RAFT Polymerization of a Biorenewable/Sustainable Monomer via a Green Process

A biorenewable polymer is synthesized via a green process using the RAFT principle for the first time in supercritical CO2 at 300 bar and 80 °C. α-Methylene-γ-butyrolactone polymers of various chain lengths and molecular weights are obtained. The molecular weights vary from 10 000 up to 20 000 with low polydispersity indexes (PDI <1.5). Furthermore, the monomer conversion in supercritical CO2 is substantially higher, respectively 85% for ScCO2 compared to ≈65% for polymerizations conducted in dimethyl formamide (DMF) solvent. Chain extensions are carried out to confirm the livingness of the formed polymers in ScCO2. This opens up future possibilities of the formation of different polymer architectures in ScCO2. The polymers synthesized in ScCO2 have glass transition temperature (Tg) values ranging from 155 up to 190 °C. However, the presence of residual monomer encapsulated inside the formed polymer matrix affects the glass transition of the polymer that is lowered by increasing monomer concentrations. Hence, additional research is required to eliminate the remaining monomer concentration in the polymer matrix in order to arrive at the optimal Tg

Quantifying Graft Detachment after Descemet's Membrane Endothelial Keratoplasty with Deep Convolutional Neural Networks

Purpose: We developed a method to automatically locate and quantify graft detachment after Descemet's Membrane Endothelial Keratoplasty (DMEK) in Anterior Segment Optical Coherence Tomography (AS-OCT) scans. Methods: 1280 AS-OCT B-scans were annotated by a DMEK expert. Using the annotations, a deep learning pipeline was developed to localize scleral spur, center the AS-OCT B-scans and segment the detached graft sections. Detachment segmentation model performance was evaluated per B-scan by comparing (1) length of detachment and (2) horizontal projection of the detached sections with the expert annotations. Horizontal projections were used to construct graft detachment maps. All final evaluations were done on a test set that was set apart during training of the models. A second DMEK expert annotated the test set to determine inter-rater performance. Results: Mean scleral spur localization error was 0.155 mm, whereas the inter-rater difference was 0.090 mm. The estimated graft detachment lengths were in 69% of the cases within a 10-pixel (~150{\mu}m) difference from the ground truth (77% for the second DMEK expert). Dice scores for the horizontal projections of all B-scans with detachments were 0.896 and 0.880 for our model and the second DMEK expert respectively. Conclusion: Our deep learning model can be used to automatically and instantly localize graft detachment in AS-OCT B-scans. Horizontal detachment projections can be determined with the same accuracy as a human DMEK expert, allowing for the construction of accurate graft detachment maps. Translational Relevance: Automated localization and quantification of graft detachment can support DMEK research and standardize clinical decision making.Comment: To be published in Translational Vision Science & Technolog

Chimeric Antigen Receptor T-Cell Therapy in Paediatric B-Cell Precursor Acute Lymphoblastic Leukaemia : Curative Treatment Option or Bridge to Transplant?

Chimeric antigen receptor T-cell therapy (CAR-T) targeting CD19 has been associated with remarkable responses in paediatric patients and adolescents and young adults (AYA) with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Tisagenlecleucel, the first approved CD19 CAR-T, has become a viable treatment option for paediatric patients and AYAs with BCP-ALL relapsing repeatedly or after haematopoietic stem cell transplantation (HSCT). Based on the chimeric antigen receptor molecular design and the presence of a 4-1BB costimulatory domain, tisagenlecleucel can persist for a long time and thereby provide sustained leukaemia control. "Real-world" experience with tisagenlecleucel confirms the safety and efficacy profile observed in the pivotal registration trial. Recent guidelines for the recognition, management and prevention of the two most common adverse events related to CAR-T - cytokine release syndrome and immune-cell-associated neurotoxicity syndrome - have helped to further decrease treatment toxicity. Consequently, the questions of how and for whom CD19 CAR-T could substitute HSCT in BCP-ALL are inevitable. Currently, 40-50% of R/R BCP-ALL patients relapse post CD19 CAR-T with either CD19(-) or CD19(+) disease, and consolidative HSCT has been proposed to avoid disease recurrence. Contrarily, CD19 CAR-T is currently being investigated in the upfront treatment of high-risk BCP-ALL with an aim to avoid allogeneic HSCT and associated treatment-related morbidity, mortality and late effects. To improve survival and decrease long-term side effects in children with BCP-ALL, it is important to define parameters predicting the success or failure of CAR-T, allowing the careful selection of candidates in need of HSCT consolidation. In this review, we describe the current clinical evidence on CAR-T in BCP-ALL and discuss factors associated with response to or failure of this therapy: product specifications, patient- and disease-related factors and the impact of additional therapies given before (e.g., blinatumomab and inotuzumab ozogamicin) or after infusion (e.g., CAR-T re-infusion and/or checkpoint inhibition). We discuss where to position CAR-T in the treatment of BCP-ALL and present considerations for the design of supportive trials for the different phases of disease. Finally, we elaborate on clinical settings in which CAR-T might indeed replace HSCT.Peer reviewe

Modelling the Cost-Effectiveness of Implementing a Dietary Intervention in Renal Transplant Recipients

Background: The Dietary Approach to Stop Hypertension (DASH) and potassium supplementation have been shown to reduce the risk of death with a functioning graft (DWFG) and renal graft failure in renal transplant recipients (RTR). Unfortunately, a key problem for patients is the adherence to these diets. The aim of this study is to evaluate the cost-effectiveness and budget impact of higher adherence to either the DASH or potassium supplementation. Methods: A Markov model was used to simulate the life course of 1000 RTR in the Netherlands. A societal perspective with a lifetime time horizon was used. The potential effect of improvement of dietary adherence was modelled in different scenarios. The primary outcomes are the incremental cost-effectiveness ratio (ICER) and the budget impact. Results: In the base case, improved adherence to the DASH diet saved 27,934,786 and gained 1880 quality-adjusted life years (QALYs). Improved adherence to potassium supplementation saved euro1,217,803 and gained 2901 QALYs. Both resulted in dominant ICERs. The budget impact over a five-year period for the entire Dutch RTR population was euro8,144,693. Conclusion: Improving dietary adherence in RTR is likely to be cost-saving and highly likely to be cost-effective compared to the current standard of care in the Netherlands

An experimental realisation of steady spanwise forcing for turbulent drag reduction

We present an experimental realisation of spatial spanwise forcing in a turbulent boundary layer flow, aimed at reducing the frictional drag. The forcing is achieved by a series of spanwise running belts, running in alternating spanwise direction, thereby generating a steady spatial square-wave forcing. Stereoscopic particle image velocimetry is used to investigate the impact of actuation on the flow in terms of turbulence statistics, performance characteristics, and spanwise velocity profiles, for a waveform of $\lambda_x^+ = 401$. An extension of the classical spatial Stokes layer theory is proposed based on the linear superposition of Fourier modes to describe the non-sinusoidal boundary condition. The experimentally obtained spanwise profiles show good agreement with the extended theoretical model. In line with reported numerical studies, we confirm that a significant flow control effect can be realised with this type of forcing. The results reveal a maximum drag reduction of 26% and a maximum net power savings of 8%. In view of the limited spatial extent of the actuation surface in the current setup, the drag reduction is expected to increase further as a result of its streamwise transient. The second-order turbulence statistics are attenuated up to a wall-normal height of $y^+ \approx 100$, with a maximum streamwise stress reduction of 44% and a reduction of integral turbulence kinetic energy production of 39%

Ventricular synchrony is not significantly determined by absolute myocardial perfusion in patients with chronic heart failure:A N-13-ammonia PET study

Background It is thought that heart failure (HF) patients may benefit from the evaluation of mechanical (dys)synchrony, and an independent inverse relationship between myocardial perfusion and ventricular synchrony has been suggested. We explore the relationship between quantitative myocardial perfusion and synchrony parameters when accounting for the presence and extent of fixed perfusion defects in patients with chronic HF. Methods We studied 98 patients with chronic HF who underwent rest and stress Nitrogen-13 ammonia PET. Multivariate analyses of covariance were performed to determine relevant predictors of synchrony (measured as bandwidth, standard deviation, and entropy). Results In our population, there were 43 (44%) women and 55 men with a mean age of 71 +/- 9.6 years. The SRS was the strongest independent predictor of mechanical synchrony variables (p <.01), among other considered predictors including: age, sex, body mass index, smoking, diabetes mellitus, dyslipidemia, hypertension, rest myocardial blood flow (MBF), and myocardial perfusion reserve (MPR). Results were similar when considering stress MBF instead of MPR. Conclusions The existence and extent of fixed perfusion defects, but not the quantitative PET myocardial perfusion parameters (sMBF and MPR), constitute a significant independent predictor of ventricular mechanical synchrony in patients with chronic HF

Corneal Pachymetry by AS-OCT after Descemet's Membrane Endothelial Keratoplasty

Corneal thickness (pachymetry) maps can be used to monitor restoration of corneal endothelial function, for example after Descemet's membrane endothelial keratoplasty (DMEK). Automated delineation of the corneal interfaces in anterior segment optical coherence tomography (AS-OCT) can be challenging for corneas that are irregularly shaped due to pathology, or as a consequence of surgery, leading to incorrect thickness measurements. In this research, deep learning is used to automatically delineate the corneal interfaces and measure corneal thickness with high accuracy in post-DMEK AS-OCT B-scans. Three different deep learning strategies were developed based on 960 B-scans from 50 patients. On an independent test set of 320 B-scans, corneal thickness could be measured with an error of 13.98 to 15.50 micrometer for the central 9 mm range, which is less than 3% of the average corneal thickness. The accurate thickness measurements were used to construct detailed pachymetry maps. Moreover, follow-up scans could be registered based on anatomical landmarks to obtain differential pachymetry maps. These maps may enable a more comprehensive understanding of the restoration of the endothelial function after DMEK, where thickness often varies throughout different regions of the cornea, and subsequently contribute to a standardized postoperative regime.Comment: Fixed typo in abstract: The development set consists of 960 B-scans from 50 patients (instead of 68). The B-scans from the other 18 patients were used for testing onl

Image-guided multisession radiosurgery of skull base meningiomas

Background: The efficacy of single-session stereotactic radiosurgery (sSRS) for the treatment of intracranial meningioma is widely recognized. However, sSRS is not always feasible in cases of large tumors and those lying close to critically radiation-sensitive structures. When surgery is not recommended, multi-session stereotactic radiosurgery (mSRS) can be applied. Even so, the efficacy and best treatment schedule of mSRS are not yet established. The aim of this study is to validate the role of mSRS in the treatment of skull base meningiomas. Methods: A retrospective analysis of patients with skull base meningiomas treated with mSRS (two to five fractions) at the University of Messina, Italy, from 2008 to 2018, was conducted. Results: 156 patients met the inclusion criteria. The median follow-up period was 36.2 \ub1 29.3 months. Progression-free survival at 2-, 5-, and 10-years was 95%, 90%, and 80.8%, respectively. There were no new visual or motor deficits, nor cranial nerves impairments, excluding trigeminal neuralgia, which was reported by 5.7% of patients. One patient reported carotid occlusion and one developed brain edema. Conclusion: Multisession radiosurgery is an effective approach for skull base meningiomas. The long-term control is comparable to that obtained with conventionally-fractionated radiotherapy, while the toxicity rate is very limited