Noise reduction in chaotic time series by a local projection with nonlinear constraints

On the basis of a local-projective (LP) approach we develop a method of noise reduction in time series that makes use of nonlinear constraints appearing due to the deterministic character of the underlying dynamical system. The Delaunay triangulation approach is used to find the optimal nearest neighboring points in time series. The efficiency of our method is comparable to standard LP methods but our method is more robust to the input parameter estimation. The approach has been successfully applied for separating a signal from noise in the chaotic Henon and Lorenz models as well as for noisy experimental data obtained from an electronic Chua circuit. The method works properly for a mixture of additive and dynamical noise and can be used for the noise-level detection.Comment: 11 pages, 12 figures. See http://www.chaosandnoise.or

Tweaking synchronization by connectivity modifications

ACKNOWLEDGMENTS The authors wish to thank the Nesin Foundation for an amazing working group activity in Nesin Math Village, and we wish to thank Tiago Pereira for fruitful discussions. P.S. and J.K. acknowledge gratefully the support of BMBF, CoNDyNet, FK. 03SF0472A. T.P. acknowledges FAPESP (No. 2012/22160-7 and No. 2015/02486-3) and IRTG 1740. D.E. acknowledge support by the Leibniz Association (WGL) under Grant No. SAW-2013-IZW-2542.Peer reviewedPublisher PD

Antifungal prophylaxis and pre-emptive therapy: When and how?

The growing pool of critically ill or immunocompromised patients leads to a constant increase of life-threatening invasive infections by fungi such as Aspergillus spp., Candida spp. and Pneumocystis jirovecii. In response to this, prophylactic and pre-emptive antifungal treatment strategies have been developed and implemented for high-risk patient populations. The benefit by risk reduction needs to be carefully weighed against potential harm caused by prolonged exposure against antifungal agents. This includes adverse effects and development of resistance as well as costs for the healthcare system. In this review, we summarise evidence and discuss advantages and downsides of antifungal prophylaxis and pre-emptive treatment in the setting of malignancies such as acute leukaemia, haematopoietic stem cell transplantation, CAR-T cell therapy, and solid organ transplant. We also address preventive strategies in patients after abdominal surgery and with viral pneumonia as well as individuals with inherited immunodeficiencies. Notable progress has been made in haematology research, where strong recommendations regarding antifungal prophylaxis and pre-emptive treatment are backed by data from randomized controlled trials, whereas other critical areas still lack high-quality evidence. In these areas, paucity of definitive data translates into centre-specific strategies that are based on interpretation of available data, local expertise, and epidemiology. The development of novel immunomodulating anticancer drugs, high-end intensive care treatment and the development of new antifungals with new modes of action, adverse effects and routes of administration will have implications on future prophylactic and pre-emptive approaches

Corporate governance compliance and disclosure in the banking sector: using data from Japan

Using regression model this study investigates which characteristics of a bank is associated with the extent of corporate governance disclosure in Japan. The findings suggest that on average 8 banks out of a sample of 46 disclose optimal corporate governance information. The regression model results reveal in general that non-executive directors, cross-ownership, capital adequacy ratio and type of auditors are associated with the extent of corporate governance disclosure. Of these four variables, non-executive directors have a more significant impact on the extent of disclosure contrary to total assets and audit firms of banks in the context of Japan. The findings of this paper are relevant for corporate regulators, professional associations and developers of corporate governance code when designing or updating corporate governance code

Data assimilation in slow-fast systems using homogenized climate models

A deterministic multiscale toy model is studied in which a chaotic fast subsystem triggers rare transitions between slow regimes, akin to weather or climate regimes. Using homogenization techniques, a reduced stochastic parametrization model is derived for the slow dynamics. The reliability of this reduced climate model in reproducing the statistics of the slow dynamics of the full deterministic model for finite values of the time scale separation is numerically established. The statistics however is sensitive to uncertainties in the parameters of the stochastic model. It is investigated whether the stochastic climate model can be beneficial as a forecast model in an ensemble data assimilation setting, in particular in the realistic setting when observations are only available for the slow variables. The main result is that reduced stochastic models can indeed improve the analysis skill, when used as forecast models instead of the perfect full deterministic model. The stochastic climate model is far superior at detecting transitions between regimes. The observation intervals for which skill improvement can be obtained are related to the characteristic time scales involved. The reason why stochastic climate models are capable of producing superior skill in an ensemble setting is due to the finite ensemble size; ensembles obtained from the perfect deterministic forecast model lacks sufficient spread even for moderate ensemble sizes. Stochastic climate models provide a natural way to provide sufficient ensemble spread to detect transitions between regimes. This is corroborated with numerical simulations. The conclusion is that stochastic parametrizations are attractive for data assimilation despite their sensitivity to uncertainties in the parameters.Comment: Accepted for publication in Journal of the Atmospheric Science

Process data of allogeneic ex vivo-expanded ABCB5+ mesenchymal stromal cells for human use: Off-the-shelf GMP-manufactured donor-independent ATMP

© 2020, The Author(s). Background: Human dermal mesenchymal stromal cells (MSCs) expressing the ATP-binding cassette (ABC) efflux transporter ABCB5 represent an easily accessible MSC population that, based on preclinical and first-in-human data, holds significant promise to treat a broad spectrum of conditions associated not only with skin-related but also systemic inflammatory and/or degenerative processes. Methods: We have developed a validated Good Manufacturing Practice-compliant expansion and manufacturing process by which ABCB5+ MSCs derived from surgical discard skin tissues are processed to an advanced-therapy medicinal product (ATMP) for clinical use. Enrichment for ABCB5+ MSCs is achieved in a three-step process involving plastic adherence selection, expansion in a highly efficient MSC-selecting medium, and immunomagnetic isolation of the ABCB5+ cells from the mixed culture. Results: Product Quality Review data covering 324 cell expansions, 728 ABCB5+ MSC isolations, 66 ABCB5+ MSC batches, and 85 final drug products reveal high process robustness and reproducible, reliable quality of the manufactured cell therapy product. Conclusion: We have successfully established an expansion and manufacturing process that enables the generation of homogenous ABCB5+ MSC populations of proven biological activity manufactured as a standardized, donor-independent, highly pure, and highly functional off-the-shelf available ATMP, which is currently tested in multiple clinical trials

Validation of the treatment identification strategy of the HEDIS addiction quality measures: concordance with medical record review

<p>Abstract</p> <p>Background</p> <p>Strategies to accurately identify the occurrence of specific health care events in administrative data is central to many quality improvement and research efforts. Many health care quality measures have treatment identification strategies based on diagnosis and procedure codes - an approach that is inexpensive and feasible but usually of unknown validity. In this study, we examined if the diagnosis/procedure code combinations used in the 2006 HEDIS Initiation and Engagement quality measures to identify instances of addiction treatment have high concordance with documentation of addiction treatment in clinical progress notes.</p> <p>Methods</p> <p>Four type of records were randomly sampled from VHA electronic medical data: (a) Outpatient records from a substance use disorder (SUD) specialty clinic with a HEDIS-qualified substance use disorder (SUD) diagnosis/CPT code combination (n = 700), (b) Outpatient records from a non-SUD setting with a HEDIS-qualified SUD diagnosis/CPT code combination (n = 592), (c) Specialty SUD Inpatient/residential records that included a SUD diagnosis (n = 700), and (d) Non-SUD specialty Inpatient/residential records that included a SUD diagnosis (n = 700). Clinical progress notes for the sampled records were extracted and two raters classified each as documenting or not documenting addiction treatment. Rates of concordance between the HEDIS addiction treatment identification strategy and the raters' judgments were calculated for each record type.</p> <p>Results</p> <p>Within SUD outpatient clinics and SUD inpatient specialty units, 92% and 98% of sampled records had chart evidence of addiction treatment. Of outpatient encounters with a qualifying diagnosis/procedure code combination outside of SUD clinics, 63% had chart evidence of addiction treatment. Within non-SUD specialty inpatient units, only 46% of sampled records had chart evidence of addiction treatment.</p> <p>Conclusions</p> <p>For records generated in SUD specialty settings, the HEDIS strategy of identifying SUD treatment with diagnosis and procedure codes has a high concordance with chart review. The concordance rate outside of SUD specialty settings is much lower and highly variable between facilities. Therefore, some patients may be counted as meeting the 2006 HEDIS Initiation and Engagement criteria without having received the specified amount (or any) addiction treatment.</p

Examining the frequency and nature of gambling marketing in televised broadcasts of professional sporting events in the United Kingdom

Objective: Gambling operators in the United Kingdom have introduced a voluntary ban on adverts broadcast during televised sport before 21:00 (the 'whistle-to-whistle' ban). To inform debates around the potential effectiveness of this ban, we examine the frequency and nature of gambling marketing in televised broadcasts across professional sporting events. Study Design: Frequency analysis of verbal and visual gambling marketing references during television broadcasts of football (n=5), tennis, Formula 1, boxing and rugby union (each n=1) from 2018. Methods: For each gambling reference, we coded: whether it appeared in-play or out-of-play; location (e.g. pitch-side advertising); format (e.g. branded merchandise); duration (seconds); number of identical references visible simultaneously; brand; and presence of age restriction or harm reduction messages. Results: Boxing contained the most gambling references, on average, per broadcast minute (4.70 references), followed by football (2.75), rugby union (0.55), and tennis (0.11). Formula 1 contained no gambling references. In boxing, references most frequently appeared within the area-of-play. For football and rugby union, references most frequently appeared around the pitch border or within the area-of-play (e.g. branded shirts). Only a small minority of references were for adverts during commercial breaks that would be subject to the whistle-to-whistle ban(e.g. 2% of references in football). Less than 1% of references in boxing, and only 3% of references in football, contained age restriction or harm-reduction messages. Conclusions: As gambling sponsorship extends much beyond adverts in commercial breaks, the 'whistle-to-whistle' ban will have limited effect on gambling exposure. Gambling sponsorship activities rarely contain harm reduction messages

Process development and safety evaluation of ABCB5+ limbal stem cells as advanced-therapy medicinal product to treat limbal stem cell deficiency

Background: While therapeutic success of the limbal tissue or cell transplantation to treat severe cases of limbal stem cell (LSC) deficiency (LSCD) strongly depends on the percentage of LSCs within the transplanted cells, prospective LSC enrichment has been hampered by the intranuclear localization of the previously reported LSC marker p63. The recent identification of the ATP-binding cassette transporter ABCB5 as a plasma membrane-spanning marker of LSCs that are capable of restoring the cornea and the development of an antibody directed against an extracellular loop of the ABCB5 molecule stimulated us to develop a novel treatment strategy based on the utilization of in vitro expanded allogeneic ABCB5+ LSCs derived from human cadaveric limbal tissue. Methods: We developed and validated a Good Manufacturing Practice- and European Pharmacopeia-conform production and quality-control process, by which ABCB5+ LSCs are derived from human corneal rims, expanded ex vivo, isolated as homogenous cell population, and manufactured as an advanced-therapy medicinal product (ATMP). This product was tested in a preclinical study program investigating the cells’ engraftment potential, biodistribution behavior, and safety. Results: ABCB5+ LSCs were reliably expanded and manufactured as an ATMP that contains comparably high percentages of cells expressing transcription factors critical for LSC stemness maintenance (p63) and corneal epithelial differentiation (PAX6). Preclinical studies confirmed local engraftment potential of the cells and gave no signals of toxicity and tumorgenicity. These findings were sufficient for the product to be approved by the German Paul Ehrlich Institute and the U.S. Food & Drug Administration to be tested in an international multicenter phase I/IIa clinical trial (NCT03549299) to evaluate the safety and therapeutic efficacy in patients with LSCD. Conclusion: Building upon these data in conjunction with the previously shown cornea-restoring capacity of human ABCB5+ LSCs in animal models of LSCD, we provide an advanced allogeneic LSC-based treatment strategy that shows promise for replenishment of the patient’s LSC pool, recreation of a functional barrier against invading conjunctival cells and restoration of a transparent, avascular cornea

Ex vivo-expanded highly pure ABCB5+ mesenchymal stromal cells as good manufacturing practice-compliant autologous advanced therapy medicinal product for clinical use: Process validation and first in-human data

© 2020 International Society for Cell & Gene Therapy Background aim: Mesenchymal stromal cells (MSCs) hold promise for the treatment of tissue damage and injury. However, MSCs comprise multiple subpopulations with diverse properties, which could explain inconsistent therapeutic outcomes seen among therapeutic attempts. Recently, the adenosine triphosphate-binding cassette transporter ABCB5 has been shown to identify a novel dermal immunomodulatory MSC subpopulation. Methods: The authors have established a validated Good Manufacturing Practice (GMP)-compliant expansion and manufacturing process by which ABCB5+ MSCs can be isolated from skin tissue and processed to generate a highly functional homogeneous cell population manufactured as an advanced therapy medicinal product (ATMP). This product has been approved by the German competent regulatory authority to be tested in a clinical trial to treat therapy-resistant chronic venous ulcers. Results: As of now, 12 wounds in nine patients have been treated with 5 × 105 autologous ABCB5+ MSCs per cm2 wound area, eliciting a median wound size reduction of 63% (range, 32–100%) at 12 weeks and early relief of pain. Conclusions: The authors describe here their GMP- and European Pharmacopoeia-compliant production and quality control process, report on a pre-clinical dose selection study and present the first in-human results. Together, these data substantiate the idea that ABCB5+ MSCs manufactured as ATMPs could deliver a clinically relevant wound closure strategy for patients with chronic therapy-resistant wounds