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ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician’s choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB). Secondary endpoints included overall survival and (serious) adverse events. Upon reaching the time to NLCB, patients could be re-randomized. The primary endpoint was met after 218 randomizations. ARPIs demonstrated ~50% longer time to NLCB compared to taxanes (median, 11.1 versus 6.9 months) and the physician’s choice arm (median, 11.1 versus 7.4 months) in the biomarker-unselected or ‘all’ patient population. ARPIs demonstrated longer overall survival (median, 38.7 versus 21.7 and 21.8 months for taxanes and physician’s choice, respectively). Biomarker signature findings suggest that the largest increase in time to NLCB was observed in AR(single-nucleotide variant/genomic structural rearrangement)-negative and TP53wild-type patients and TMPRSS2–ERGfusion-positive patients, whereas no difference between ARPIs and taxanes was observed in TP53-altered patients. In summary, ARPIs outperform taxanes and physician’s choice treatment in patients with metastatic castration-resistant prostate cancer with detectable circulating tumor DNA. ClinicalTrials.gov registration: NCT03903835.

The enhanced utilization of noble metal catalysts through highly porous nanostructures is crucial to advancing the commercialization prospects of proton exchange membrane water electrolysis (PEMWE). In this study, hierarchically structured IrOx-based nanofiber catalyst materials for acidic water electrolysis are synthesized by electrospinning, a process known for its scalability and ease of operation. A calcination study at various temperatures from 400 to 800 °C is employed to find the best candidates for both electrocatalytic activity and stability. Morphology, structure, phase, and chemical composition are investigated using a scale-bridging approach by SEM, TEM, XRD, and XPS to shed light on the structure–function relationship of the thermally prepared nanofibers. Activity and stability are monitored by a scanning flow cell (SFC) coupled with an inductively coupled plasma mass spectrometer (ICP-MS). We evaluate the dissolution of all metals potentially incorporated into the final catalyst material throughout the synthesis pathway. Despite the opposite trend of performance and stability, the present study demonstrates that an optimum between these two aspects can be achieved at 600 °C, exhibiting values that are 1.4 and 2.4 times higher than those of the commercial reference material, respectively. The dissolution of metal contaminations such as Ni, Fe, and Cr remains minimal, exhibiting no correlation with the steps of the electrochemical protocol applied, thus exerting a negligible influence on the stability of the nanofibrous catalyst materials. This work demonstrates the scalability of electrospinning to produce nanofibers with enhanced catalyst utilization and their testing by SFC-ICP-MS. Moreover, it illustrates the influence of calcination temperature on the structure and chemical composition of the nanofibers, resulting in outstanding electrocatalytic performance and stability compared to commercial catalyst materials for PEMWE.

IMPORTANCE: Cardiovascular disease (CVD) is increased in people with HIV (PWH) and is characterized by premature noncalcified coronary plaque. In the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), pitavastatin reduced major adverse cardiovascular events (MACE) by 35% over a median of 5.1 years. OBJECTIVE: To investigate the effects of pitavastatin on noncalcified coronary artery plaque by coronary computed tomography angiography (CTA) and on inflammatory biomarkers as potential mechanisms for MACE prevention. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled randomized clinical trial enrolled participants from April 2015 to February 2018 at 31 US clinical research sites.PWH without known CVD who were taking antiretroviral therapy and had low to moderate 10-year CVD risk were included. Data were analyzed from April to November 2023. INTERVENTION: Oral pitavastatin calcium, 4 mg per day. MAIN OUTCOMES AND MEASURES: Coronary CTA and inflammatory biomarkers at baseline and 24 months. The primary outcomes were change in noncalcified coronary plaque volume and progression of noncalcified plaque. RESULTS: Of 804 enrolled persons, 774 had at least 1 evaluable CTA. Plaque changes were assessed in 611 who completed both CT scans. Of 611 analyzed participants, 513 (84.0%) were male, the mean (SD) age was 51 (6) years, and the median (IQR) 10-year CVD risk was 4.5% (2.6-7.0). A total of 302 were included in the pitavastatin arm and 309 in the placebo arm. The mean noncalcified plaque volume decreased with pitavastatin compared with placebo (mean [SD] change, −1.7 [25.2] mm3 vs 2.6 [27.1] mm3; baseline adjusted difference, −4.3 mm3; 95% CI, −8.6 to −0.1; P = .04; 7% [95% CI, 1-12] greater reduction relative to placebo). A larger effect size was seen among the subgroup with plaque at baseline (−8.8 mm3 [95% CI, −17.9 to 0.4]). Progression of noncalcified plaque was 33% less likely with pitavastatin compared with placebo (relative risk, 0.67; 95% CI, 0.52-0.88; P = .003). Compared with placebo, the mean low-density lipoprotein cholesterol decreased with pitavastatin (mean change: pitavastatin, −28.5 mg/dL; 95% CI, −31.9 to −25.1; placebo, −0.8; 95% CI, −3.8 to 2.2). The pitavastatin arm had a reduction in both oxidized low-density lipoprotein (−29% [95% CI, −32 to −26] vs −13% [95% CI, −17 to −9]; P < .001) and lipoprotein-associated phospholipase A2 (−7% [95% CI, −11 to −4] vs 14% [95% CI, 10-18]; P < .001) compared with placebo at 24 months. CONCLUSIONS AND RELEVANCE: In PWH at low to moderate CVD risk, 24 months of pitavastatin reduced noncalcified plaque volume and progression as well as markers of lipid oxidation and arterial inflammation. These changes may contribute to the observed MACE reduction in REPRIEVE. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02344290

Modification of electrocatalysts with ionic liquids (ILs) allows us to control the activity and selectivity on the one hand but also directly affects the stability of the electrode. In this work, we studied the interaction of the IL 1-ethyl-3-methylimidazolium dicyanamide [C2C1Im][DCA] with a Au(111) surface in an aqueous electrolyte (phosphate buffer, pH 7) and the impact of the IL on the electrochemical stability of the surface. We combined complementary electrochemical in situ methods, namely, electrochemical infrared reflection absorption spectroscopy (EC-IRRAS), cyclic voltammetry (CV), electrochemical scanning tunneling microscopy (EC-STM), and online inductively coupled plasma mass spectrometry. We observe the potential-dependent and reversible adsorption–desorption of ionic species on the Au(111) surface in the potential window between 0.1 and 1.1 VRHE. We identified two types of adsorbed [DCA]−species, showing different adsorption kinetics. Already at low concentrations, the IL (10 mM) enhances the dissolution during oxidation and reduction cycles by a factor of more than 40. We observe a suppressed redeposition of dissolved Au-ions in the presence of the IL due to the formation of gold complexes with the [DCA]−anions. Our result provides molecular insights into the interplay between ionic liquid–surface interactions and surface stability.

Purpose: Intimate partner violence and abuse (IPVA) is a major public health issue with long-term negative impacts on abused adults and affected children. Addressing this complex problem requires a multi-agency response, but barriers to effective joint working remain. This review aimed to understand the factors that influence multi-agency response to families who experience IPVA and to their children. Method: We undertook a qualitative systematic review of international literature via five electronic databases and supplemented the review by citation searches, online searches of grey literature, and hand searches of relevant journals. We analyzed data thematically. Results: The 31 identified papers reported findings from 29 unique studies undertaken in six countries and drew on data from 1049 professionals across health care, social care, the police, courts, schools and voluntary organisations. The main factors influencing service provider response to IPVA were siloed approaches to IPVA, particularly the separation between adult and childrens services. This influenced assessment and response to risk. Risk was also a consideration when child-protection staff were expected to work with perpetrators in ‘family settings’, even in lower-risk cases. Multi-agency working facilitated information sharing between agencies, an understanding of each other’s remit, and building trust. Conclusion: Multi-agency collaboration needs to be supported by clear policies of interaction between agencies. Providers of child protection services, health, mental health, housing police and probation need to be supported by specialist training in IPVA, not only in high-risk cases, but also to relieve pressure on an already overstretched workforce.

Anonymous credential systems allow users to obtain a credential on multiple attributes from an organization and then present it to verifiers in a way that no information beyond what attributes are required to be shown is revealed. Moreover, multiple uses of the credential cannot be linked. Thus they represent an attractive tool to realize fine-grained privacy-friendly authentication and access control. In order to avoid a single point of trust and failure, decentralized AC systems have been proposed. They eliminate the need for a trusted credential issuer, e.g., by relying on a set of credential issuers that issue credentials in a threshold manner (e.g., $t$t out of $n$nf). In this article, we present a novel AC system with such a threshold issuance that additionally provides credential delegation. It represents the first decentralized and delegatable AC system. We provide a rigorous formal framework for such threshold delegatable anonymous credentials ($\mathsf {TDAC}$TDAC’s). Our concrete approach departs from previous delegatable ACs and is inspired by the concept of functional credentials. More precisely, we propose a threshold delegatable subset predicate encryption ($\mathsf {TDSPE}$TDSPE) scheme and use $\mathsf {TDSPE}$TDSPE to construct a $\mathsf {TDAC}$TDAC scheme and present a comparison with previous work and performance benchmarks based on a prototype implementation.

Graphical Abstract

The present study examines the nexus of religiosity and two career-success elements: positive impact and financial success. The cross-sectional analysis from 985 individuals of various religious backgrounds in Indonesia reveals that collectively religiosity positively relates to the importance of both positive impacts and financial success. Positive impact importance also positively relates to financial success importance, and it partially mediates the relationship between religiosity and financial success importance. The partial mediation indicates that when religious individuals aim for financial success, they will use their financial resources for their own religious fulfillment and for others. This remark illustrates “to be rich but not only for me” phrase in the title. In addition to the combined results of four major religions (Islam, Christianity—divided into Protestantism and Catholicism—Hinduism, and Buddhism), we also explore each religion separately within this study.

The dissolution of cathode active material (CAM) results in performance degradation and safety issues and is, thus, a major issue regarding battery aging. While dissolution data have been reported for different cathode compositions after extended cycling, information on potential-dependent transition metal (TM) dissolution for individual charge–discharge cycles is still scarce. In this work, we tackle this subject using an electrochemical flow cell coupled to an inductively coupled plasma mass spectrometry (EFC-ICP-MS) setup presented in our previous publications. By employing radio frequency magnetron-sputtered thin-film LiCoO2(tf-LCO) cathodes, we obtain time- and potential-resolved dissolution profiles for an accelerated cycling protocol. These results are compared to operando dissolution data of commercial composite cathode tapes (c-LCO). We find uniform dissolution throughout three cycles for tf-LCO, but relative dissolution is higher compared to that of the composite samples by a factor of about 50. During the second cycle, the dissolution characteristics of the c-LCO change and strongly resemble the tf-LCO pattern henceforth. Both types of LCO cathodes experience the largest dissolution during the second cycle, which can be correlated to the irreversible phase transitions of the materials during cycling. Our work represents the first direct investigation of mechanistic changes in transition metal dissolution from lithium-ion battery cathodes and highlights the importance of morphology and cathodic interface properties for dissolution phenomena and battery performance.

Setbacks at career transitions can have an enduring impact on how people enact their subsequent careers. Drawing on an enacted sensemaking perspective, we examine the micro-mechanisms of career choice and navigation with and without a setback experience. Empirically, we conducted 42 interviews with Austrian apprentices and compared their career transitions and subsequent navigation through abductive analysis. We found that the apprentices overcoming setbacks at the outset of their careers engaged in more deliberate sensemaking, leading them to aspirations and expectations associated with thriving and career growth. Conceptually, we present a model of enacted sensemaking during career transitions, showing how the expectations and aspirations people enact lead to different kinds of possibilities within their career space. Contributing to career setback and sensemaking literature, we further show how deliberate sensemaking continues to shape individuals’ awareness of possibility beyond the setback experience.

AbstractOptimizing research on the developmental origins of health and disease (DOHaD) involves implementing initiatives maximizing the use of the available cohort study data; achieving sufficient statistical power to support subgroup analysis; and using participant data presenting adequate follow-up and exposure heterogeneity. It also involves being able to undertake comparison, cross-validation, or replication across data sets. To answer these requirements, cohort study data need to be findable, accessible, interoperable, and reusable (FAIR), and more particularly, it often needs to be harmonized. Harmonization is required to achieve or improve comparability of the putatively equivalent measures collected by different studies on different individuals. Although the characteristics of the research initiatives generating and using harmonized data vary extensively, all are confronted by similar issues. Having to collate, understand, process, host, and co-analyze data from individual cohort studies is particularly challenging. The scientific success and timely management of projects can be facilitated by an ensemble of factors. The current document provides an overview of the ‘life course’ of research projects requiring harmonization of existing data and highlights key elements to be considered from the inception to the end of the project.

Anforderungen an Datenschutz und Informationssicherheit, aber auch an Datenaktualität und Vereinfachung bewirken einen kontinuierlichen Trend hin zu plattformübergreifenden ID-Systemen für die digitale Welt. Das sind typischerweise föderierte Single-Sign-On-Lösungen großer internationaler Konzerne wie Apple, Facebook und Google. Dieser Beitrag beleuchtet die Frage, wie ein dezentrales, offenes, globales Ökosystem nach dem Vorbild des Single-Sign-On für die digitale, biometrische Identifikation in der physischen Welt aussehen könnte. Im Vordergrund steht dabei die implizite Interaktion mit vorhandener Sensorik, mit der Vision, dass Individuen in der Zukunft weder Plastikkarten noch mobile Ausweise am Smartphone mit sich führen müssen, sondern ihre Berechtigung für die Nutzung von Diensten rein anhand ihrer biometrischen Merkmale nachweisen können. Während diese Vision bereits jetzt problemlos durch Systeme mit einer zentralisierten Datenbank mit umfangreichen biometrischen Daten aller Bürger*innen möglich ist, wäre ein Ansatz mit selbstverwalteten, dezentralen digitalen Identitäten erstrebenswert, bei dem die Nutzer*in in den Mittelpunkt der Kontrolle über ihre eigene digitale Identität gestellt wird und die eigene digitale Identität an beliebigen Orten hosten kann. Anhand einer Analyse des Zielkonflikts zwischen umfangreichem Privatsphäreschutz und Praktikabilität, und eines Vergleichs der Abwägung dieser Ziele mit bestehenden Ansätzen für digitale Identitäten wird ein Konzept für ein dezentrales, offenes, globales Ökosystem zur privaten, digitalen Authentifizierung in der physischen Welt abgeleitet.

The present study deals with the development of dexamethasone (DM)-loaded implants using ester end-capped Resomer RG 502 poly(lactic acid-co-glycolic acid) (PLGA) (502), acid end-capped Resomer RG 502H PLGA (502H), and a 502H:502 mixture (3:1) via hot melt extrusion (HME). The prepared intravitreal implants (20 and 40% DM loaded in each PLGA) were thoroughly investigated to determine the effect of different end-capped PLGA and drug loading on the long-term release profile of DM. The implants were characterized for solid-state active pharmaceutical ingredient (APIs) using DSC and SWAXS, water uptake during stability study, the crystal size of API in the implant matrix using hot-stage polarized light microscopy, and in vitro release profile. The kinetics of PLGA release was thoroughly investigated using quantitative 1H NMR spectroscopy. The polymorph of DM crystal was found to remain unchanged after the extrusion and stability study. However, around 3 times reduction in API particle size was observed after the HME process. The morphology and content uniformity of the RT-stored samples were found to be comparable to the initial implant samples. Interestingly, the samples (mainly 502H) stored at 40 °C and 75% RH for 30 d demonstrated marked deformation and a change in content uniformity. The rate of DM release was higher in the case of 502H samples with a higher drug loading (40% w/w). Furthermore, a simple digital in vitro DM release profile derived for the formulation containing a 3:1 ratio of 502H and 502 was comparable with the experimental release profile of the respective polymer mixture formulation. The temporal development of pores and/or voids in the course of drug dissolution, evaluated using μCT, was found to be a precursor for the PLGA release. Overall, the release profile of DM was found to be dependent on the PLGA type (independent of subtle changes in the formulation mass and diameter). However, the extent of release was found to be dependent on DM loading. Thus, the present investigation led to a thorough understanding of the physicochemical properties of different end-capped PLGAs and the underlying formulation microstructure on the release profile of a crystalline water-insoluble drug, DM, from the PLGA-based implant.

The purpose of this article is to analyse the influence of three host country-specific variables (political risk, cultural distance, level of economic development) on International Joint Venture (IJV) survival in the Middle East and North Africa (MENA). The authors compiled a database of 124 IJVs established in MENA countries. The findings demonstrate that cultural distance and the level of economic development have an impact on IJV survival whereas political risk does not seem to affect IJV sustainability in this region. The study contributes to the debate about the role of host country factors for IJV survival, indicating that these factors may vary across geographic regions.

The near-surface regions of rail wheels experience a complex thermo-mechanical loading, which varies along the location of the tread and causes severe changes to the microstructure. Occasionally, brittle white etching layers (WEL) are formed, representing a high risk of wheel damage. Therefore, we studied the depth-evolution of the surface-near microstructure along different regions of the tread of a wheel being ~ 200,000 km in service. The microstructural variations point toward a higher thermal loading history in the middle of the tread and predominant mechanical loading in the neighboring regions, where a severe plastic deformed microstructure with rolling contact fatigue cracks is present. Varieties of WEL-like microstructures were investigated, the presented analysis contributes to the knowledge of their microstructural characteristics and outpoints these regions in terms of potential crack initiation sites on railway wheels.

Cooling lubricants in machining perform important tasks, from cooling and lubrication of the friction partners in contact to the removal of the separated chips. An essential, determining and largely unresolved question in relation to cooling lubricants in machining is to what extent the coolant can get into the cutting zone. The aim of this paper is to address this question by using a multiscale approach to determine the penetration of the cooling lubricant gap. This is achieved by multiscale simulations by means of coupling the results of flow, structural and continuum mechanical simulations. Comparatively, the results of the simulated machining operation are compared with experimental orthogonal cutting tests of AISI 4140.

Im Psychodrama werden Körper, Geist und Szene als Einheit verstanden, wobei der körperlichen Dimension in letzter Zeit zunehmende Beachtung geschenkt wird. Die Erkenntnisse der modernen Embodimentforschung, der Neuropsychologie und der Psychophysiologie zeigen, wie körperliche Phänomene unser Erleben und Verhalten beeinflussen und ermöglichen ein umfassenderes Verständnis von Therapieprozessen sowie neue Anwendungsmöglichkeiten.

Fingerprinting smartphones based on acoustic characteristics of their loudspeaker may have a number of applications in device-to-device authentication as well as in forensic investigations. In this work we propose an efficient fingerprinting methodology by using the roll-off characteristics of the device speaker, i.e., the transition between the low and high stopbands to the passband segment of the speaker. We extract roll-off characteristics from sweep signals, also know as chirps, that are commonly used in practice to test speaker response. This procedure appears to be more stable against variations of the volume level and allows the use of simple linear approximations, which are intuitive and easy to compute, in order to extract the fingerprint. To increase detection accuracy, on the basis of the proven performance of deep learning techniques, a convolutional and a bi-directional long short term memory neural network are further proposed and their performance demonstrated for authentication purposes. While numerous applications may be envisioned, we specifically focus on the use of speaker characteristics in relation to in-vehicle infotainment units, checking if recordings from these units can be used to fingerprint a specific phone.

An increasing number of European research projects return, or plan to return, individual genomic research results (IRR) to participants. While data access is a data subject’s right under the General Data Protection Regulation (GDPR), and many legal and ethical guidelines allow or require participants to receive personal data generated in research, the practice of returning results is not straightforward and raises several practical and ethical issues. Existing guidelines focusing on return of IRR are mostly project-specific, only discuss which results to return, or were developed outside Europe. To address this gap, we analysed existing normative documents identified online using inductive content analysis. We used this analysis to develop a checklist of steps to assist European researchers considering whether to return IRR to participants. We then sought feedback on the checklist from an interdisciplinary panel of European experts (clinicians, clinical researchers, population-based researchers, biobank managers, ethicists, lawyers and policy makers) to refine the checklist. The checklist outlines seven major components researchers should consider when determining whether, and how, to return results to adult research participants: 1) Decide which results to return; 2) Develop a plan for return of results; 3) Obtain participant informed consent; 4) Collect and analyse data; 5) Confirm results; 6) Disclose research results; 7) Follow-up and monitor. Our checklist provides a clear outline of the steps European researchers can follow to develop ethical and sustainable result return pathways within their own research projects. Further legal analysis is required to ensure this checklist complies with relevant domestic laws.