bluuebunny/crossref_metadata_2025 huggingface dataset:
4 Ethics of Pandemic Research
Authors: Smith Maxwell J.
Published: August 2024

Research conducted during infectious disease outbreaks or pandemics can be crucial to control or ameliorate their consequences, but scientists are confronted with significant ethical questions about how to conduct research in such contexts. This chapter examines foundational ethical questions and considerations undergirding the research enterprise in pandemic contexts, including whether pandemics necessitate deviations from ethical and scientific standards for research, how research priorities are and ought to be set during pandemics, the ethics of conducting research alongside pandemic response efforts, and how pandemic research ought to be governed and coordinated. Scientists may have only a brief interval to understand the disease and develop medical countermeasures, and social pressures to produce fast results may seem overwhelming. Despite these challenges, this does not justify relaxing fundamental ethical or scientific standards, although there is scope for accelerating procedural requirements. Even during a pandemic, provision of most biomedical research funding by high-resource countries can influence the directions and results of research, leading to interventions that are more applicable in resource-rich than in resource-poor countries. The World Health Organization and other institutions are trying to correct or at least reduce these discrepancies. Biomedical research and health care response to a pandemic need not be rivals for funding support. The 2014 Ebola and 2019 COVID-19 experiences have demonstrated that the two can work synergistically. Both medical care and research responses are integral to our defenses against emerging or re-emerging infectious disease. Finally, the COVID-19 pandemic has made clear the need for changes in global architecture for pandemic response. The scientific and organizational adaptations required must be guided by ethical principles, such as the need to reduce the glaring inequities between high-income and low-income settings across the world as well as within countries. Preparing for the next pandemic will require a blueprint to accelerate the organization, coordination, and conduct of critical research and development.
27 A Global Framework for Research Preparedness and Response
Authors: Lurie Nicole , Keusch Gerald T.
Published: August 2024

The world has faced many infectious disease emergencies during this century and is certain to see more in the decades ahead. Urgent research to study new pathogens and how to control and counter them is now increasingly being integrated into global response to infectious diseases to chronicle their clinical presentation, identify treatment alternatives, and develop approaches to prevention or control—and to do so with the urgency befitting a pandemic with many lives at stake. The recent Ebola outbreaks in Africa and the coronavirus disease 2019 (COVID-19) pandemic have spurred more coordination on response among global stakeholders. However, they also revealed many shortcomings and spurred movement toward a global framework providing more consistent resources, coordination, and governance. A well thought-out, realistic framework is needed not only for more effective scientific research including clinical trials, but to better account for popular perceptions of and reactions to events, and to ensure that the products of emergency research are equitably distributed among the world’s population. The key elements of the research ecosystem must be in place before a new infectious disease appears.
30.1 In Focus: Research and Medical Humanitarian NGOs
Authors: Grais Rebecca F. , Baron Emmanuel
Published: August 2024

It is a commonplace belief that medical humanitarian organizations, of which Médecins Sans Frontières (MSF), or Doctors without Borders, have a mission very different from that of research scientists investigating medical interventions against disease. While this may be so to an extent, MSF has also been a leader not only in effective humanitarian action but also in incorporating needed research into its response to infectious disease emergencies. Epicentre is a research organization within MSF that can work with MSF humanitarian staff to facilitate potentially useful research in an emergency, especially as the possibility of generating data for medical countermeasure approval during an emergency has become more realistic in recent years. Epicentre promotes research that is most useful to the disadvantaged populations it often serves, in part because it does not depend on pharmaceutical company or government funding. Moreover, Epicentre is committed to making its colleagues from developing countries full partners in research as in medical care, thus contributing to medical research capacity building—an area that often gets more lip service than investment.
31 Operational Recommendations for Streamlining Emergency Research Responses to Pandemics
Authors: Larson Gregg , Harrigan Rachel , McNay Laura A.
Published: August 2024

This chapter describes clinical research operations and some of the obstacles to accelerated research response during Ebola outbreaks since 2014 and the coronavirus disease 2019 (COVID-19) pandemic. It makes recommendations for streamlining operational requirements in order to accelerate research response without comprising ethical and scientific rigor. The Ebola outbreaks provided invaluable experience in emergency research operations in resource-poor settings for hundreds of research staff and served as a proving ground for rapid implementation of clinical research. They helped broaden acceptance of expedited clinical research as an integral part of emergency response to an infectious disease outbreak with pandemic potential. The COVID-19 outbreak offered further lessons for assessment of future vaccines, therapeutics, and diagnostics (VTDs) in time to mitigate morbidity and mortality during the course of the pandemic. Illustrative research programs include the Randomised Evaluation of COVID-19 Therapy (RECOVERY) study in the UK and the US-based Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) studies. Learning from these and other response research programs can guide swift, coherent, and flexible research response to new public health emergencies if sufficient funding is available for preparedness and response.
32.2 In Focus: Clinical Trial Insurance and Indemnification
Authors: Larson Gregg
Published: August 2024

For clinical trials to proceed, an agreement on how to meet costs from possible injuries or deaths associated with a clinical study is needed. Health risks to clinical trial participants can result from administration of investigative vaccines, pharmaceuticals, or treatments during clinical research in emergency response settings, or from other injuries that occur at trial sites. Various risk management strategies are available in the form of insurance and indemnification. International examples relate to both commercial insurance and sponsor funding of injury and death claims from the 2014–2015 West Africa Ebola pandemic. The related subject of in-country back-up medical care and medical evacuation insurance for local and international medical and research personnel is also covered.
33.1 In Practice: Ethical Review During Emergencies: The Liberian Experience
Authors: Bolay Fatorma , Sorenson Robert A.
Published: August 2024

Ethical review for human subject research is challenging during an infectious disease emergency, all the more so in a lower-income country where there has been little previous clinical research. The Ebola experience in Liberia demonstrated that it is possible to advance and empower a local ethical review board even while launching an urgent, ambitious research program. The strengthened institution(s) can serve the country and biomedical research well in the follow-through and in subsequent emergencies.
33.2 In Practice: Independent Monitoring of Emergency Response Clinical Trials
Authors: Vogel Susan , Pierson Jerome F.
Published: August 2024

Independent monitoring of clinical trial studies safeguards the rights, safety, and welfare of patients who have agreed to participate in clinical trials of experimental medical countermeasures. Monitoring is especially important and may be more difficult to implement, in countries with limited medical care and medical research infrastructure and personnel, a shortfall often exacerbated by poverty, poor transport and communications, and uncertain security. The randomized controlled trial of Ebola virus disease therapeutics implemented in the northeastern Democratic Republic of the Congo (DRC) during the 2018–2020 Ebola outbreak there demonstrates that it is possible to monitor the adequacy of trial sites and resources, qualifications and proper training of investigators, protocol implementation, and study task assignments even during an emerging outbreak in an insecure environment. Independent monitoring buttresses continuous quality improvement by and for all research stakeholders. It requires flexibility and efficient communications and can help build local capacity for research when that is a goal of the program.
34 Information and Communications Technology to Support Research in Low-Resource Settings
Authors: Galcik Mike , Parrish David
Published: August 2024

Any emergency research response requires continual communication and collaboration between people, organizations, and systems to meet dynamically evolving circumstances. This chapter will lay out the essentials for providing communications and information and communications technology (ICT) to a research response in a low-resource area. ICT needs are similar everywhere, but procurement, configuration, and operations are especially demanding tasks where ICT infrastructure is lacking and skilled personnel scarce. The key questions are how, when, and what technologies and tools to introduce, and how to balance overhead and running costs with operational efficiencies. Changes in program activities and in the roster of partner organizations can complicate matters in what may be a high-mortality outbreak with a steep learning curve. Response activities will at first depend largely on existing local infrastructure, supplemented by equipment the incoming team can bring. The team will also initially depend on the operational infrastructure of its primary local partner, which will influence the research program’s communications and decision-making style. As the response becomes more established, and centralized ICT support solidifies, the ICT infrastructure must be adapted as appropriate to the evolving needs of the collective research organization.
39 Cold Chain and Electrical Power for Emergency Research Response
Authors: Littlefield Daniel J.
Published: August 2024

Many pharmaceutical products, and particularly investigational products, must be kept at specified temperatures during manufacturing, shipment, and storage before they are administered to patients or clinical trial participants. That is simply stated but not simply accomplished, especially when the products must be shipped long distances and arrive unharmed at remote clinical trial sites where there is little infrastructure or experience with such requirements. We describe many considerations involved in ensuring that this essential element of clinical trials and patient treatment can be met as required where capacity is wanting and review some principles and practices of physics and electrical supply to help research program planners and logisticians carry out their mission successfully.
4.2 In Practice: Research Ethics Committee Review in Public Health Emergencies
Authors: Koneti Rao V.
Published: August 2024

In order to conduct clinical research early in an epidemic of a new or poorly understood infectious disease, preparatory requirements include scientific deliberations, essential health care infrastructure, and assessment of readiness for rapid research response, including expedited ethical review. Essential ethical safeguards must be met as for all clinical trials, but review of ethics should not become an impediment and delay clinical trials in an emergency. As with all research involving human participants, emergency response research protocols must be approved prospectively by a research ethics committee (REC) to ensure that study participant safety and welfare are protected. Upholding ethical and scientific standards in medical research cannot be left to the discretion of individual investigators, as was understood at least as far back as the Nuremburg Medical Trial of 1947. The structure of today’s medical research review mechanisms evolved gradually over the decades after World War II, culminating in a deliberative process that is effective at preventing most abuses. In more recent years, there have been concerns that established procedures for funding, reviewing, and implementing clinical research can be too slow and tardy in an outbreak one hopes to contain expeditiously, especially an outbreak of a high-mortality disease or a pandemic with widespread mortality (Ebola and coronavirus disease 2019 [COVID-19]). Since outbreaks are likely to arise in developing countries with little capacity for rapid research response, it is especially important to increase their review and oversight capacity along with their broader research capacity to facilitate rigorous clinical research studies that can provide global benefits.
40 Selecting and Opening a Clinical Research Site in a Low-Resource Setting
Authors: Mbaya Olivier Tshiani , Njoh Wissedi , Barrett Kevin , Smolskis Mary , Miranda Alejandra , Gettinger Nikki
Published: August 2024

Conducting clinical research in a public health emergency response not only involves the collective efforts of the scientific community to establish relevant protocols designed to provide answers to the most pressing questions regarding the infectious disease threat, but also requires an infrastructure where research can take place. This chapter identifies factors to consider regarding the who, what, where, when, and how of establishing a clinical research site in a setting where infrastructure may be lacking and few or no clinical trials have been conducted in the past. The chapter also provides a roadmap that describes site selection criteria, checklists for site activation, and considerations for flowcharts to ensure that protocols can be implemented at the site. The chapter concludes with the important reminder that, while every emergency is different from the previous one and lessons learned may not be directly applicable, the experience provides a framework within which to creatively address the next challenge.
6 Meeting Regulatory Criteria and Seeking Licensure: Medicines Development Before and During Public Health Emergencies
Authors: Cavaleri Marco , Gruber Marion , Gaspar Rogerio , Darko Mimi
Published: August 2024

The Ebola outbreak of 2014 and the COVID-19 pandemic have underscored the importance of expedited preclinical and clinical product development to assure access to life-saving therapies during public health emergencies. Advances in manufacturing methods and the availability of platform technologies provide opportunities for streamlined product development by leveraging data derived from other products based on the same platform. Use of adaptive and seamless clinical trial designs, especially during the COVID-19 pandemic, led to more rapid progress through phases of clinical development and resulted in earlier availability of therapeutics and vaccines to billions of people.

Regulatory agencies played a critical role in this process as they were tasked with an expedited assessment of preclinical, clinical, and manufacturing protocols and data to ensure product safety and effectiveness. At the same time, regulators had to balance benefits and risks in a rapidly evolving scenario, thus emphasizing the importance of transparent communication. Close collaboration between the global regulatory community, manufacturers, the scientific community, and global public health authorities was essential in this process. Lessons learned from these public health emergencies demonstrate that use of novel preclinical and clinical testing strategies, continued improvements in efficiency of product assessment, and further strengthening of global regulatory collaboration, using more convergence in standards and reliance in procedural aspects, are necessary to ensure an effective and timely response to future pandemics.
7 Research, Sample, and Data Sharing During Outbreaks, Pandemics, and Beyond
Authors: Terry Robert Fraser , Littler Katherine
Published: August 2024

The agreement at the time the human genome was first sequenced to release the data to the public domain set an example that encouraged other scientists doing other types of research to share their data freely to empower scientific discovery and minimize the burden of disease. There are still many barriers to data sharing, including how to ensure patient privacy, manage intellectual property, and reduce inequity in data reuse, with a one-way flow of raw data from less developed countries to wealthy countries and corporations that produce medical countermeasures that may first go to the highest bidder. In an era of increasing infectious disease outbreaks, ensuring the efficient exchange of research data is essential to expeditious response to emerging pathogens, especially in the urgent case of a potential or actual pandemic. This chapter will review principles of open access to research highlighted by the coronavirus disease 2019 (COVID-19) pandemic and current challenges to establishment of a global data-sharing system meeting the needs and interests of all the stakeholders, that is, every living human being.
Introduction: Germany and Korea as Partners in International Development and Green Transitions
Authors: Klingebiel Stephan , Kalinowski Thomas , Keijzer Niels
Published: August 2024

This chapter introduces the book and its three parts, which explore the alignment of global sustainable development priorities between Germany and the Republic of Korea. Notably, both nations share a common commitment to development policy and international climate action, an alignment that holds immense potential for enhanced cooperation in today’s evolving global landscape. Germany's historical role as a founding member of the international development cooperation system juxtaposes with Korea's more recent entry into the Organisation for Economic Co-operation and Development (OECD) and its Development Assistance Committee (DAC) in 2010. Korea has transformed from a significant development assistance recipient to an active provider, a transition mirrored in its engagement in international climate finance.
Germany and Korea: Comparing Systems, Policies and Cooperation Patterns
Authors: Keijzer Niels , Klingebiel Stephan , Oh Min Jee
Published: August 2024

Although geographically distant, there is considerable convergence in the development policy priorities of Germany and the Republic of Korea (hereafter referred to as Korea)—and indeed scope for cooperation between them. Whereas Germany was a founding member of the Organisation for Economic Co-operation and Development (OECD) and its Development Assistance Committee (DAC), Korea joined the DAC more recently in 2010 as an important former recipient as well as a current provider of development cooperation. Both countries maintain a centralized political responsibility for development policy—in Germany’s case with a dedicated ministry, whereas in Korea, two ministries share the responsibility for development cooperation. With various line ministries and organizations with implementing mandates involved in both countries’ development cooperation systems, fragmentation is a challenge and raises questions about issues that include results reporting, the introduction and use of standard indicators, independent evaluations, consistent official development assistance (ODA) reporting and ensuring effective cooperation.
Conclusion and Implications for the Russia-Ukraine War and Other Conflicts in Ukraine
Authors: Katchanovski Ivan
Published: August 2024

The final chapter summaries the main findings of the comprehensive evidence-based and theoretically based analysis of the Maidan massacre in Ukraine. The analysis of various evidence, such as synchronized videos, audio recordings, testimonies of the absolute majority of wounded Maidan protesters, and some 500 other witnesses, shows beyond any reasonable doubt that the Maidan protesters and the police were massacred by Maidan snipers located in Maidan-controlled buildings in a rationally organized operation with involvement of far-right and oligarchic elements of the Maidan opposition.
Exit, Voice, and Networks. Die Digitalisierung als Katalysator für Widerspruch und Netzwerkbildung in Organisationen
Authors: Baumgart Lene
Published: August 2024

Die Verfügbarmachung digitaler Plattformen in Organisationen beeinflusst, wie deren Mitglieder miteinander kommunizieren und sich vernetzen. Entlang eines empirischen Beispiels wird in dem Beitrag gezeigt, dass Kommunikationsplattformen nicht nur genutzt werden, um die Arbeit in der Organisation zu strukturieren, sondern auch, um Unzufriedenheit und Widerspruch zu äußern. Statt Unterstützung von institutionalisierten Interessenvertretungen einzuholen, greifen Organisationsmitglieder auf digitale Plattformen zurück, vernetzen sich über diese informal und gründen alternative Repräsentationsgruppen. Damit wird die Digitalisierung zum Katalysator für Widerspruchskommunikation und für eine Vernetzung jenseits der Formalstruktur. Für Organisationen stellen solche Widerspruchsnetzwerke eine potenzielle Gefahr dar. Sie reagieren daher mit Kooptation, das heißt, sie integrieren die Netzwerke in ihre Formalstruktur, unterstützen sie so bei deren Arbeit und wenden das Problem produktiv für die beteiligten Akteure.
Algorithmisches Management jenseits der Plattformökonomie. Digitale Assistenzsysteme in Industrie und Logistik
Authors: de Paiva Lareiro Patricia
Published: August 2024

Digitale Technologien durchziehen immer stärker unseren privaten und beruflichen Alltag. Im beruflichen Alltag können sie Arbeits- und Lernprozesse unterstützen und strukturieren, der Qualitätskontrolle dienen oder zur Überwachung und Kontrolle von Arbeitsprozessen eingesetzt werden. Unter dem Begriff des algorithmischen Managements wurde der Einsatz digitaler Technologien zur Ausübung und Ausweitung von Kontrolle im Arbeitsprozess in den Bereichen der plattformbasierten Gig- und Crowdwork vielfach kritisch diskutiert. Dieser Beitrag befasst sich mit der Frage, wie sich algorithmisches Management jenseits der Plattformökonomie gestaltet. Anhand einer Metaanalyse aktueller Forschungsergebnisse zum Einsatz digitaler Assistenzsysteme in Industrie und Logistik wird dargestellt, welche Bedeutung algorithmisches Management in stärker regulierten innerbetrieblichen Kontexten im Rahmen der Kontrolle und Steuerung von Arbeit einnimmt.
Die digitale Transformation von Arbeit – vermessen und verstehen. Ein interdisziplinärer und methodischer Dialog zwischen Wirtschaftswissenschaft und Arbeitssoziologie
Authors: Bachmann Ronald , Pfeiffer Sabine
Published: August 2024

Im Beitrag werden quantitative wirtschaftswissenschaftliche mit überwiegend qualitativen, arbeitssoziologischen Studien kontrastiert, die sich mit verschiedenen Aspekten der Auswirkungen der digitalen Transformation auf Arbeit befassen. Gegenübergestellt werden zunächst die je einzeldisziplinären Ansätze und zentrale Ergebnisse zu Robotik und zum Routinegehalt von Tätigkeiten. Dadurch treten die jeweils unterschiedlichen Sichtweisen, Methodiken und Resultate hervor und geben bereits einen ersten Einblick in die Erkenntnispotenziale und -grenzen der jeweiligen Ansätze. Abschließend wird diskutiert, wo methodisch und erkenntnistheoretisch Synergien zu heben sein werden und welche konkreten Ansatzpunkte sich für eine systematisch-interdisziplinäre und konsequente Mixed-Methods-Forschung ergeben. Ergänzt werden diese um konkrete Vorschläge zur Erfassung der digitalen Transformation der Arbeitswelten.
Computer in der Fabrik. Die digitale Transformation in der Produktionstechnik, 1950 bis 1990
Authors: Thorade Nora , Erdogan Julia Gül
Published: August 2024

Der Beitrag untersucht die Entwicklung der Mikroelektronik und ihre Auswirkungen auf die industrielle Arbeitswelt der Fabrik. Er zeigt, dass die Digitalisierung graduell erfolgte, zu Teildigitalisierungen und -automatisierungen führte und historische Wurzeln in der Standardisierung von Arbeitsprozessen hatte. Dabei verfolgt der Beitrag die Entwicklung von der Einführung der NC-Steuerung in den 1950er Jahren bis zum Einzug der Mikroelektronik in den 1970er Jahren. Deutlich zeigt sich, die Ambivalenz von Alt und Neu in der Techniknutzung. Denn auch die Digitalisierung der Arbeitswelt war von Aushandlungsprozessen zwischen alter und neuer Technik sowie menschlicher Einflussnahme geprägt und knüpfte an bestehende Leitbilder an. Der technische Wandel vollzog sich also nicht isoliert, sondern wurde von langen Linien des Suchens, Ausprobierens und der Beständigkeit etablierter Arbeitsprozesse gerahmt.
Analysing the Digital Traces of Collaborative Work in Large-Scale Enterprise Collaboration Systems
Authors: Williams Susan P. , Schubert Petra
Published: August 2024

In this chapter, we present an overview of our work to investigate transformations to work processes and work practices arising from the appropriation and use of collaboration technologies to support distributed work in organisations. We begin with an overview of the emerging collaboration technology landscape and present the findings of an empirical study to examine the portfolios of collaboration software being used to implement enterprise collaboration platforms (ECP) in organisations. We explain how the ECP enables organisational workgroups to form digital workspaces to support different types of collaborative work. We identify several research challenges relating to the investigation of such heterogeneous technological infrastructures and address them through the development of novel methods and tools to i) enable the capture and harmonisation of trace data from ECP, and ii) use the trace data to analyse transformations to collaborative work and work practices.
Mutations in starch BRANCHING ENZYME 2a suppress the traits caused by the loss of ISOAMYLASE1 in barley
Authors: Matsushima Ryo , Hisano Hiroshi , Kim June-Sik , McNelly Rose , Oitome Naoko F. , Seung David , Fujita Naoko , Sato Kazuhiro
Published: August 2024

Key message

The hvbe2a mutations restore the starch-deficient phenotype caused by the hvisa1 and hvflo6 mutations in barley endosperm.

The genetic interactions among starch biosynthesis genes can be exploited to alter starch properties, but they remain poorly understood due to the various combinations of mutations to be tested. Here, we isolated two novel barley mutants defective in starch BRANCHING ENZYME 2a (hvbe2a-1 and hvbe2a-2) based on the starch granule (SG) morphology. Both hvbe2a mutants showed elongated SGs in the endosperm and increased resistant starch content. hvbe2a-1 had a base change in HvBE2a gene, substituting the amino acid essential for its enzyme activity, while hvbe2a-2 is completely missing HvBE2a due to a chromosomal deletion. Further genetic crosses with barley isoamylase1 mutants (hvisa1) revealed that both hvbe2a mutations could suppress defects in endosperm caused by hvisa1, such as reduction in starch, increase in phytoglycogen, and changes in the glucan chain length distribution. Remarkably, hvbe2a mutations also transformed the endosperm SG morphology from the compound SG caused by hvisa1 to bimodal simple SGs, resembling that of wild-type barley. The suppressive impact was in competition with floury endosperm 6 mutation (hvflo6), which could enhance the phenotype of hvisa1 in the endosperm. In contrast, the compound SG formation induced by the hvflo6 hvisa1 mutation in pollen was not suppressed by hvbe2a mutations. Our findings provide new insights into genetic interactions in the starch biosynthetic pathway, demonstrating how specific genetic alterations can influence starch properties and SG morphology, with potential applications in cereal breeding for desired starch properties.
Metformin and small for gestational age babies: findings of a randomised placebo-controlled clinical trial of metformin in gestational diabetes (EMERGE)
Authors: Dunne Fidelma , Newman Christine , Alvarez-Iglesias Alberto , O’Shea Paula , Devane Declan , Gillespie Paddy , Egan Aoife , O’Donnell Martin , Smyth Andrew
Published: August 2024

Aims/hypothesis

Gestational diabetes mellitus (GDM) is associated with adverse perinatal outcomes because of suboptimal glucose management and glucose control and excessive weight gain. Metformin can offset these factors but is associated with small for gestational age (SGA) infants. We sought to identify risk factors for SGA infants, including the effect of metformin exposure on SGA status.

Methods

In this prespecified secondary analysis of the EMERGE trial, which evaluated the effectiveness of metformin vs placebo in treating GDM and found reduced gestational weight gain and longer time to insulin initiation with metformin use, we included women with a live-born infant and known infant birthweight and gestational age at delivery. We compared the numbers of SGA infants in both groups and explored baseline predictive factors to help identify those at highest risk of delivering an SGA infant.

Results

Baseline maternal characteristics were similar between SGA and non-SGA pregnancies. On multivariable-adjusted regression, no baseline maternal variables were associated with SGA status. Mothers of SGA infants were more likely to develop pre-eclampsia or gestational hypertension (18.2% vs 2.0%, p=0.001; 22.7% vs 5.4%, p=0.005, respectively); after multivariable adjustment, pre-eclampsia was positively associated with SGA status). Among SGA pregnancies, important perinatal outcomes including preterm birth, Caesarean delivery and neonatal care unit admission did not differ between the metformin and placebo groups (20.0% vs 14.3%, p=1.00; 50.0% vs 28.6%, p=0.25; 13.3% vs 42.9%, p=0.27, respectively).

Conclusions/interpretation

Pre-eclampsia was strongly associated with SGA infants. Metformin-exposed SGA infants did not display a more severe SGA phenotype than infants treated with placebo.

Trial registration

Clinical Trials.gov NCT02980276; EudraCT number: 2016-001644-19

Graphical Abstract
Cold case: COVID-19-triggered type 1 cryoglobulinemia
Authors: van Gils L.A.J. , Corsten M.F. , Koelman C.A. , Bosma R.J. , Fijnheer R. , Mulder A.H.L. , Regelink J.C.
Published: August 2024

A 42-year-old male was referred to the internal medicine department because of renal failure and persistent malaise after a recent SARS-CoV-2 infection. Blood results showed anemia and severe renal insufficiency (hemoglobin of 10.3 g/dL and a creatinine of 2.19 mg/dL). Additional tests revealed a type I cryoglobulinemia with a cryoprecipitate composed of dual IgM (kappa and lambda). Further investigations on the cryoprecipitate revealed that the immunoglobulins were directed against SARS-CoV-2 antigens. In the meanwhile, our patient noticed improvement of his symptoms accompanied by resolution of laboratory abnormalities. Three months later, the cryoglobulin could no longer be detected.

Type 1 cryoglobulinemia is usually associated with lymphoproliferative disorders and is characterized by various symptoms caused by cryoprecipitates occluding small blood vessels. This is, to our knowledge, the first case of type I cryoglobulinemia with proven precipitation of SARS-CoV-19 antibodies. COVID-19 induced cryoglobulinemia appears to have a mild disease course and to be self-limiting upon viral clearance.
Simultaneous measurement of the distributed longitudinal strain and velocity field for a cantilevered cylinder exposed to turbulent cross flow
Authors: G. de Oliveira Francisco J. , Khodaei Zahra Sharif , Buxton Oliver R. H.
Published: August 2024

The structural response of a cantilevered cylinder under free-stream conditions both with low and high turbulence intensity generated by turbulence-generating grids is analysed with concurrent measurements of the velocity field and the distributed strain. The thin-walled cylinder, with a diameter (D) of 50 mm, is mounted in a water flume as a cantilevered beam supported at one end, with 95% of its body submerged and exposed to cross flow yielding a Reynolds number of Re = 25000. We employ a novel combination of simultaneous particle image velocimetry and distributed strain measurements using Rayleigh backscattering fibre optic sensors. These sensors are embedded onto the surface of the cylinder to measure the experienced strain ($$\varepsilon $$
ε
) of the structure along its spanwise direction, covering both the windward and leeward faces of the cylinder. The sensors fine spatial resolution allows us to discern the influence of the flow on the structural response of the cylinder in two distinct regions of the structure: upstream and downstream of the mean separation location. This differentiation allows us to isolate the local effects introduced by the free-stream conditions on the loading events over the body from the global force generated by the vortex shedding and other coherent motions present within the flow. Distinguishing between these direct and indirect effects helps determine which is more relevant for fatigue-life cycle analysis. The cross power spectral density between the fluctuating velocity field and the strain reveals that the load is dominated by the vortex shedding, and this relationship is intensified with the introduction of free-stream turbulence. It also helps to discern the different dynamics imposed by the two free-stream turbulence conditions.
Pressure drop measurements over anisotropic porous substrates in channel flow
Authors: Vijay Shilpa , Luhar Mitul
Published: August 2024

Previous theoretical and simulation results indicate that anisotropic porous materials have the potential to reduce turbulent skin friction in wall-bounded flows. This study experimentally investigates the influence of anisotropy on the drag response of porous substrates. A family of anisotropic periodic lattices was manufactured using 3D printing. Rod spacing in different directions was varied systematically to achieve different ratios of streamwise, wall-normal, and spanwise bulk permeabilities ($$\kappa _{xx}$$

κ

xx

, $$\kappa _{yy}$$

κ

yy

, and $$\kappa _{zz}$$

κ

zz

). The 3D printed materials were flush-mounted in a benchtop water channel. Pressure drop measurements were taken in the fully developed region of the flow to systematically characterize drag for materials with anisotropy ratios $$\frac{\kappa _{xx}}{\kappa _{yy}} \in [0.035,28.6]$$

κ

xx

κ

yy

∈

[
0.035
,
28.6
]

. Results show that all materials lead to an increase in drag compared to the reference smooth wall case over the range of bulk Reynolds numbers tested ($$\hbox {Re}_b \in [500,4000]$$

Re
b

∈

[
500
,
4000
]

). However, the relative increase in drag is lower for streamwise-preferential materials. We estimate that the wall-normal permeability for all tested cases exceeded the threshold identified in previous literature ($$\sqrt{\kappa _{yy}}^+> 0.4$$

κ

yy

+

>
0.4

) for the emergence of energetic spanwise rollers similar to Kelvin–Helmholtz vortices, which can increase drag. The results also indicate that porous walls exhibit a departure from laminar behavior at different values for bulk Reynolds numbers depending on the geometry.

Graphical abstract
Disability independent of cerebral white matter demyelination in progressive multiple sclerosis
Authors: Singh Vikas , Zheng Yufan , Ontaneda Daniel , Mahajan Kedar R , Holloman Jameson , Fox Robert J , Nakamura Kunio , Trapp Bruce D
Published: August 2024

The pathogenic mechanisms contributing to neurological disability in progressive multiple sclerosis (PMS) are poorly understood. Cortical neuronal loss independent of cerebral white matter (WM) demyelination in myelocortical MS (MCMS) and identification of MS patients with widespread cortical atrophy and disability progression independent of relapse activity (PIRA) support pathogenic mechanisms other than cerebral WM demyelination. The three-dimensional distribution and underlying pathology of myelinated T2 lesions were investigated in postmortem MCMS brains. Postmortem brain slices from previously characterized MCMS (10 cases) and typical MS (TMS) cases (12 cases) were co-registered with in situ postmortem T2 hyperintensities and T1 hypointensities. T1 intensity thresholds were used to establish a classifier that differentiates MCMS from TMS. The classifier was validated in 36 uncharacterized postmortem brains and applied to baseline MRIs from 255 living PMS participants enrolled in SPRINT-MS. Myelinated T2 hyperintensities in postmortem MCMS brains have a contiguous periventricular distribution that expands at the occipital poles of the lateral ventricles where a surface-in gradient of myelinated axonal degeneration was observed. The MRI classifier distinguished pathologically confirmed postmortem MCMS and TMS cases with an accuracy of 94%. For SPRINT-MS patients, the MRI classifier identified 78% as TMS, 10% as MCMS, and 12% with a paucity of cerebral T1 and T2 intensities. In SPRINT-MS, expanded disability status scale and brain atrophy measures were similar in MCMS and TMS cohorts. A paucity of cerebral WM demyelination in 22% of living PMS patients raises questions regarding a primary role for cerebral WM demyelination in disability progression in all MS patients and has implications for clinical management of MS patients and clinical trial outcomes in PMS. Periventricular myelinated fiber degeneration provides additional support for surface-in gradients of neurodegeneration in MS.
Hippocampal, thalamic, and amygdala subfield morphology in major depressive disorder: an ultra-high resolution MRI study at 7-Tesla
Authors: Liu Weijian , Heij Jurjen , Liu Shu , Liebrand Luka , Caan Matthan , van der Zwaag Wietske , Veltman Dick J. , Lu Lin , Aghajani Moji , van Wingen Guido
Published: August 2024

Morphological changes in the hippocampal, thalamic, and amygdala subfields have been suggested to form part of the pathophysiology of major depressive disorder (MDD). However, the use of conventional MRI scanners and acquisition techniques has prevented in-depth examinations at the subfield level, precluding a fine-grained understanding of these subfields and their involvement in MDD pathophysiology. We uniquely employed ultra-high field MRI at 7.0 Tesla to map hippocampal, thalamic, and amygdala subfields in MDD. Fifty-six MDD patients and 14 healthy controls (HCs) were enrolled in the final analysis. FreeSurfer protocols were used to segment hippocampal, thalamic, and amygdala subfields. Bayesian analysis was then implemented to assess differences between groups and relations with clinical features. While no effect was found for MDD diagnosis (i.e., case–control comparison), clinical characteristics of MDD patients were associated with subfield volumes of the hippocampus, thalamus, and amygdala. Specifically, the severity of depressive symptoms, insomnia, and childhood trauma in MDD patients related to lower thalamic subfield volumes. In addition, MDD patients with typical MDD versus those with atypical MDD showed lower hippocampal, thalamic, and amygdala subfield volumes. MDD patients with recurrent MDD versus those with first-episode MDD also showed lower thalamic subfield volumes. These findings allow uniquely fine-grained insights into hippocampal, thalamic, and amygdala subfield morphology in MDD, linking some of them to the clinical manifestation of MDD.
Characteristics and outcomes of atrial fibrillation detected before and after acute ischemic stroke
Authors: D’Anna Lucio , Romoli Michele , Harvey Kirsten , Korompoki Eleni , Veltkamp Roland
Published: August 2024

Background

Atrial fibrillation (AF) can be known before the stroke (KAF) or be newly detected after stroke (AFDAS). It is unknown whether the outcome of stroke differs between KAF and AFDAS. We performed a propensity-matched analysis to investigate the outcome of patients with AFDAS and their counterparts with KAF.

Methods

We analysed a consecutive series of patients enrolled into the EIDASAF study, a single centre, retrospective study of ischemic stroke patients with a diagnosis of AF before or after the event who had been admitted to the Hyperacute Stroke Unit of Imperial College Healthcare NHS Trust between 2010 and 2017.

Results

Overall, our cohort included 959 patients with AF and acute ischemic stroke. After propensity score matching, 547 patients were matched (404 KAF group and 143 AFDAS group). The rates of in hospital death and of haemorrhagic transformation were significantly higher in KAF patients compared to AFDAS patients. Logistic regression analysis did not reveal a statistically significant influence of AF subtypes on the outcome of death. However, in logistic regression analysis KAF was associated with increased probability of haemorrhagic transformation (OR 9.64; CI 1.29–71.68, p = 0.022) after the index event.

Conclusion

KAF is associated with an increased risk of haemorrhagic transformation but not of death when compared to AFDAS.
Modeling cellular self-organization in strain-stiffening hydrogels
Authors: Erhardt A. H. , Peschka D. , Dazzi C. , Schmeller L. , Petersen A. , Checa S. , Münch A. , Wagner B.
Published: August 2024

We derive a three-dimensional hydrogel model as a two-phase system of a fibre network and liquid solvent, where the nonlinear elastic network accounts for the strain-stiffening properties typically encountered in biological gels. We use this model to formulate free boundary value problems for a hydrogel layer that allows for swelling or contraction. We derive two-dimensional plain-strain and plain-stress approximations for thick and thin layers respectively, that are subject to external loads and serve as a minimal model for scaffolds for cell attachment and growth. For the collective evolution of the cells as they mechanically interact with the hydrogel layer, we couple it to an agent-based model that also accounts for the traction force exerted by each cell on the hydrogel sheet and other cells during migration. We develop a numerical algorithm for the coupled system and present results on the influence of strain-stiffening, layer geometry, external load and solvent in/outflux on the shape of the layers and on the cell patterns. In particular, we discuss alignment of cells and chain formation under varying conditions.
Trilaciclib use in extensive-stage small cell lung cancer (ES-SCLC): are clinical benefits seen in the real-world setting?
Authors: Elijah Joseph , Jain Prantesh , Holdsworth Allison , Baron Jeffrey , Przespolewski Eugene , Wang Katy , Attwood Kristopher , Billias Christina , Dy Grace K.
Published: August 2024

Background

Trilaciclib, in comparison to placebo plus carboplatin, etoposide, ± atezolizumab (PEA), has shown significant reductions in incidence of severe neutropenia (SN) among patients with extensive-stage small cell lung cancer (ES-SCLC). Despite these findings, real-world utility remains limited.

Methods

A single-center quasi-experimental study compared trilaciclib + PEA (PEAT) versus PEA in ES-SCLC patients. The study period ranged from April 1, 2021 to July 31, 2022, for the PEAT recipients and February 1, 2020, to February 28, 2021, for PEA recipients. The primary endpoint evaluated was incidence of SN after cycle 1 and during the treatment period. Secondary endpoints included measures related to myelopreservation and patient outcomes.

Results

Among 34 PEAT and 44 PEA patients, baseline characteristics were similar, except for a higher median age (69 vs 64 years) and more males (64.7% vs 38.6%) in the PEAT cohort. The PEAT cohort exhibited a lower SN rate (3%) versus the PEA cohort (18%), with statistical significance demonstrated on multivariate analysis (p = 0.015). Additionally, the PEAT cohort also demonstrated significant reductions in red blood cell transfusion requirements (3% vs 23%; p = 0.02), grade 3–4 anemia (6% vs 25%; p = 0.03), and grade 3–4 thrombocytopenia (0% vs 11%, p = 0.045).

Conclusion

Trilaciclib, in combination with PEA, demonstrated an improvement in the safety profile without compromising survival outcomes in ES-SCLC patients. These findings underscore the potential benefits of incorporating trilaciclib in real-world clinical settings for enhanced patient care.
Statistical prediction for nonlinear failure function of linear loads: application to plate buckling in ship structure
Authors: Matsui Sadaoki
Published: August 2024

This study presents a practical method for calculating the probability of exceedance (PoE) of the nonlinear failure function of the linear loads randomly fluctuating in irregular waves. In general, obtaining the exact PoE of such nonlinear quantities requires sophisticated computational method that are not well-suited for practical design. In contrast, the author in a previous study proposed a practical formula of the PoE distribution for von Mises stresses by asymptotic approximation, which can be applied when the criterion surface is ellipsoid in the stochastic variable space. Following this, the present study shows a method for calculating the PoE for a more general function of which the isosurface is expressed as a combination of ellipsoids. As a specific example of its application, this paper takes the limit state of the plates in ship structures specified in the common structural rules (CSR) and presents the calculation procedure of direct numerical integration as well as asymptotic approximation approaches. Calculation of the 1/1000 maximum expected value of the evaluation function of plates in short-term sea states using 700 actual plates in a ship structure confirms that the proposed method, which does not require integration, is in good agreement with rigorous methods using numerical integration.
Simulating a breakup event and propagating the orbits of space debris
Authors: Apetrii Marius , Celletti Alessandra , Efthymiopoulos Christos , Galeş Cǎtǎlin , Vartolomei Tudor
Published: August 2024

Explosions or collisions of satellites around the Earth generate space debris, whose uncontrolled dynamics might raise serious threats for operational satellites. Mitigation actions can be realized on the basis of our knowledge of the characteristics of the fragments produced during the breakup event and their subsequent propagation. In this context, important information can be obtained by implementing a breakup simulator, which provides, for example, the number of fragments, their area-to-mass ratio or the relative velocity distribution as a function of the characteristic length of the fragments. Motivated by the need to analyze the dynamics of the fragments, we reconstruct a simulator based on the NASA/JSC breakup model EVOLVE 4.0 that we review for self-consistency. This model, created at the beginning of the XXI century, is based on laboratory and on-orbit tests. Given that materials and methods for building satellites are constantly progressing, we leave some key parameters variable and produce results for different choices of the parameters. We will also present an application to the Iridium–Cosmos collision and we discuss the distribution function after a breakup event. The breakup model is strongly related to the propagation of the fragments; in this work, we discuss how to choose the models and the numerical integrators, we propose examples of how fragments can disperse in time, and we study the behavior of multiple simultaneous fragmentations. Finally, we compute some indicators for detecting streams of fragments. Breakup and propagation are performed using our own simulator SIMPRO, built from EVOLVE 4.0; the executable program will be freely available on GitHub.