2 did not differ relative to scores of 0 (HR, 1.12 [95% CI, 0.93-1.34]), but HCT-CI of 3 to 4 and ≥5 posed significantly greater risks of mortality (HR, 1.33 [95% CI, 1.09-1.63]; and HR, 2.31 [95% CI, 1.79-2.96], respectively). The effect of HCT-CI differed by disease indication. Patients with acquired aplastic anemia, primary immune deficiencies, and congenital bone marrow failure syndromes with scores ≥3 had increased risk of death after HCT. However, higher HCT-CI scores among hemoglobinopathy patients did not increase mortality risk. In conclusion, this is the largest study to date reporting on patients with nonmalignant diseases demonstrating HCT-CI scores ≥3 that had inferior survival after HCT, except for patients with hemoglobinopathies. Our findings suggest that using the HCT-CI score, in addition to disease-specific factors, could be useful when developing treatment plans for nonmalignant diseases.

This paper addresses the design of a novel interventional robotic platform, aiming to perform an autonomous sampling and measurement under the thin ice in the Antarctic environment. We propose a pantograph mechanism, which can effectively generate a constant interaction force to the surface during the contact, which is crucial for reliable measurements. We provide the proof-of-concept design of the pantograph with a robotic prototype with foldable actuation, and preliminary results of the pantograph mechanism and the localisation system are provided, confirming the feasibility of the system.

Presentation for UCT's Open Data Day held on the 06 March 2020. The presentation focuses on open government data for SDG reporting in African countries.

Presentation for UCT's Open Data Day held on the 06 March 2020. The presentation focuses on open government data for SDG reporting in African countries.

Calcineurin (CaN) phosphatase signaling is regulated by targeting CaN to substrates, inhibitors, and scaffold proteins containing docking motifs with the consensus sequence of PxIxIT. Here, we identify the docking of CaN to the γ isoform of MKK7, a component of the c-Jun N-terminal kinase (JNK) pathway. Because of alternative splicing of a single exon within the N-terminal domain, MKK7γ encodes a unique PxIxIT motif (PIIVIT) that is not present in MKK7α or β We found that MKK7γ bound directly to CaN through this PIIVIT motif in vitro, immunoprecipitated with CaN from cell extracts, and exhibited fluorescence resonance energy transfer (FRET) with CaN in the cytoplasm but not in the nucleus of living cells. In contrast, MKK7α and β exhibited no direct binding or FRET with CaN and were localized more in the nucleus than the cytoplasm. Furthermore, the inhibition of CaN phosphatase activity increased the basal phosphorylation of MKK7γ but not MKK7β Deletion of the MKK7γ PIIVIT motif eliminated FRET with CaN and promoted MKK7γ redistribution to the nucleus; however, the inhibition of CaN activity did not alter MKK7γ localization, indicating that MKK7γ cytoplasmic retention by CaN is phosphatase activity independent. Finally, the inhibition of CaN phosphatase activity in vascular smooth muscle cells, which express MKK7γ mRNA, enhances JNK activation. Overall, we conclude that the MKK7γ-specific PxIxIT motif promotes high-affinity CaN binding that could promote novel cross talk between CaN and JNK signaling by limiting MKK7γ phosphorylation and restricting its localization to the cytoplasm.

Despite biosimilars of the granulocyte-colony stimulating factor (G-CSF) filgrastim being approved by the European Medicines Agency since 2008, there is still some debate regarding their use in related and unrelated healthy haematopoietic stem cell donors. We present a review of published experiences using biosimilar filgrastim for healthy donor mobilisation as well as the results of a survey by the World Marrow Donor Association (WMDA) of its current use by register-associated transplant and collection centres for both related and unrelated donors. A total of 1287 healthy donors and volunteers are included in the reviewed studies. The pharmacokinetics and pharmacodynamics studies show a high degree of similarity to the reference product Neupogen. Mobilisation of CD34 + cells as well as reported adverse events are also found to be comparable, although there is still a lack of long-term follow up for both Neupogen and filgrastim biosimilars. No evidence is found of a higher risk of filgrastim antibody formation using filgrastim biosimilars. Based on this increased experience, the WMDA therefore recommend that Stem Cell Donor Registries can use filgrastim biosimilars for the mobilisation of peripheral blood progenitor cells in healthy donors, provided that they are approved by national and/or regional agencies.

A hallmark of Fanconi anemia is accelerated decline in hematopoietic stem and progenitor cells (CD34 +) leading to bone marrow failure. Long-term treatment requires hematopoietic cell transplantation from an unaffected donor but is associated with potentially severe side-effects. Gene therapy to correct the genetic defect in the patient’s own CD34+ cells has been limited by low CD34+ cell numbers and viability. Here we demonstrate an altered ratio of CD34Hi to CD34Lo cells in Fanconi patients relative to healthy donors, with exclusive in vitro repopulating ability in only CD34Hi cells, underscoring a need for novel strategies to preserve limited CD34+ cells. To address this need, we developed a clinical protocol to deplete lineage+(CD3+, CD14+, CD16+ and CD19+) cells from blood and marrow products. This process depletes >90% of lineage+cells while retaining ≥60% of the initial CD34+cell fraction, reduces total nucleated cells by 1–2 logs, and maintains transduction efficiency and cell viability following gene transfer. Importantly, transduced lineage− cell products engrafted equivalently to that of purified CD34+ cells from the same donor when xenotransplanted at matched CD34+ cell doses. This novel selection strategy has been approved by the regulatory agencies in a gene therapy study for Fanconi anemia patients (NCI Clinical Trial Reporting Program Registry ID NCI-2011-00202; clinicaltrials.gov identifier: 01331018).

Technical skill acquisition for rare procedures can be challenging given the few real-life training opportunities. In situ simulation (ISS), a training technique that takes place in the actual workplace, is a promising method to promote environmental fidelity for rare procedures. This study evaluated a simulation-based technical skill curriculum for cricothyroidotomy using deliberate practice, followed by an ISS evaluation session.Twenty emergency medicine residents participated in a two-part curriculum to improve cricothryoidotomy performance. A pretest established participant baseline technical skill. The training session consisted of two parts, didactic teaching followed by deliberate practice using a task-training manikin. A posttest consisted of an unannounced, high-fidelity ISS, during an emergency department shift. The primary outcome was the mean performance time between the pretest and posttest sessions. Skill performance was also evaluated using a checklist scale and global rating scale.Cricothyroidotomy performance time improved significantly from pretest to posttest sessions (mean difference, 59 seconds; P0.0001). Both checklist and global rating scales improved significantly from the pretest to the posttest with a mean difference of 1.82 (P = 0.002) and 6.87 (P = 0.0025), respectively. Postcourse survey responses were favorable for both the overall curriculum experience and the unannounced ISS.This pilot study demonstrated that unannounced ISS is feasible and can be used to effectively measure cricothyroidotomy performance among EM residents. After a two-part training session consisting of didactic learning and deliberate practice, improved cricothyroidotomy skill performance was observed during an unannounced ISS in the emergency department. The integration of ISS in cricothyroidotomy training represents a promising approach; however, further study is needed to establish its role.

We developed a haploidentical transplantation protocol with post-transplant cyclophosphamide (CY) for in vivo T-cell depletion using a novel adapted-dosing schedule (25 mg/kg on days +3 and +4) for Fanconi Anemia. With median follow-up of 3 years (range, 37 days to 6.2 years), all six patients engrafted. Two patients with multiple co-morbidities and late referrals to transplant died from sepsis (n=2) and chronic graft-versus-host disease (GVHD) (n=1). Four patients without pre-existing co-morbidities and early transplant referrals are alive with 100% donor chimerism and excellent performance status. We conclude that modulated-dosing post-transplant CY is effective in vivo T-cell depletion to promote full donor engraftment in patients with Fanconi anemia.

© 2019 Elsevier Ltd This paper shows that Gaussian Process Regression (GPR) with a periodic kernel has better mean prediction accuracy and uncertainty bounds than time series or Fourier series when forecasting motion data of underwater vehicles subject to wave excitation. Many robotic systems, such as autonomous underwater vehicles (AUVs), are required to operate in environments with disturbances and relative motion that make task performance difficult. This motion often exhibits periodic, near-sinusoidal behaviour. By predicting this motion, control strategies can be developed to improve accuracy. Moreover, factoring in uncertainty can aid the robustness of these predictive control methods. Time series and Fourier series have been applied to several predictive control problems in a variety of fields. However, there are contradictory results in performance based on parameters, assessment criteria, and application. This paper seeks to clarify these discrepancies using AUV motion as a case study. GPR is also introduced as a third candidate for prediction based on previous applications to time series forecasting in other fields of science. In addition to assessing mean prediction accuracy, the ability of each model to adequately bound prediction error is also considered as a key performance indicator.

Natural killer (NK) cell recognition and killing of target cells are enhanced when inhibitory killer immunoglobulin-like receptors (KIR) are unable to engage their cognate HLA class I ligands. The genes of the KIR locus are organized into either KIR B haplotypes, containing 1 or more activating KIR genes or KIR A haplotypes, which lack those genes. Analysis of unrelated donor (URD) hematopoietic cell transplants (HCT), given to acute myeloid leukemia (AML) patients between 1988 and 2009, showed that KIR B haplotype donors were associated with better outcomes, primarily from relapse protection. Most of these transplants involved marrow grafts, fully myeloablative (MAC) preparative regimens, and significant HLA mismatch. Because the practice of HCT continues to evolve, with increasing use of reduced intensity conditioning (RIC), peripheral blood stem cell grafts, and better HLA match, we evaluated the impact of URD KIR genotype on HCT outcome for AML in the modern era (2010-2016). This analysis combined data from a prospective trial testing URD selection based on KIR genotypes (n = 243) with that from a larger contemporaneous cohort of transplants (n = 2419). We found that KIR B haplotype donors conferred a significantly reduced risk of leukemia relapse and improved disease-free survival after RIC, but not MAC HCT. All genes defining KIR B haplotypes were associated with relapse protection, which was significant only in transplant recipients expressing the C1 epitope of HLA-C. In the context of current HCT practice using RIC, selection of KIR B donors could reduce relapse and improve overall outcome for AML patients receiving an allogeneic HCT.

© 2019, The Author(s). In this paper, a control method is developed for minimizing joint torque on a redundant manipulator where an external force acts on the end-effector. Using null space control, the redundant task is designed to minimize the torque required to oppose the external force, and reduce the dynamic torque. Furthermore, the joint motion can be weighted to factor in physical constraints such as joint limits, collision avoidance, etc. Conventional methods for joint torque minimization only consider the internal dynamics of the manipulator. If external forces acting on the end-effector are inadvertently implemented in to these control methods this could lead to joint configurations that amplify the resulting joint torque. The proposed control method is verified through two different case studies. The first case study involves simulation of high-pressure blasting. The second is a simulation of a manipulator lifting and moving a heavy object. The results show that the proposed control method reduces overall joint torque compared to conventional methods. Furthermore, the joint torque is minimized such that there is potential for a manipulator to execute certain tasks beyond its nominal payload capacity.

Presentation for UCT's Open Data Day. The presentation is on the role of DataFirst's African Open Data Repository in providing seamless access to disaggregated data for data-intensive Africa-focused research

Cell Reports paper

We studied 232 consecutive children transplanted between 1990 and 2011 with relapse after 1(st) hematopoietic cell transplant (HCT). Kaplan-Meier survival and hazard ratios for mortality were calculated for factors known at time of relapse using Cox proportional hazards models. The median (range) age at time of 1(st) HCT was 10.9 (0.5–20.9) years, time to relapse was 6.1 (0.2–89.5) months after HCT, and age at relapse was 11.7 (0.7–23.6) yrs. The 3-year overall survival (OS) after relapse was 13% (95% Confidence Interval (CI): 9%, 18%).The median (range) follow-up for the 18 surviving patients was 7.2 (3.0–24.4) years after relapse. The remaining 214 died after a median of 3 months (0.02–190.4). OS was not significantly different for patients with ALL as compared to AML. Fifty-one patients proceeded to 2(nd) transplant of whom 9 survive. Factors associated with improved survival included late relapse (greater than 12 months), ALL in first CR at the time of first transplant and chemotherapy-based first conditioning regimens. These results can be used to counsel patients at the time of relapse after first transplant and as a baseline for comparison as to the effectiveness of newer therapies which are greatly needed for treatment of post-transplant relapse.

A total of 21 patients with severe aplastic anemia (SAA) underwent marrow transplantation from HLA-identical siblings following a standard conditioning regimen with cyclophosphamide (50 mg/kg/day × 4 days) and horse antithymocyte globulin (30 mg/kg/day × 3 days). Post-grafting immunosuppression consisted of a short course of methotrexate (MTX) combined with cyclosporine (CSP). The transplant protocol tested the hypothesis that the incidence of chronic GvHD could be reduced by limiting the marrow grafts to ⩽2.5 × 108 nucleated marrow cells/kg. None of the patients rejected the graft, all had sustained engraftment and all are surviving at a median of 4 (range 1–8) years after transplantation. Chronic GvHD developed in 16% of patients given ⩽2.5 × 108 nucleated marrow cells/kg. Post-grafting immunosuppression has been discontinued in 20 of the 21 patients. In conclusion, limiting the number of transplanted marrow cells may have resulted in minimal improvement in the incidence and severity of chronic GvHD.

BACKGROUND Patients with FMS like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML) have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (HCT). METHODS Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were used to evaluate 511 adult patients with de novo AML who underwent HCT during 2008 through 2011 to determine whether FLT3 mutations had an impact on HCT outcomes. RESULTS In total, 158 patients (31%) had FLT3 mutations. Univariate and multivariate analyses revealed an increased risk of relapse at 3 years in the FLT3 mutated group compared with the wild-type (WT) group (38% [95% confidence interval (CI), 30%-45%] vs 28% [95% CI, 24%-33%]; P = .04; relative risk, 1.60 [95% CI, 1.15-2.22]; P = .0048). However, FLT3 mutation status was not significantly associated with nonrelapse mortality, leukemia-free survival, or overall survival. Although more patients in the FLT3 mutated group died from relapsed primary disease compared with those in the WT group (60% vs 46%), the 3-year overall survival rate was comparable for the 2 groups (mutated group: 49%; 95% CI, 40%-57%; WT group: 55%, 95% CI, 50%-60%; P = .20). CONCLUSIONS The current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long-term survivors. Cancer 2016;122:3005-3014. © 2016 American Cancer Society.

For adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in first complete remission (CR1), allogeneic hematopoietic cell transplantation (HCT) is an established curative strategy. However, pediatric-inspired chemotherapy may also offer durable leukemia-free survival in the absence of HCT. We compared 422 HCT recipients aged 18-50 years with Ph-ALL in CR1 reported to the CIBMTR with an age-matched concurrent cohort of 108 Ph- ALL CR1 patients who received a Dana-Farber Consortium pediatric-inspired non-HCT regimen. At 4 years of follow-up, incidence of relapse after HCT was 24% (95% CI 19-28) versus 23% (95% CI 15-32) for the non-HCT (chemo) cohort (P=0.97). Treatment-related mortality (TRM) was higher in the HCT cohort [HCT 37% (95% CI 31-42) versus chemo 6% (95% CI 3-12), P

The interdisciplinary science of conservation biology provides undergraduate biology students with the opportunity to connect the biological sciences with disciplines including economics, social science and philosophy to address challenging conservation issues. Because of its complexity, students do not often have the opportunity to practise conservation biology. To increase exposure to this science, this paper describes a virtual rainforest island on which students collect data related to forest carbon storage, while also confronting ethical issues. Students are asked to independently make decisions, collect data and explore the island before writing a research report with recommendations for the future management of the island’s forests. The ethics of decision-making are addressed in the students’ research reports and are reinforced through guided class discussion. Students will complete this activity with increased ethical awareness, as well as a better understanding of the challenges associated with t...

The ability to continue combination antiretroviral therapy (cART) in human immunodeficiency virus (HIV)–infected patients undergoing hematopoietic cell transplantation (HCT) for treatment of hematologic malignancies is likely a critical factor in preventing the establishment of an HIV reservoir in transplanted stem cells. Thus, we studied the feasibility of continued antiretroviral therapy in our HIV-infected patients undergoing autologous or allogeneic transplantation. All HIV-infected adults undergoing HCT for hematologic malignancy at Fred Hutchinson Cancer Research Center between 2006 and 2014 were included; most were enrolled in a prospective clinical study to monitor HIV reservoirs after transplantation (NCT00968630 and NCT00112593). Non-nucleotide reverse transcriptase inhibitor or integrase-strand inhibitor–anchored antiretroviral therapy regimens were continued or selected before HCT by infectious disease physicians. Plasma HIV RNA was measured every other day for the first 2 weeks after transplantation and then every 2 weeks. Missed doses of cART and reasons for changing the cART regimen during the post-transplantation hospitalization were documented through review of inpatient pharmacy records. Seven autologous and 8 allogeneic transplantations were performed. In 9 transplantations, the cART regimen was not altered after HCT and no doses were missed. In 2 patients who required alterations in their cART regimen because of development of acute renal failure (n = 1) and small bowel obstruction (n = 1) after HCT, enfuvirtide was used as a bridging component of the regimen. Plasma HIV RNA remained suppressed during the first 28 days in 12 of 15 transplantations, and no patients had a plasma HIV RNA >1000 copies/mL during long-term follow up. Non-nucleotide reverse transcriptase inhibitor– and integrase-strand inhibitor–based cART are safe and effective in HIV-infected persons during the peri-HCT period. Most patients undergoing HCT were able to continue cART without missed doses. Sustained HIV viremia and emergence of resistance were not detected.

We previously reported that acute myelogenous leukemia (AML) transplants using killer cell immunoglobulin-type receptor (KIR) B haplotype better or best (≥2 B activating gene loci ± Cen B/B) unrelated donors (URDs) yield less relapse and better survival. In this prospective trial we evaluated 535 AML searches from 14 participating centers with centralized donor KIR genotyping for donor selection. This represented 3% to 48% of all AML searches (median 20%) per center, totaling 3 to 172 patients (median 22) per center. Donor KIR genotype was reported at a median of 14 days after request (≤26 days for 76% of searches). In 535 searches, 2080 donors were requested for KIR genotyping (mean 4.3 per search); and a median of 1.8 (range, 0 to 4.5) per search were KIR typed. Choosing more donors for confirmatory HLA and KIR haplotype identification enriched the likelihood of finding KIR better or best donors. The search process identified a mean of 30% KIR better or best donors; the success ranged from 24% to 38% in the 11 centers enrolling ≥8 patients. More donors requested for KIR genotyping increased the likelihood of identifying KIR better or best haplotype donors. Of the 247 transplants, 9.3% used KIR best, 19% used KIR better, and 48% used KIR neutral donors while 24% used a non–KIR-tested donor. KIR genotyping did not delay transplantation. The time from search to transplant was identical for transplants using a KIR-genotyped versus a non–KIR-genotyped donor. Prospective evaluation can rapidly identify KIR favorable genotype donors, but choosing more donors per search would substantially increase the likelihood of having a KIR best or better donor available for transplantation. Transplant centers and donor registries must both commit extra effort to incorporate new characteristics (beyond HLA, age, and parity) into improved donor selection. Deliberate efforts to present additional genetic factors for donor selection will require novel procedures.

Background and method We examined specimens from 111 HIV-infected participants virally suppressed on ART for a minimum of 5 years who had donated serial peripheral blood mononuclear cell (PBMC) specimens to the University of Washington/Fred Hutch Center for AIDS Research (CFAR) Specimen Repository. We determined the HIV proviral copy number per million PBMCs, corrected for CD4 cell count, in 477 specimens collected after a minimum of 5 years of follow-up and up to 15.5 years of clinical viral suppression. Generalized estimating equation regression was used to examine the association between the reservoir size and time, age at study entry, antiretroviral regimen, and risk factors for HIV acquisition. Results and conclusion We found that the inter-participant baseline HIV DNA level varied widely between 0.01 and 4.8 pol-copies per microgram genomic DNA and per CD4 cell number/micoliter; the HIV DNA level declined with time (half-life was estimated at 12 years, 95% confidence interval of 6.2-240 years); the HIV DNA level was lower for those who achieved viral suppression at a younger age; and the HIV DNA level was not affected by the specific antiretroviral regimen used to achieve and maintain suppression.

SUMMARY Ca2+-permeable AMPA-type glutamate receptors (CP-AMPARs) containing GluA1 but lacking GluA2 subunits contribute to multiple forms of synaptic plasticity, including long-term potentiation (LTP), but mechanisms regulating CP-AMPARs are poorly understood. A-kinase anchoring protein (AKAP) 150 scaffolds kinases and phosphatases to regulate GluA1 phosphorylation and trafficking, and trafficking of AKAP150 itself is modulated by palmitoylation on two Cys residues. Here, we developed a palmitoylation-deficient knockin mouse to show that AKAP150 palmitoylation regulates CP-AMPAR incorporation at hippocampal synapses. Using biochemical, super-resolution imaging, and electrophysiological approaches, we found that palmitoylation promotes AKAP150 localization to recycling endosomes and the postsynaptic density (PSD) to limit CP-AMPAR basal synaptic incorporation. In addition, we found that AKAP150 palmitoylation is required for LTP induced by weaker stimulation that recruits CP-AMPARs to synapses but not stronger stimulation that recruits GluA2-containing AMPARs. Thus, AKAP150 palmitoylation controls its subcellular localization to maintain proper basal and activity-dependent regulation of synaptic AMPAR subunit composition., In Brief Purkey et al. uncover a requirement for palmitoylation of the postsynaptic scaffold protein AKAP150 in regulating Ca2+-permeable AMPA receptors to control synaptic plasticity., Graphical Abstract

Calcineurin (CaN) phosphatase signaling is regulated by targeting CaN to substrates, inhibitors, and scaffold proteins containing docking motifs with the consensus sequence of PxIxIT. Here, we identify the docking of CaN to the γ isoform of MKK7, a component of the c-Jun N-terminal kinase (JNK) pathway. Because of alternative splicing of a single exon within the N-terminal domain, MKK7γ encodes a unique PxIxIT motif (PIIVIT) that is not present in MKK7α or β. We found that MKK7γ bound directly to CaN through this PIIVIT motif in vitro, immunoprecipitated with CaN from cell extracts, and exhibited fluorescence resonance energy transfer (FRET) with CaN in the cytoplasm but not in the nucleus of living cells. In contrast, MKK7α and β exhibited no direct binding or FRET with CaN and were localized more in the nucleus than the cytoplasm. Furthermore, the inhibition of CaN phosphatase activity increased the basal phosphorylation of MKK7γ but not MKK7β. Deletion of the MKK7γ PIIVIT motif eliminated FRET with CaN and promoted MKK7γ redistribution to the nucleus; however, the inhibition of CaN activity did not alter MKK7γ localization, indicating that MKK7γ cytoplasmic retention by CaN is phosphatase activity independent. Finally, the inhibition of CaN phosphatase activity in vascular smooth muscle cells, which express MKK7γ mRNA, enhances JNK activation. Overall, we conclude that the MKK7γ-specific PxIxIT motif promotes high-affinity CaN binding that could promote novel cross talk between CaN and JNK signaling by limiting MKK7γ phosphorylation and restricting its localization to the cytoplasm.

Background and challenges to implementation Research-driven tobacco and alcohol control policies need country-specific data. Although several institutions collect data on tobacco and alcohol, few tools exist for discovering and accessing these data in Africa. The goal of the Data on Alcohol and Tobacco in Africa (DATA) Project is to catalogue economic data on tobacco and alcohol in Africa and publish these data for research purposes. The pilot stage of the project focuses on Botswana, Kenya, Namibia, Senegal, and South Africa, with the goal of expanding across Africa. Intervention or response The DATA Project establishes relationships with data producers and obtains permission to share their data on the project's site. The Project documents our experience in securing data and identifies best practices for increasing open access to data. The Project curates all secured data, shares these in research-ready datasets, uses metadata to describe data available in external repositories and redirects users to these sites. It also collates time-series data from various publicly available sources into referenced data sheets. Our work saves researchers the time and effort involved in finding and collating data. Results and lessons learnt Currently 69 datasets are listed on the DATA Project's site. These include open access data as well as discovery metadata and links to relevant data available on other sites. Our findings reveal that despite the availability of relevant tobacco and alcohol data, data producers are not using the available tools to facilitate data visibility and access from their websites. We find that data collectors are still reluctant to make their data Open. Conclusions and key recommendations We hope to encourage Open access to data, by providing the essential infrastructure and expertise for data sharing. Additionally, we wish to advance the quality of these data, through data users' feedback. Our efforts should increase Open access data for alcohol and tobacco control in Africa.

A central theme in nervous system function is equilibrium: synaptic strengths wax and wane, neuronal firing rates adjust up and down, and neural circuits balance excitation with inhibition. This push/pull regulatory theme carries through to the molecular level at excitatory synapses, where protein function is controlled through phosphorylation and dephosphorylation by kinases and phosphatases. However, these opposing enzymatic activities are only part of the equation as scaffolding interactions and assembly of multi-protein complexes are further required for efficient, localized synaptic signaling. This review will focus on coordination of postsynaptic serine/threonine kinase and phosphatase signaling by scaffold proteins during synaptic plasticity.

Since 2000, the International Liaison Committee on Resuscitation (ILCOR) has published the International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (CoSTR) every 5 years based on review of cardiopulmonary resuscitation (CPR) science. Seven task forces with representatives from the 7 member resuscitation organizations create the CoSTR that enables regional resuscitation organizations to create their individual guidelines. The different guidelines are based on the scientific evidence and incorporate or adjust for regional considerations. Coronary heart disease remains among the leading causes of mortality globally. There is considerable research focus worldwide on improving outcomes in patients with acute coronary syndromes (ACS). Undoubtedly, this has led to improved health and dramatically improved morbidity and mortality in much of the world. Indeed, timely and appropriate care of ACS can reduce and prevent cardiac arrest. Some of the recommended interventions for ACS, however, are considered resource intensive and/or require significant infrastructure, such as well-trained emergency medical services personnel to administer fibrinolysis, and cardiac catheterization laboratories that require capital and experienced staff. These regional disparities present challenges to regional and national health authorities as guidelines evolve and become more complex. The American College of Cardiology with the American Heart Association, European Society of Cardiology, and other organizations have developed guidelines for treatment and management of patients with ST-segment elevation myocardial infarction (STEMI) and non-STEMI ACS. These guidelines primarily focus on the hospital setting, and, for many years, the prehospital and emergency department (ED) management of patients was based on extrapolation of in-hospital evidence. There is now increasing interest and evidence on the prehospital decisions and management of ACS. The time-sensitive nature of ACS forces us to scrutinize not only the time goals to deliver the interventions but also the proper sequencing of them. For …

Summary Background Antimicrobial stewardship is a key component in the reduction of healthcare-associated infections, particularly Clostridium difficile infection (CDI). We successfully restricted the use of cephalosporins and, subsequently, fluoroquinolones. From an endemically high level of >280 cases per year in 2007–08, the number of CDIs reduced to 72 cases in 2011–12. Aim To describe the implementation and impact of fluoroquinolone restriction on CDI. Methods This was an interrupted time-series analysis pre and post fluoroquinolone restriction for 60 months based on a Poisson distribution model. Findings In June 2008, fluoroquinolone consumption halved to about 5 defined daily doses (DDD) per 100 occupied bed-days (OBD). This was followed by a significant fall in CDI number [rate ratio (RR): 0.332; 95% confidence interval (CI): 0.240–0.460] which remained low over the subsequent months. Subsequently, fluoroquinolone consumption was further reduced to about 2 DDD/100 OBD in June 2010 accompanied by further reduction in CDI rate (RR: 0.394; 95% CI: 0.199–0.781). In a univariate Poisson model the CDI rate was associated with fluoroquinolone usage (RR: 1.086; 95% CI: 1.077–1.094). Conclusion We conclude that in an environment where cephalosporin usage is already low, the reduction in fluoroquinolone usage was associated with an immediate, large, and significant reduction in CDI cases.

Natural killer cells are regulated by killer cell immunoglobulin-like receptor (KIR) interactions with HLA class I ligands. Several models of natural killer cell reactivity have been associated with improved outcomes after myeloablative allogeneic hematopoietic cell transplantation (HCT), but this issue has not been rigorously addressed in reduced-intensity conditioning (RIC) unrelated donor (URD) HCT. We studied 909 patients undergoing RIC-URD HCT. Patients with acute myeloid leukemia (AML, n = 612) lacking ≥ 1 KIR ligands experienced higher grade III to IV acute graft-versus-host disease (GVHD) (HR, 1.6; 95% CI, 1.16 to 2.28; P = .005) compared to those with all ligands present. Absence of HLA-C2 for donor KIR2DL1 was associated with higher grade II to IV (HR, 1.4; P = .002) and III to IV acute GVHD (HR, 1.5; P = .01) compared with HLA-C2+ patients. AML patients with KIR2DS1+, HLA-C2 homozygous donors had greater treatment-related mortality compared with others (HR, 2.4; 95% CI, 1.4 to 4.2; P = .002) but did not experience lower relapse. There were no significant associations with outcomes for AML when assessing donor-activating KIRs or centromeric KIR content or for any donor–recipient KIR-HLA assessments in patients with myelodysplastic syndrome (n = 297). KIR-HLA combinations in RIC-URD HCT recapitulate some but not all KIR-HLA effects observed in myeloablative HCT.