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BackgroundUse of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment.MethodsThe ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232.FindingsThe seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2-18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT.InterpretationRegulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression.FundingThe 7th EU Framework Programme.

Abstract Background While several studies report on accuracy rates of pedicle screws, risk factors associated with inaccurate pedicle screw positioning in patients with thoracolumbar fractures are reported rarely. CT scan as a routine postoperative control is advocated by various authors, however its necessity remains unclear. Methods Two hundred forty-five patients were included in this retrospective study. Percutaneous dorsal instrumentation was most commonly performed (n = 201). Classification of Zdichavsky et al. and Rao et al. were used to classify screw misplacement and anterior perforation was further evaluated according to the extent of perforation ( 2 mm). Multivariate analysis was performed to identify risk factors for misplacement of screws. Results One thousand sixty-eight pedicle screws were inserted in 245 patients. Misplacement was found in 51 screws (4.8%) in 42 patients (17.1%) according to the classification of Zdichavsky et al. and in 75 screws (7.0%) in 64 patients (26.1%) according to the classification of Rao et al.. An anterior perforation of the vertebral cortex was found in 56 screws (5.2%). Multivariate analysis showed fracture location in the upper thoracic (p = 0.048) and lumbar spine (p = 0.013) to be the only independent predictors for screw misplacement. In addition a significant correlation between pedicle diameter and the occurrence of screw malposition was found (p = 0.003). No consequences were drawn from postoperative routine CT in asymptomatic patients. Conclusion An overall low rate of screw misplacement was found with fracture location in the upper thoracic and lumbar spine being the only factors independently associated with the risk of screw misplacement. No consequences were drawn from postoperative routine CT in asymptomatic patients. Therefore its use has to be discussed critically.

Regulatory T cell (Treg) therapy has the potential to induce transplantation tolerance so that immunosuppression and associated morbidity can be minimized. Alloantigen-reactive Tregs (arTregs) are more effective at preventing graft rejection than polyclonally expanded Tregs (PolyTregs) in murine models. We have developed a manufacturing process to expand human arTregs in short-term cultures using good manufacturing practice-compliant reagents. This process uses CD40L-activated allogeneic B cells to selectively expand arTregs followed by polyclonal restimulation to increase yield. Tregs expanded 100- to 1600-fold were highly alloantigen reactive and expressed the phenotype of stable Tregs. The alloantigen-expanded Tregs had a diverse TCR repertoire. They were more potent than PolyTregs in vitro and more effective at controlling allograft injuries in vivo in a humanized mouse model.

A naturalistic observational single case study was carried out to investigate the form and function of private speech (PS) in a young man with Dandy-Walker variant syndrome and trisomy 22. Video recordings were observed, transcribed and coded to identify all combinations of type and form of PS. Through comparison between theories of PS and the results, five putative functions were identified in this case. In contrast to the predominant theoretical models of inner and PS, it is proposed that PS cannot necessarily be reduced to a single functional definition.

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The management of sediment and other non-point source (NPS) pollution has proven difficult, and requires a sound understanding of particle movement through the drainage system. The primary objective of this investigation was to obtain an understanding of NPS sediment source(s), transport, and storage within the Mkabela Basin, a representative agricultural catchment within the KwaZulu–Natal Midlands of eastern South Africa, by combining geomorphic, hydrologic and geochemical fingerprinting analyses. The Mkabela Basin can be subdivided into three distinct subcatchments that differ in their ability to transport and store sediment along the axial valley. Headwater (upper catchment) areas are characterized by extensive wetlands that act as significant sediment sinks. Mid-catchment areas, characterized by higher relief and valley gradients, exhibit few wetlands, but rather are dominated by a combination of alluvial and bedrock channels that are conducive to sediment transport. The lower catchment exhibits a low-gradient alluvial channel that is boarded by extensive riparian wetlands that accumulate large quantities of sediment (and NPS pollutants). Fingerprinting studies suggest that silt- and clay-rich layers found within wetland and reservoir deposits of the upper and upper-mid subcatchments are derived from the erosion of fine-grained, valley bottom soils frequently utilized as vegetable fields. Coarser-grained deposits within these wetlands and reservoirs result from the erosion of sandier hillslope soils extensively utilized for sugar cane, during relatively high magnitude runoff events that are capable of transporting sand-sized sediment off the slopes. Thus, the source of sediment to the axial valley varies as a function of sediment size and runoff magnitude. Sediment export from upper to lower catchment areas was limited until the early 1990s, in part because the upper catchment wetlands were hydrologically disconnected from lower parts of the watershed during low to moderate flood events. The construction of a drainage ditch through a previously unchanneled wetland altered the hydrologic connectivity of the catchment, allowing sediment to be transported from the headwaters to the lower basin where much of it was deposited within riparian wetlands. The axial drainage system is now geomorphically and hydrologically connected during events capable of overflowing dams located throughout the study basin. The study indicates that increased valley connectivity partly negated the positive benefits of controlling sediment/nutrient exports from the catchment by means of upland based, best management practices.

Machining of large scale thin-walled workpieces pose high requirements for fixturing because of large stiffness changes due to material removal. Automatically reconfigurable fixtures that allow in-process reconfiguration are a promising approach. In this paper, an efficient approach based on feature analysis is proposed for fixture reconfiguration planning. For this, material removal is simulated. At discrete points in time, feature analysis is performed and an approximated local stiffness map is calculated with weight functions derived from the features' parameterizations. Viable fixture configurations are then identified through root finding and validated through simulation in Ansys and experimentally with a fixture jig. In both validations, workpiece deformation for drilling operations could be reduced to an acceptable level enabling the implementation's future use in industrial application. [ABSTRACT FROM AUTHOR]

Layered part manufacturing enables part topology to be optimized internally by structuring individual layers separately, which is especially promising for large machine parts. However, the resulting part properties as a function of the selected manufacturing parameters are largely unexplored. Therefore, this paper investigates the impacts of the slicing direction, the sheet thickness as well as the adhesive on anisotropic damping and stiffness values of adhesively bonded steel parts. A cantilever beam of symmetric cross-section is chosen as an easy-to-manufacture geometry. Three redundant specimens were prepared for each of six parameter variations investigated within this study, resulting in a total of 18 investigated beams. The results indicate highly anisotropic stiffness and damping as a function of the layer build-up direction and it was found that the modal damping rises with increasing amount of adhesive. These findings must be taken into account for future applications of layered lightweight machine parts and their simulative predictability should be studied. [ABSTRACT FROM AUTHOR]