Deutsche Forschungsgemeinschaft Research Articles

Robust Multiple Stopping—A Duality Approach

We develop a method to solve, theoretically and numerically, general optimal stopping problems. Our general setting allows for multiple exercise rights—that is, optimal multiple stopping—for a robust evaluation that accounts for model uncertainty with a dominated family of priors and for general reward processes driven by multidimensional jump-diffusions. Our approach relies on first establishing robust martingale dual representation results for the multiple stopping problem that satisfy appealing almost sure pathwise optimality properties. Next, we exploit these theoretical results to develop upper and lower bounds that, as we formally show, not only converge to the true solution asymptotically, but also constitute genuine prelimiting upper and lower bounds. We illustrate the applicability of our approach in a few examples and analyze the impact of model uncertainty on optimal multiple stopping strategies. Funding: R. J. A. Laeven received financial support from the Netherlands Organization for Scientific Research (NWO) [Grants NWO-Vidi and NWO-Vici]. J. G. M. Schoenmakers received financial support from the Deutsche Forschungsgemeinschaft Excellence Cluster Math+ Berlin [Project AA4-2]. Supplemental Material: The online appendix is available at https://doi.org/10.1287/moor.2021.0237 .

The Algorithmic Assignment of Incentive Schemes

The assignment of individuals with different observable characteristics to different treatments is a central question in designing optimal policies. We study this question in the context of increasing workers’ performance via targeted incentives using machine learning algorithms with worker demographics, personality traits, and preferences as input. Running two large-scale experiments, we show that (i) performance can be predicted by accurately measured worker characteristics, (ii) a machine learning algorithm can detect heterogeneity in responses to different schemes, (iii) a targeted assignment of schemes to individuals increases performance significantly above the level of the single best scheme, and (iv) algorithmic assignment is more effective for workers who have a high likelihood to repeatedly interact with the employer or who provide more consistent survey answers. This paper was accepted by Yan Chen, behavioral economics and decision analysis. Funding: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy [Grant EXC 2126/1-390838866]. Supplemental Material: The online appendix and data files are available at https://doi.org/10.1287/mnsc.2022.03362 .

Patents, Freedom to Operate, and Follow-on Innovation: Evidence from Post-Grant Opposition

We study the blocking effect of patents on follow-on innovation by others. We posit that follow-on innovation requires freedom to operate (FTO), which firms typically obtain through a license from the patentee holding the original innovation. Where licensing fails, follow-on innovation is blocked unless firms gain FTO through patent invalidation. Using large-scale data from post-grant oppositions at the European Patent Office, we find that patent invalidation increases follow-on innovation, measured in citations, by 16% on average. This effect exhibits a U-shape in the value of the original innovation. For patents on low-value original innovations, invalidation predominantly increases low-value follow-on innovation outside the patentee’s product market. Here, transaction costs likely exceed the joint surplus of licensing, causing licensing failure. In contrast, for patents on high-value original innovations, invalidation mainly increases high-value follow-on innovation in the patentee’s product market. We attribute this latter result to rent dissipation, which renders patentees unwilling to license out valuable technologies to (potential) competitors. This paper was accepted by Ashish Arora, entrepreneurship and innovation. Funding: This work was supported by the Deutsche Forschungsgemeinschaft [Collaborative Research Center TRR 190]. F. Gaessler acknowledges financial support from the Spanish Agencia Estatal de Investigación through the Severo Ochoa Programme for Centres of Excellence in R&D [Barcelona School of Economics CEX2019-000915-S]. Supplemental Material: The online appendices and data files are available at https://doi.org/10.1287/mnsc.2019.02294 .

Trade Secret Protection and the Integration of Information Within Firms

We examine the effect of trade secret protection laws on internal information integration (i.e., the extent to which economic agents are provided with access to decision-relevant information from other economic agents within a firm). We argue that stronger trade secret protection laws increase firms’ internal information integration because they reduce the proprietary costs of information leakage. To test our prediction, we measure a firm’s internal information integration by the share of its sites integrated into its enterprise management system. Exploiting the staggered adoption of trade secret protection laws via the Uniform Trade Secrets Act (UTSA), we find that these laws increase firms’ internal information integration. This effect is stronger (weaker) for firms with higher proprietary costs (coordination benefits). Further, we provide evidence that the UTSA-induced increase in internal information integration translates into improvements of firms’ internal information quality and decision-making quality. Taken together, our results enhance the understanding of the economic trade-offs shaping firms’ internal information environment. This paper was accepted by Ranjani Krishnan, accounting. Funding: S. Bormann and K. Hombach gratefully acknowledge funding from Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [Grant Project-ID 403041268–TRR 266 Accounting for Transparency]. Supplemental Material: The online appendix and data files are available at https://doi.org/10.1287/mnsc.2021.03484 .

Risk Taking Under Limited Liability and Moral Hazard: Quantifying the Role of Motivated Beliefs

This paper investigates whether limited liability and moral hazard affect risk taking through motivated beliefs. On the one hand, limited liability encourages investors to take excessive risks. On the other, excessive risk taking makes it hard for investors to maintain a positive self-image when moral hazard is present. Using a novel experimental design, we show that subjects form motivated beliefs to self-justify their excessive risk taking. For the same investment opportunity, subjects invest more and are significantly more optimistic about the success of the investment if its failure can harm others. We show that more than one third of the investment increases under limited liability, and moral hazard can be explained through motivated beliefs. Moreover, through a treatment with limited liability but no moral hazard, we show that motivated beliefs are formed subconsciously and can lead to the paradoxical result of investors taking larger risks when their investment can harm a third party compared with when it cannot. These results underscore the importance of motivated beliefs in regulatory policy, emphasizing that policymakers must not only address bad incentives, but also address the role of bad beliefs. This paper was accepted by Bruno Biais, finance. Funding: Financial support by Deutsche Forschungsgemeinschaft [Grant CRC TRR 190, project number 280092119] is gratefully acknowledged. Supplemental Material: The online appendix and data files are available at https://doi.org/10.1287/mnsc.2021.03947 .

Beyond cemeteries – excavation of a settlement of Poieneşti-Lucaşeuca Culture in Ivancea, Republic of Moldova

Summary The Poieneşti-Lucaşeuca-culture (late 3rd to second half of the 1st century BC), which is distributed in the forest steppe between the east Carpathian Mountains and the river Dniestr, is seen as the result of an immigration of groups from the Jastorf area in North-East Germany. This concept is based on cemeteries: both the form of the grave4s and their material culture (ceramics, jewellery, costume) are foreign in the area, but show clear connections to the North and the North-West. Up to now large settlement excavations are missing that would allow for an evaluation of that concept based on settlement and economic structures as well as on the material culture of everyday life. The project that is presented here with first results, aims to that desideratum. With surveys and test excavations as a starting point on different sites in Central part of Republic of Moldova, the authors are excavating the Poieneşti-Lucaşeuca settlement of Ivancea-Sub Pădure on a large scale. The project is funded by Deutsche Forschungsgemeinschaft. The paper presents first results like different post buildings and pit dwellings, the spectrum of small finds and a selection of the numerous ceramics including greek imports, and discusses the connectivity that becomes visible. The post buildings have no regional parallels and seem to have the best parallels in the Northwest. In opposite to that the small finds show a broad entanglement especially to the south and West and thus contradict the evidence from the grave. Also, in opposite to the graves the settlement ceramics show clear regional traditions, bus also relations to the North and the Northeast.

Increased cardiovascular risks and mortality in prurigo nodularis: a global cohort study

BackgroundPrurigo nodularis (PN) presents with intensely itchy hard nodules. Despite being limited to the skin, PN was noted to be associated with systemic diseases including diabetes and chronic renal failure. In previous smaller retrospective studies, several cardiac and vascular diseases were found more frequently in patients with PN. However, small cohort sizes, partially discrepant outcomes, missing data, and incomplete risk assessment limit these findings. MethodsElectronic health records (EHR)s of 64,801 patients (59.44% females) with PN and an equal sized propensity-matched control group were retrieved. In these cohorts, the risks to develop cardiac and vascular diseases and mortality following diagnosis of PN were determined. Sub-analyses included stratification for sex, ethnicity, and treatments. FindingsPN was associated with a higher risk for a broad range of acute cardiac events including heart failure and myocardial infarction. For example, the hazard ratio of myocardial infarction was 1.11 (95%-CI: 1.041-1.184, p=0.0015) following PN diagnosis. Also, all-cause mortality was higher in patients with PN. Further, chronic vascular as well as structural heart diseases, e.g., peripheral arterial disease, chronic ischaemic heart disease and valval disorders were found more frequently following a PN diagnosis. Risks were more pronounced in white and female patients. Having established an increased risk for death and cardiovascular disease, we next addressed if dupilumab that has been recently licenced for use in this indication can modulate these risks. The risk of death but not of any cardiovascular disease was slightly reduced in patients with PN treated with dupilumab as opposed to those treated with systemic therapies other than dupilumab. The study is limited by retrospective data collection and reliance on ICD10-disease classification. InterpretationPN is associated with higher mortality and an increased risk for the development of a wide range of cardiac and vascular diseases. Health care professionals should take this into account when managing patients with PN. FundingThis work was supported by the University of Lübeck, the Deutsche Forschungsgemeinschaft and the State of Schleswig-Holstein.

Computing Optimality Certificates for Convex Mixed-Integer Nonlinear Problems

Every optimization problem has a corresponding verification problem that checks whether a given optimal solution is in fact optimal. In the literature, there are a lot of such ways to verify optimality for a given solution, for example, the branch-and-bound tree. To simplify this task, optimality certificates were introduced for convex mixed-integer nonlinear programs, and it was shown that the sizes of the certificates are bounded in terms of the number of integer variables. We introduce an algorithm to compute the certificates and conduct computational experiments. Through the experiments, we show that the optimality certificates can be surprisingly small. History: Accepted by Andrea Lodi, Area Editor for Design & Analysis of Algorithms—Discrete. Funding: This work was supported by the Deutsche Forschungsgemeinschaft [CRC 154 Subproject A05, CRC 154 Subproject B07, and SFB Transregio 154], the Bundesministerium für Wirtschaft und Energie. Supplemental Material: The software that supports the findings of this study is available within the paper and its Supplemental Information ( https://pubsonline.informs.org/doi/suppl/10.1287/ijoc.2022.0099 ) as well as from the IJOC GitHub software repository ( https://github.com/INFORMSJoC/2022.0099 ). The complete IJOC Software and Data Repository is available at https://informsjoc.github.io/ .

MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: a proof-of-concept study

Matrix metalloproteinases (MMPs) are implied in blood-brain barrier degradation and haemorrhagic transformation following ischaemic stroke, but their local relevance in the hyperacute disease phase is unknown. We aimed to examine ultra-early MMP-9 and MMP-2 release into collateral blood vessels, and to assess its prognostic value before therapeutic recanalisation by endovascular thrombectomy (EVT). We report a cross-sectional proof-of-concept study including patients undergoing EVT for large-vessel ischaemic stroke at the University Hospital Würzburg, Germany. We obtained liquid biopsies from the collateral circulation before recanalisation, and systemic control samples. Laboratory workup included quantification of MMP-9 and MMP-2 plasma concentrations by cytometric bead array, immunohistochemical analyses of cellular MMP-9 and MMP-2 expression, and detection of proteolytic activity by gelatine zymography. The clinical impact of MMP concentrations was assessed by stratification according to intracranial haemorrhagic lesions on postinterventional computed tomography (Heidelberg Bleeding Classification, HBC) and early functional outcome (modified Rankin Scale, mRS). We used multivariable logistic regression, receiver-operating-characteristic (ROC) curves, and fixed-level estimates of test accuracy measures to study the prognostic value of MMP-9 concentrations. Between August 3, 2018, and September 16, 2021, 264 matched samples from 132 patients (86 [65.2%] women, 46 [34.8%] men, aged 40-94 years) were obtained. Median (interquartile range, IQR) MMP-9 (279.7 [IQR 126.4-569.6] vs 441 [IQR 223.4-731.5] ng/ml, p<0.0001) but not MMP-2 concentrations were increased within collateral blood vessels. The median MMP-9 expression level of invading neutrophils was elevated (fluorescence intensity, arbitrary unit: 2276 [IQR 1007-5086] vs 3078 [IQR 1108-7963], p=0.0018). Gelatine zymography experiments indicated the locally confined proteolytic activity of MMP-9 but not of MMP-2. Pretherapeutic MMP-9 release into stroke-affected brain regions predicted the degree of intracerebral haemorrhages and clinical stroke severity after recanalisation, and independently increased the odds of space-occupying parenchymal haematomas (HBC1c-3a) by 1.54 times, and the odds of severe disability or death (mRS ≥5at hospital discharge) by 2.33 times per 1000ng/ml increase. Excessive concentrations of MMP-9 indicated impending parenchymal haematomas and severe disability or death with high specificity. Measurement of MMP-9 within collateral blood vessels is feasible and identifies patients with stroke at risk of major intracerebral haemorrhages and poor outcome before therapeutic recanalisation by EVT, thereby providing evidence of the concept validity of ultra-early local stroke biomarkers. This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) and the Interdisciplinary Centre for Clinical Research (IZKF) at the University of Würzburg.

Early postnatal high-dose fat-soluble enteral vitamin A supplementation for moderate or severe bronchopulmonary dysplasia or death in extremely low birthweight infants (NeoVitaA): a multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial.

Vitamin A plays a key role in lung development, but there is no consensus regarding the optimal vitamin A dose and administration route in extremely low birthweight (ELBW) infants. We aimed to assess whether early postnatal additional high-dose fat-soluble enteral vitamin A supplementation versus placebo would lower the rate of moderate or severe bronchopulmonary dysplasia or death in ELBW infants receiving recommended basic enteral vitamin A supplementation. This prospective, multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial conducted at 29 neonatal intensive care units in Austria and Germany assessed early high-dose enteral vitamin A supplementation (5000 international units [IU]/kg per day) or placebo (peanut oil) for 28 days in ELBW infants. Eligible infants had a birthweight of more than 400 g and less than 1000 g; gestational age at birth of 32+0 weeks postmenstrual age or younger; and the need for mechanical ventilation, non-invasive respiratory support, or supplemental oxygen within the first 72 h of postnatal age after admission to the neonatal intensive care unit. Participants were randomly assigned by block randomisation with variable block sizes (two and four). All participants received basic vitamin A supplementation (1000 IU/kg per day). The composite primary endpoint was moderate or severe bronchopulmonary dysplasia or death at 36 weeks postmenstrual age, analysed in the intention-to-treat population. This trial was registered with EudraCT, 2013-001998-24. Between March 2, 2015, and Feb 27, 2022, 3066 infants were screened for eligibility at the participating centres. 915 infants were included and randomly assigned to the high-dose vitamin A group (n=449) or the control group (n=466). Mean gestational age was 26·5 weeks (SD 2·0) and mean birthweight was 765 g (162). Moderate or severe bronchopulmonary dysplasia or death occurred in 171 (38%) of 449 infants in the high-dose vitamin A group versus 178 (38%) of 466 infants in the control group (adjusted odds ratio 0·99, 95% CI 0·73-1·55). The number of participants with at least one adverse event was similar between groups (256 [57%] of 449 in the high-dose vitamin A group and 281 [60%] of 466 in the control group). Serum retinol concentrations at baseline, at the end of intervention, and at 36 weeks postmenstrual age were similar in the two groups. Early postnatal high-dose fat-soluble enteral vitamin A supplementation in ELBW infants was safe, but did not change the rate of moderate or severe bronchopulmonary dysplasia or death and did not substantially increase serum retinol concentrations. Deutsche Forschungsgemeinschaft and European Clinical Research Infrastructures Network (ECRIN).

Market Liquidity and Competition Among Designated Market Makers

Do competition and incentives offered to designated market makers (DMMs) improve market liquidity? We employ data from NYSE Euronext Paris to show that exogenous changes in contract design lead to significant decreases in quoted and effective spreads. In particular, market liquidity increases the most for stocks with the largest increase in competition among DMMs. Our analysis shows that competition among DMMs is an important aspect of contract design, along with elements such as rebates and requirements. This paper was accepted by Kay Giesecke, finance. Funding: M. G. Subrahmanyam thanks the Alexander von Humboldt Foundation for generous financial support via the Anneliese Maier Award. L. Pelizzon thanks the Leibniz Institute for Financial Research SAFE for financially sponsoring this research and Italian Ministry for University and Research [MIUR–2017RSMPZZ]. This work was also supported by the Deutsche Forschungsgemeinschaft [Grant 329107530]. Supplemental Material: The Internet Appendix and data files are available at https://doi.org/10.1287/mnsc.2022.01801 .

GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort

BackgroundGAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA)≥250 expansions in the fibroblast growth factor 14 (FGF14) gene, but its phenotypic spectrum, pathogenic threshold, and evidence-based treatability remain to be established. We report on the frequency of FGF14 (GAA)≥250 and (GAA)200-249 expansions in a large cohort of patients with idiopathic downbeat nystagmus (DBN) and their response to 4-aminopyridine. MethodsRetrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial. FindingsFrequency of FGF14 (GAA)≥250 expansions was 48% (82/170) in patients with idiopathic DBN. Additional cerebellar ocular motor signs were observed in 100% (82/82) and cerebellar ataxia in 43% (35/82) of patients carrying an FGF14 (GAA)≥250 expansion. FGF14 (GAA)200-249 alleles were enriched in patients with DBN (12%; 20/170) compared to controls (0·87%; 19/2,191; OR, 15·20; 95% CI, 7·52 to 30·80; p<0·0001). The phenotype of patients carrying a (GAA)200-249 allele closely mirrored that of patients carrying a (GAA)≥250 allele. Patients carrying a (GAA)≥250 or a (GAA)200-249 allele had a significantly greater clinician-reported (80%, 33/41 vs 31%, 5/16; RR, 2·58; 95% CI, 1·23 to 5·41; Fisher’s exact test, p=0·0011) and self-reported (59%, 32/54 vs 11%, 2/19; RR, 5·63; 95% CI, 1·49 to 21·27; Fisher’s exact test, p=0·00033) response to 4-aminopyridine treatment compared to patients carrying a (GAA)<200 allele. Placebo-controlled video-oculography data, available for four patients carrying an FGF14 (GAA)≥250 expansion, showed a significant decrease in slow phase velocity of DBN with 4-aminopyridine, but not placebo. InterpretationThis study confirms that FGF14 GAA expansions are a frequent cause of DBN syndromes. It provides preliminary evidence that (GAA)200-249 alleles might be pathogenic. Finally, it provides large real-world and preliminary piloting placebo-controlled evidence for the efficacy of 4-aminopyridine in GAA-FGF14 disease. FundingThis work was supported by the Clinician Scientist program "PRECISE.net" funded by the Else Kröner-Fresenius-Stiftung (to CW, AT, and MSy), the grant 779257 “Solve-RD” from the European’s Union Horizon 2020 research and innovation program (to MSy), and the grant 01EO 1401 by the German Federal Ministry of Education and Research (BMBF) (to MSt). This work was also supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) N° 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N° 825575 (to MSy, BB and – as associated partner – SZ), the NIH National Institutes of Neurological Disorders and Stroke (grant 2R01NS072248-11A1 to SZ), the Fondation Groupe Monaco (to BB), and the Montreal General Hospital Foundation (grant PT79418 to BB). The Care4Rare Canada Consortium is funded in part by Genome Canada and the Ontario Genomics Institute (OGI-147 to KMB), the Canadian Institutes of Health Research (CIHR GP1-155867 to KMB), Ontario Research Fund, Genome Quebec, and the Children’s Hospital of Eastern Ontario Foundation. The funders had no role in the conduct of this study.

Optimal Service Time Windows

Because customers must usually arrange their schedules to be present for home services, they desire an accurate estimate of when the service will take place. However, even when firms quote large service time windows, they are often missed, leading to customer dissatisfaction. Wide time windows and frequent failures occur because time windows must be communicated to customers in the face of several uncertainties: future customer requests are unknown, final service plans are not yet determined, and when fulfillment is outsourced to a third party, the firm has limited control over routing procedures and eventual fulfillment times. Even when routing is performed in-house, time windows often do not receive explicit consideration. In this paper, we show how companies can communicate reliable and narrow time windows to customers in the face of arrival time uncertainty when time window decisions are decoupled from routing procedures. Under assumptions on the shape of arrival time distributions, our main result characterizes the optimal policy, identifying structure that reduces a high-dimensional stochastic nonlinear optimization problem to a root-finding problem in one dimension. The result inspires a practice-ready heuristic for the more general case. Relative to the industry standard of communicating uniform time windows to all customers, and to other policies applied in practice, our method of quoting customer-specific time windows yields a substantial increase in customer convenience without sacrificing reliability of service. Our results show that time windows should be tailored to individual customers, time window sizes should be proportional to the service level, larger time windows should be assigned to earlier requests and smaller time windows to later requests, larger time windows should be assigned to customers further from the depot of operation and smaller time windows to closer customers, high quality time windows can be identified even with limited data, and cost savings afforded by routing efficiency should be measured against potential losses to customer convenience. Funding: M. W. Ulmer’s work is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Emmy Noether Programme, [project 444657906]. Supplemental Material: The e-companion is available at https://doi.org/10.1287/trsc.2023.0004 .

Deep-learning-based reconstruction of undersampled MRI to reduce scan times: a multicentre, retrospective, cohort study

The extended acquisition times required for MRI limit its availability in resource-constrained settings. Consequently, accelerating MRI by undersampling k-space data, which is necessary to reconstruct an image, has been a long-standing but important challenge. We aimed to develop a deep convolutional neural network (dCNN) optimisation method for MRI reconstruction and to reduce scan times and evaluate its effect on image quality and accuracy of oncological imaging biomarkers. In this multicentre, retrospective, cohort study, MRI data from patients with glioblastoma treated at Heidelberg University Hospital (775 patients and 775 examinations) and from the phase 2 CORE trial (260 patients, 1083 examinations, and 58 institutions) and the phase 3 CENTRIC trial (505 patients, 3147 examinations, and 139 institutions) were used to develop, train, and test dCNN for reconstructing MRI from highly undersampled single-coil k-space data with various acceleration rates (R=2, 4, 6, 8, 10, and 15). Independent testing was performed with MRIs from the phase 2/3 EORTC-26101 trial (528 patients with glioblastoma, 1974 examinations, and 32 institutions). The similarity between undersampled dCNN-reconstructed and original MRIs was quantified with various image quality metrics, including structural similarity index measure (SSIM) and the accuracy of undersampled dCNN-reconstructed MRI on downstream radiological assessment of imaging biomarkers in oncology (automated artificial intelligence-based quantification of tumour burden and treatment response) was performed in the EORTC-26101 test dataset. The public NYU Langone Health fastMRI brain test dataset (558 patients and 558 examinations) was used to validate the generalisability and robustness of the dCNN for reconstructing MRIs from available multi-coil (parallel imaging) k-space data. In the EORTC-26101 test dataset, the median SSIM of undersampled dCNN-reconstructed MRI ranged from 0·88 to 0·99 across different acceleration rates, with 0·92 (95% CI 0·92-0·93) for 10-times acceleration (R=10). The 10-times undersampled dCNN-reconstructed MRI yielded excellent agreement with original MRI when assessing volumes of contrast-enhancing tumour (median DICE for spatial agreement of 0·89 [95% CI 0·88 to 0·89]; median volume difference of 0·01 cm3 [95% CI 0·00 to 0·03] equalling 0·21%; p=0·0036 for equivalence) or non-enhancing tumour or oedema (median DICE of 0·94 [95% CI 0·94 to 0·95]; median volume difference of -0·79 cm3 [95% CI -0·87 to -0·72] equalling -1·77%; p=0·023 for equivalence) in the EORTC-26101 test dataset. Automated volumetric tumour response assessment in the EORTC-26101 test dataset yielded an identical median time to progression of 4·27 months (95% CI 4·14 to 4·57) when using 10-times-undersampled dCNN-reconstructed or original MRI (log-rank p=0·80) and agreement in the time to progression in 374 (95·2%) of 393 patients with data. The dCNN generalised well to the fastMRI brain dataset, with significant improvements in the median SSIM when using multi-coil compared with single-coil k-space data (p<0·0001). Deep-learning-based reconstruction of undersampled MRI allows for a substantial reduction of scan times, with a 10-times acceleration demonstrating excellent image quality while preserving the accuracy of derived imaging biomarkers for the assessment of oncological treatment response. Our developments are available as open source software and hold considerable promise for increasing the accessibility to MRI, pending further prospective validation. Deutsche Forschungsgemeinschaft (German Research Foundation) and an Else Kröner Clinician Scientist Endowed Professorship by the Else Kröner Fresenius Foundation.

CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-up

BackgroundTreatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission.MethodsWe evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology–European League against Rheumatism (ACR–EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded.ResultsThe median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR–EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell–associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization.ConclusionsIn this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.)

Salami slicing and other kinds of scientific misconduct: A faux pas for the author, a disaster for science

Abstract As part of the research project “Summa cum fraude – Wissenschaftliches Fehlverhalten und der Versuch einer Gegenoffensive” at Saarland University (funded by the Deutsche Forschungsgemeinschaft DFG) an interview with Ivan Oransky in October 2022 was conducted. He became well-known for co-founding the Retraction Watch Database and the Retraction Watch blog, which covers topics such as retracting published articles or exposing misconduct in science.

Combinatorial Optimization-Enriched Machine Learning to Solve the Dynamic Vehicle Routing Problem with Time Windows

With the rise of e-commerce and increasing customer requirements, logistics service providers face a new complexity in their daily planning, mainly due to efficiently handling same-day deliveries. Existing multistage stochastic optimization approaches that allow solving the underlying dynamic vehicle routing problem either are computationally too expensive for an application in online settings or—in the case of reinforcement learning—struggle to perform well on high-dimensional combinatorial problems. To mitigate these drawbacks, we propose a novel machine learning pipeline that incorporates a combinatorial optimization layer. We apply this general pipeline to a dynamic vehicle routing problem with dispatching waves, which was recently promoted in the EURO Meets NeurIPS Vehicle Routing Competition at NeurIPS 2022. Our methodology ranked first in this competition, outperforming all other approaches in solving the proposed dynamic vehicle routing problem. With this work, we provide a comprehensive numerical study that further highlights the efficacy and benefits of the proposed pipeline beyond the results achieved in the competition, for example, by showcasing the robustness of the encoded policy against unseen instances and scenarios. History: This paper has been accepted for the Transportation Science special issue on DIMACS Implementation Challenge: Vehicle Routing Problems. Funding: This work was supported by Deutsche Forschungsgemeinschaft [Grant 449261765].

Phenotypic and genome-wide studies on dicarbonyls: major associations to glomerular filtration rate and gamma-glutamyltransferase activity

The dicarbonyl compounds methylglyoxal (MG), glyoxal (GO) and 3-deoxyglucosone (3-DG) have been linked to various diseases. However, disease-independent phenotypic and genotypic association studies with phenome-wide and genome-wide reach, respectively, have not been provided. MG, GO and 3-DG were measured by LC-MS in 1304 serum samples of two populations (KORA, n=482; BiDirect, n=822) and assessed for associations with genome-wide SNPs (GWAS) and with phenome-wide traits. Redundancy analysis (RDA) was used to identify major independent trait associations. Mutual correlations of dicarbonyls were highly significant, being stronger between MG and GO (ρ=0.6) than between 3-DG and MG or GO (ρ=0.4). Significant phenotypic results included associations of all dicarbonyls with sex, waist-to-hip ratio, glomerular filtration rate (GFR), gamma-glutamyltransferase (GGT), and hypertension, of MG and GO with age and C-reactive protein, of GO and 3-DG with glucose and antidiabetics, of MG with contraceptives, of GO with ferritin, and of 3-DG with smoking. RDA revealed GFR, GGT and, in case of 3-DG, glucose as major contributors to dicarbonyl variance. GWAS did not identify genome-wide significant loci. SNPs previously associated with glyoxalase activity did not reach nominal significance. When multiple testing was restricted to the lead SNPs of GWASs on the traits selected by RDA, 3-DG was found to be associated (p=2.3×10-5) with rs1741177, an eQTL of NF-κB inhibitor NFKBIA. This large-scale, population-based study has identified numerous associations, with GFR and GGT being of pivotal importance, providing unbiased perspectives on dicarbonyls beyond the current state. Deutsche Forschungsgemeinschaft, Helmholtz Munich, German Centre for Cardiovascular Research (DZHK), German Federal Ministry of Research and Education (BMBF).

Robust Charging Network Planning for Metropolitan Taxi Fleets

We study the robust charging station location problem for a large-scale commercial taxi fleet. Vehicles within the fleet coordinate on charging operations but not on customer acquisition. We decide on a set of charging stations to open to ensure operational feasibility. To make this decision, we propose a novel solution method situated between the location routing problems with intraroute facilities and flow refueling location problems. Additionally, we introduce a problem variant that makes a station sizing decision. Using our exact approach, charging stations for a robust operation of citywide taxi fleets can be planned. We develop a deterministic core problem employing a cutting plane method for the strategic problem and a branch-and-price decomposition for the operational problem. We embed this problem into a robust solution framework based on adversarial sampling, which allows for planner-selectable risk tolerance. We solve instances derived from real-world data of the metropolitan area of Munich containing 1,000 vehicles and 60 potential charging station locations. Our investigation of the sensitivity of technological developments shows that increasing battery capacities shows a more favorable impact on vehicle feasibility of up to 10 percentage points compared with increasing charging speeds. Allowing for depot charging dominates both of these options. Finally, we show that allowing just 1% of operational infeasibility risk lowers infrastructure costs by 20%. Funding: This work was partially funded by the Deutsche Forschungsgemeinschaft [Project 277991500]. Supplemental Material: The online appendix is available at https://doi.org/10.1287/trsc.2022.0207 .

Exact and Heuristic Solution Techniques for Mixed-Integer Quantile Minimization Problems

We consider mixed-integer linear quantile minimization problems that yield large-scale problems that are very hard to solve for real-world instances. We motivate the study of this problem class by two important real-world problems: a maintenance planning problem for electricity networks and a quantile-based variant of the classic portfolio optimization problem. For these problems, we develop valid inequalities and present an overlapping alternating direction method. Moreover, we discuss an adaptive scenario clustering method for which we prove that it terminates after a finite number of iterations with a global optimal solution. We study the computational impact of all presented techniques and finally show that their combination leads to an overall method that can solve the maintenance planning problem on large-scale real-world instances provided by the ROADEF/EURO challenge 2020 1 and that they also lead to significant improvements when solving a quantile-version of the classic portfolio optimization problem. History: Accepted by Andrea Lodi, Area Editor for Design &amp; Analysis of Algorithms—Discrete. Funding: This work was supported by the Deutsche Forschungsgemeinschaft [CRC TRR 154], Fonds De La Recherche Scientifique [PDR T0098.18], and Bundesministerium für Bildung und Forschung. Supplemental Material: The online appendix is available at https://doi.org/10.1287/ijoc.2022.0105 .