bluuebunny/crossref_metadata_2025 huggingface dataset:
A Phase II Clinical Trial of Pembrolizumab and Enobosarm in Patients with Androgen Receptor-Positive Metastatic Triple-Negative Breast Cancer
Authors: Yuan Yuan , Lee Jin Sun , Yost Susan E. , Frankel Paul H. , Ruel Christopher , Egelston Colt A. , Guo Weihua , Gillece John D. , Folkerts Megan , Reining Lauren , Highlander Sarah K. , Robinson Kim , Padam Simran , Martinez Norma , Tang Aileen , Schmolze Daniel , Waisman James , Sedrak Mina , Lee Peter P. , Mortimer Joanne
Published: November 2020

Lessons Learned

The combination of enobosarm and pembrolizumab was well tolerated and showed a modest clinical benefit rate of 25% at 16 weeks. Future trials investigating androgen receptor-targeted therapy in combination with immune checkpoint inhibitors are warranted.

Background

Luminal androgen receptor is a distinct molecular subtype of triple-negative breast cancer (TNBC) defined by overexpression of androgen receptor (AR). AR-targeted therapy has shown modest activity in AR-positive (AR+) TNBC. Enobosarm (GTx-024) is a nonsteroidal selective androgen receptor modulator (SARM) that demonstrates preclinical and clinical activity in AR+ breast cancer. The current study was designed to explore the safety and efficacy of the combination of enobosarm and pembrolizumab in patients with AR+ metastatic TNBC (mTNBC).

Methods

This study was an open-label phase II study for AR+ (≥10%, 1+ by immunohistochemistry [IHC]) mTNBC. Eligible patients received pembrolizumab 200 mg intravenous (IV) every 3 weeks and enobosarm 18 mg oral daily. The primary objective was to evaluate the safety of enobosarm plus pembrolizumab and determine the response rate. Peripheral blood, tumor biopsies, and stool samples were collected for correlative analysis.

Results

The trial was stopped early because of the withdrawal of GTx-024 drug supply. Eighteen patients were enrolled, and 16 were evaluable for responses. Median age was 64 (range 36–81) years. The combination was well tolerated, with only a few grade 3 adverse events: one dry skin, one diarrhea, and one musculoskeletal ache. The responses were 1 of 16 (6%) complete response (CR), 1 of 16 (6%) partial response (PR), 2 of 16 (13%) stable disease (SD), and 12 of 16 (75%) progressive disease (PD). Response rate (RR) was 2 of 16 (13%). Clinical benefit rate (CBR) at 16 weeks was 4 of 16 (25%). Median follow-up was 24.9 months (95% confidence interval [CI], 17.5–30.9). Progression-free survival (PFS) was 2.6 months (95% CI, 1.9–3.1) and overall survival (OS) was 25.5 months (95% CI, 10.4–not reached [NR]).

Conclusion

The combination of enobosarm and pembrolizumab was well tolerated, with a modest clinical benefit rate of 25% at 16 weeks in heavily pretreated AR+ TNBC without preselected programmed death ligand-1 (PD-L1). Future clinical trials combining AR-targeted therapy with immune checkpoint inhibitor (ICI) for AR+ TNBC warrant investigation.
Polymers for enhanced photodynamic cancer therapy: Phthalocyanines as a photosensitzer model
Authors: Darwish Wael
Published: November 2020

The use of photosensitizers (PSs) in cancer therapy opened new avenues for developing minimally‐invasive treatment of cancer. However, problems related to lack of biocompatibility and tumor targeting of many photosensitizers limited their clinical use for many years. Tailor‐made polymeric nanoparticles can significantly enhance the biocompatibility of the photosensitizers, achieve high cellular internalization and prolonged blood circulation. Further, attachement of the photosensitizer to bifunctional polymeric chains can be used for building novel nano‐constructions such as combination therapy and image‐guided therapy. This review describes the innovations pertaining to polymeric drug delivery systems of laser‐based cancer therapeutics as disclosed in recent literature. Phthalocyanines were considered a model of photosensitizers and photodynamic therapy (PDT) as a model of phototherapy. Interestingly, these models are applicable to other biomedical photoreceptors such as porphyrins, Chlorin e6, gold nanoparticles, quantum dots, carbon dots, etc.
Generative models in pathology: synthesis of diagnostic quality pathology images†
Authors: Safarpoor Amir , Kalra Shivam , Tizhoosh Hamid R
Published: November 2020

Within artificial intelligence and machine learning, a generative model is a powerful tool for learning any kind of data distribution. With the advent of deep learning and its success in image recognition, the field of deep generative models has clearly emerged as one of the promising fields for medical imaging. In a recent issue of The Journal of Pathology, Levine, Peng et al demonstrate the ability of generative models to synthesize high‐quality pathology images. They suggested that generative models can serve as an unlimited source of images either for educating freshman pathologists or training machine learning models for diverse image analysis tasks, especially in scarce cases, while resolving patients’ privacy and confidentiality concerns. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
NMR‐based screening for natural product subfraction to precisely identify ligand of target protein
Authors: Jiang Haipeng , Liu Yang , Guo Jian
Published: November 2020

Introduction

The inherent diversity of natural product extracts has not only made their value for biological activity attractive, but has also presented significant challenges for separation and detection techniques to enable rapid characterisation of the biologically active component present in the complicated mixture.

Objective

Nuclear magnetic resonance (NMR) is routinely valued for its ability to shed light on molecular structure, when NMR is used as a promising tool in drug screening, it can detect and quantify molecular interactions, and at the same time provide detailed structural information with atomic level resolution. Here, we introduced an accurate and efficient strategy for discovering ligands from natural product extracts, by taking the advantage of NMR‐based drug screening.

Methodology

The characteristic pre‐purified subfraction libraries were brought into screening, and combinatorial ligand‐observed NMR interaction detection experiments were performed, once hits were found from one subfraction, the repository of the subfraction would be subject to separation and preparation, and the structure of the hits would be easily identified.

Results

Screening procedure of Radix Polygoni Multiflori water extract against human serum albumin (HSA) was used as an example, to discuss and verify the detailed methodology. Furthermore, human fatty acid binding protein 4 (FABP4) was presented as an example target protein, to illustrate the utility of this method for discovering biologically active component.

Conclusions

It is proved that suitable subfraction library and well‐combined ligand‐detected NMR experiments will make the screening streamline more accurate and efficient. NMR is a promising tool to integrate natural product extracts into modern drug screening.
Crystalline orientation assessment in transversely isotropic semicrystalline polymer: Application to oedometric compaction of PTFE
Authors: Guenoun Gabriel , Schmitt Nicolas , Roux Stéphane , Régnier Gilles
Published: November 2020

The Hermans orientation factor is a scalar giving a simple assessment of molecular or crystal orientation in a polymer. It is usually determined from X‐ray diffraction measurements. The evaluation of the Hermans orientation factor is proposed from the diffraction analysis of only a single diffracting plane. The estimation relies on (a) the assumption that the polymer crystals possess a cylindrical symmetry with respect to the chain direction and (b) that the processing conditions induce a transverse isotropy of the polymer chains. A practical consequence of the proposed analysis is that the Hermans orientation factor can be computed from a single 1D diffractogram. This enables fast evaluations since even low signal‐to‐noise ratio signals can be processed with optimal noise reduction. An illustration of this method for uniaxially compacted polytetrafluoroethylene (PTFE) powder is presented. The crystalline orientation is followed during in situ crystallization experiments with a fine time resolution.
The roles of family and friends in the immobility decisions of university graduates staying in a peripheral urban area in the Netherlands
Authors: Thomassen Jonne A. K.
Published: November 2020

Highly educated individuals constitute great assets for regional development and economic growth. Nevertheless, young university graduates are relatively geographically mobile and less likely to stay in peripheral regions. Based on semi‐structured, life‐calendar interviews, this study explored the immobility decisions of graduates who have stayed in a peripheral urban area in the Netherlands where they completed their university education. The study specifically focused on the roles of family and friends in the staying processes of these young adults. The results indicate that the decision to stay was frequently and consciously re‐evaluated by some, whereas for others, it resulted from a ‘lack of triggers’ for moving elsewhere. Notably, the interviews revealed that family and friends act as more than motives for staying or deterrents to migration. On various occasions, family and friends had played crucial roles as advisors, influencers, triggers, exemplars and facilitators in the staying processes of highly educated young adults.
iTRAQ‐based quantitative proteomics analysis of immune thrombocytopenia patients before and after Qishunbaolier treatment
Authors: Burenbatu  , Wang Yanbo , Wang Shuanglian , Narisu  , Wuritunashun  , Gong Cuiqin , Hashengaowa  , Eerdunduleng  , Sarula  , Guihua  , Bai Haihua
Published: November 2020

Rationale

Treatment of immune thrombocytopenia (ITP) usually involves long‐term use of immunosuppressive corticosteroids and splenectomy. However, these treatments often have side effects in patients. The Mongolian medicine Qishunbaolier (QSBLE) has a high curative effect, reduces the chances of relapse, and has no obvious side effects. This study was designed to identify potential therapeutic targets of QSBLE for treating ITP.

Methods

To reveal differences in protein expression between ITP patients (ITPs) before and after QSBLE treatment, comparative proteomics studies were performed using isobaric tags for relative and absolute quantification (iTRAQ). The analysis used nanospray liquid chromatography/tandem mass spectrometry (nano‐LC/MS/MS) in positive ion electrospray ionization mode. Key proteins relevant to ITP were revealed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and other bioinformatics tools. Real‐time polymerase chain reaction (RT‐PCR) analysis was carried out for confirmation of differentially expressed proteins.

Results

A total of 982 differentially expressed proteins were identified in ITPs compared with the controls. Compared with the pre‐QSBLE treatment group, 61 differentially expressed proteins were identified in the post‐QSBLE treatment group, with 48 proteins being significantly upregulated and 13 downregulated. Twenty‐nine pathways were significantly enriched. Q6N030 and other proteins were the key players in the protein‐pathway network. Twenty proteins that may play important roles in the treatment of ITP were further filtered. RT‐PCR and Western blot analyses further confirmed that MIF, PGK1 and IGHM were upregulated in ITPs after QSBLE treatment, in accordance with the proteomics data.

Conclusions

It is believed that the identified proteins and the results of bioinformatics analysis will provide a potential therapeutic target site for QSBLE for ITP therapy and biomarkers.
Relating social networks, ecological health, and reservoir basin governance
Authors: Trebitz Karen I. , Wulfhorst J.D.
Published: November 2020

The Columbia River Basin is a complex social‐ecological system, spanning political, legal, socio‐economic, geographic, and biophysical boundaries. Outreach to others in social networks develops fundamental communications needed for sustainable collaborations in adaptive management. However, operationalizing and comparing measures of social processes and outcome success in biophysical indicators remains challenging for resource managers. Using survey‐based research, we examined the interactions for water resource governance of five Columbia River reservoir basins in the northwestern US and Canada: Lakes Chelan, Roosevelt, Pend Oreille, Koocanusa, and člq'etkw (Flathead). Respondents included: water resource professionals working for Tribes/First Nations, federal, state, or provincial departments in water quality and/or fisheries, and people who engage in the networks on behalf of area businesses, government offices, public services, non‐profit organizations, and other entities. Perceived social process metrics in these governance networks included the levels of collaboration and inclusiveness, common goals, common strategies, identifying issues, implementing action, and the adequacy of available scientific data. We evaluated social measures relative to participant‐reported changes in physical lake health indicators. Qualitative data‐enhanced understanding of basin‐specific differences. Correlations of social by ecological measures varied widely between basins. Even moderate to strong functionality parameters did not scale well from individual to cross‐basin levels, as many correlations vanished with data aggregated. However, data analysis at the basin scale revealed important variability across the region in scope and governance functionality. Process indicators such as identifying issues and implementing action yielded stronger relationships for 10‐year horizons than for 2 years, reflecting the lag‐time in resource action.
Core–Shell FeSe2/C Nanostructures Embedded in a Carbon Framework as a Free Standing Anode for a Sodium Ion Battery
Authors: Yousaf Muhammad , Wang Zhipeng , Wang Yunsong , Chen Yijun , Ali Usman , Maqbool Muhammad , Imran Ali , Mahmood Nasir , Gao Peng , Han Ray P. S.
Published: November 2020

Embedding the functional nanostructures into a lightweight nanocarbon framework is very promising for developing high performance advanced electrodes for rechargeable batteries. Here, to realize workable capacity, core–shell (FeSe2/C) nanostructures are embedded into carbon nanotube (CNT) framework via a facile wet‐chemistry approach accompanied by thermally induced selenization. The CNT framework offers 3D continuous routes for electronic/ionic transfer, while macropores provide adequate space for high mass loading of FeSe2/C. However, the carbon shell not only creates a solid electronic link among CNTs and FeSe2 but also improves the diffusivity of sodium ions into FeSe2, as well as acts as a buffer cushion to accommodate the volume variations. These unique structural features of CNT/FeSe2/C make it an excellent host for sodium storage with a capacity retention of 546 mAh g−1 even after 100 cycles at 100 mA g−1. Moreover, areal and volumetric capacities of 5.06 mAh cm−2 and 158 mAh cm−3 are also achieved at high mass loading 16.9 mg cm−2, respectively. The high performance of multi‐benefited engineered structure makes it a potential candidate for secondary ion batteries, while its easy synthesis makes it extendable to further complex structures with other morphologies (such as nanorods, nanowires, etc.) to meet the high energy demands.
Ostwald Ripening Tailoring Hierarchically Porous Na3V2(PO4)2O2F Hollow Nanospheres for Superior High‐Rate and Ultrastable Sodium Ion Storage
Authors: Zhao Lina , Rong Xiaohui , Niu Yaoshen , Xu Rui , Zhang Teng , Li Tao , Yu Yan , Hou Yanglong
Published: November 2020

Sodium‐ion batteries (SIBs) are receiving considerable attention as economic candidates for large‐scale energy storage applications. Na3V2(PO4)2O2F (NVPF) is intensively regarded as one of the most promising cathode materials for SIBs, due to its high energy density, fast ionic conduction, and robust Na+‐super‐ionic conductor (NASICON) framework. However, poor rate capability ascribed to the intrinsically low electronic conductivity severely hinders their practical applications. Here, high‐rate and highly reversible Na+ storage in NVPF is realized by optimizing nanostructure and rational porosity construction. Hierarchical porous NVPF hollow nanospheres are designed to modify the issues of inconvenient electrolyte transportation and unfavorable charge transfer behavior faced by solid‐structured electrode materials. The individual unique nanosphere is assembled from numerous nanoparticles, which shortens the length of Na+ transport in solid state and thus facilites the Na+ migration. Hollow nanostructure hierarchically porous configuration enables adequate electrolyte penetration, continuous electrolyte supplementation, and facile electrolyte transportation, leading to barrier‐free Na+/e− diffusion and high‐rate cycling. In addition, the large electrolyte accessible surface area boosts the charge transfer in the whole electrode. Therefore, the present NVPF demonstrates unprecedented rate capability (85.4 mAh g−1 at 50 C) and long‐term cyclability (62.2% capacity retention after 2000 cycles at 20 C).
Strategies to Develop Earth‐Abundant Heterogeneous Oxygen Evolution Reaction Catalysts for pH‐Neutral or pH‐Near‐Neutral Electrolytes
Authors: Dong Yan , Komarneni Sridhar
Published: November 2020

The anodic oxygen evolution reaction (OER) is the bottleneck of water splitting to produce hydrogen due to its sluggish kinetics. In order to lower the energy cost, highly active and cost‐efficient OER catalysts need to be used to overcome the OER reaction barrier, especially in neutral pH. Compared to alkaline or acidic electrolytes, pH‐neutral or pH‐near‐neutral electrolytes are considered to be cheaper and safer, and water from rivers and the sea could be used directly under such conditions. However, OER under neutral pH is challenging compared to the OER catalysts for alkaline conditions. Therefore, OER catalysts for neutral or near‐neutral pH have not been pursued significantly and, hence, there are limited advances in this area. Here, the progress made in the research and development of earth‐abundant heterogeneous catalysts for OER in three pH‐neutral or pH‐near‐neutral systems, namely, the phosphate system, the carbonate system, and the borate system, are systematically reviewed and summarized for the first time. Strategies to develop high‐performance OER catalysts for neutral pH are reviewed and summarized. In addition, future challenges and opportunities in this field are discussed, which may shed some light on the future developments of earth‐abundant heterogeneous catalysts for OER in neutral or near‐neutral pH.
Providing a sustainable sonographer workforce in Australia: Clinical training solutions
Authors: McGregor Rod , Pollard Karen , Davidson Rob , Moss Cameron
Published: November 2020

Introduction

At present, sonography in Australia is experiencing a workforce shortage and increasing demand for services. This shortage has been linked to a lack of clinical placements for sonography students, creating a need to develop solutions to the paucity of training opportunities.

Methods

A three‐round ranking‐type Delphi analysis in conjunction with thematic analysis was used to develop and rank a list of potential solutions to the shortage of clinical placements. Participants were recruited purposively based on their roles in the field of sonography that involved management of students in clinical placements.

Results

In total, 32 potential solutions were developed based on thematic analysis of open‐ended questionnaires completed by participants. Of which, 13 were deemed essential and ranked from most to least important.

Discussion

The potential solutions developed in the present study has implications for how sonography services, governing bodies and universities could overcome barriers to providing clinical placements. The highest ranked solution among participants was support from management to employ student sonographers, with the remaining solutions primarily pertaining to assistance in structuring and financing placements, and further support from higher education institutions. It was recommended that future research focus on structuring and financing placements.
A Hirnantian holdover from the Late Ordovician mass extinction: phylogeny and biogeography of a new anthracocrinid crinoid from Estonia
Authors: Cole Selina R. , Ausich William I. , Wilson Mark A.
Published: November 2020

Relatively few Hirnantian (Late Ordovician) crinoids are known, and none has been previously described from the palaeocontinent of Baltica. This has impaired our ability to understand the patterns of extinction and biogeographic dispersal surrounding the Late Ordovician mass extinction, which triggered a major turnover in crinoid faunas. Here, we describe Tallinnicrinus toomae gen. et sp. nov., an anthracocrinid diplobathrid from the Hirnantian of northern Estonia. Tallinnicrinus is the youngest member of the Anthracocrinidae and the first representative of the family to occur in Baltica. Morphologically, Tallinnicrinus is unusual in that the radial and basal plates are in a single circlet of 10 plates, similar to the anthracocrinid Rheocrinus Haugh, 1979 from the Katian of Laurentia. Phylogenetic analysis further confirms a close relationship between Tallinnicrinus and Laurentian anthracocrinids, suggesting biogeographic dispersal of the lineage from Laurentia to Baltica during the late Katian or early Hirnantian. The occurrence of this new taxon establishes that the family Anthracocrinidae survived the first pulse of the Late Ordovician mass extinction. However, the lineage remained a ‘dead clade walking’ because it failed to diversify in the wake of the end‐Katian extinction and ultimately went extinct itself by the end of the Ordovician.
Effect of Peroxide on Compatibility, Microstructure, Rheology, Crystallization, and Mechanical Properties of PBS/Waxy Starch Composites
Authors: Yan Yue , Dou Qiang
Published: November 2020

Polybutylene succinate (PBS)/waxy starch (WS)/dibenzoyl peroxide (BPO) bio‐composites are prepared via one‐step blending in an internal mixer. The results of scanning electron microscopy, polarized light microscopy, Fourier transform infrared spectroscopy, dynamic mechanical analyses, rheological tests, contact angle measurements, thermogravimetric analyses, and Soxhlet extraction experiments show that a crosslinked graft copolymer (WS‐g‐PBS) is produced with the aid of BPO during melt blending, resulting in improved compatibility between PBS and WS. The results of differential scanning calorimetry and wide‐angle X‐ray diffraction indicate that WS‐g‐PBS affects both the crystallization and melting processes. However, the crystal form of PBS is not modified by adding WS and BPO. The mechanical properties of the composites increase significantly with the addition of BPO.
Anatomy of the Aqueous Outflow Drainage Pathways
Authors: Lam Kay , Lawlor Mitchell
Published: November 2020

Lowering intraocular pressure (IOP) has been central to glaucoma care for over a century. Minimally invasive glaucoma surgical (MIGS) devices are able to exploit different aspects of aqueous outflow to reduce IOP. Increasing aqueous humour outflow may be achieved either through facilitating the existing pathways of Schlemm’s canal and the suprachoroidal space or to bypass the normal angle anatomy to create a full thickness fistula into the subconjunctival space. A complete understanding of angle anatomy and outflow pathways is important to develop new treatment strategies, improve current ones and better target the right operation for particular glaucoma subtypes.
Scalar anomaly cancellation reveals the hidden superalgebraic structure of the quantum chiral SU(2/1) model of leptons and quarks
Authors: Thierry-Mieg Jean
Published: November 2020

Abstract

At the classical level, the SU(2/1) superalgebra offers a natural description of the elementary particles: leptons and quarks massless states, graded by their chirality, fit the smallest irreducible representations of SU(2/1). Our new proposition is to pair the left/right space-time chirality with the superalgebra chirality and to study the model at the one-loop quantum level. If, despite the fact that they are non-Hermitian, we use the odd matrices of SU(2/1) to minimally couple an oriented complex Higgs scalar field to the chiral Fermions, novel anomalies occur. They affect the scalar propagators and vertices. However, these undesired new terms cancel out, together with the Adler-Bell-Jackiw vector anomalies, because the quarks compensate the leptons. The unexpected and striking consequence is that the scalar propagator must be normalized using the anti-symmetric super-Killing metric and the scalar-vector vertex must use the symmetric d_aij structure constants of the superalgebra. Despite this extraordinary structure, the resulting Lagrangian is actually Hermitian.
Spectral Properties of Schrödinger Operators Associated with Almost Minimal Substitution Systems
Authors: Eichinger Benjamin , Gohlke Philipp
Published: November 2020

We study the spectral properties of ergodic Schrödinger operators that are associated with a certain family of non-primitive substitutions on a binary alphabet. The corresponding subshifts provide examples of dynamical systems that go beyond minimality, unique ergodicity and linear complexity. In some parameter region, we are naturally in the setting of an infinite ergodic measure. The almost sure spectrum is singular and contains an interval. We show that under certain conditions, eigenvalues can appear. Some criteria for the exclusion of eigenvalues are fully characterized, including the existence of strongly palindromic sequences. Many of our structural insights rely on return word decompositions in the context of non-uniformly recurrent sequences. We introduce an associated induced system that is conjugate to an odometer.
Correction to: Gender norms about romantic relationships and sexual experiences among very young male adolescents in Korogocho slum in Kenya
Authors: Maina Beatrice W. , Orindi Benedict O. , Sikweyiya Yandisa , Kabiru Caroline W.
Published: November 2020

The authors would like to correct an error in the publication of the original article. The error is described below and correct details provided. What is presented in the lines 23, 29, 38 , and in table 4 is the corrected version.
Impact of a school-based water, sanitation and hygiene programme on children’s independent handwashing and toothbrushing habits: a cluster-randomised trial
Authors: Duijster Denise , Buxton Helen , Benzian Habib , Dimaisip-Nabuab Jed , Monse Bella , Volgenant Catherine , Dreibelbis Robert
Published: November 2020

Objectives

To explore whether a school-based water, sanitation and hygiene programme, which includes group hygiene activities, contributes to the formation of independent handwashing and toothbrushing habits among Filipino children.

Methods

In this cluster-randomised trial, twenty primary schools were randomly allocated to the intervention or control arm. Intervention schools received group handwashing facilities and implemented daily group handwashing and toothbrushing activities. A soap use to toilet event ratio was calculated to measure children’s independent handwashing behaviour after toilet use, and dental plaque accumulation on Monday morning was measured as a proxy indicator for children’s independent toothbrushing behaviour at home.

Results

Four months after implementation, handwashing and toothbrushing behaviours did not significantly differ between intervention and control schools. The mean soap use in intervention schools and control schools was 0.41 g and 0.30 g per toilet event, respectively (p = 0.637). Compared to baseline, mean plaque scores reduced by 4.2% and 3.5% in intervention and control schools, respectively (p = 0.857).

Conclusions

Although health benefits have been established, school-based group handwashing and toothbrushing may not be sufficient to increase children’s uptake of independent hygiene behaviours.
Corona bei Kindern: Die Co-Ki Studie
Authors: Schwarz Silke , Jenetzky Ekkehart , Krafft Hanno , Maurer Tobias , Steuber Christian , Reckert Till , Fischbach Thomas , Martin David
Published: November 2020

Hintergrund

In Deutschland werden über 80 % der Kinder und Jugendlichen von niedergelassenen Kinder- und Jugendärztinnen und -ärzten (KJÄ) betreut. Diese haben eine spezifische Perspektive auf die COVID-19-Pandemie.

Methode

Zentrale Onlineerfassung von Fallzahlen, individuellen Fallbeschreibungen und Beobachtungen zu Infektion und Erkrankung mit SARS-CoV‑2 (www.co-ki.de).

Ergebnisse

An der Fallzahlerfassung beteiligten sich bisher 557 KJÄ. Diese betreuen ca. 670.000 Kinder. Sie meldeten 9803 Kinder, die als Verdachtsfälle vorgestellt wurden. Die KJÄ selber hatten einen klinischen Verdacht auf SARS-CoV-2-Infektion bei 3654 Kindern. Bei 7707 Kindern wurden PCR-Testungen mittels Nasen‑/Rachenabstrich durchgeführt, von denen 198 Abstriche (2,6 %) positiv ausfielen. Zudem wurden 731 Kinder auf SARS-CoV-2-Antikörper getestet, mit einem Nachweis in 82 Fällen (11,2 %). Trotz initial positivem PCR-Test hatten 47 Kinder mindestens 2 Wochen danach einen negativen Antikörpertest. Die Abfrage nach Ansteckung eines Erwachsenen durch ein Kind ergab nur einen einzigen mutmaßlichen, nach telefonischer Rückfrage unwahrscheinlichen, Verdachtsfall.

Diskussion

Aus ambulant-pädiatrischer Sicht sind COVID-19-Erkrankungen bei Kindern sehr selten. In unserem Kollektiv fand sich kein überzeugender Hinweis, dass Kinder eine relevante Infektionsquelle für SARS-CoV‑2 darstellen oder dass Kinder relevant gefährdet wären.
The role of dendritic cells for therapy of B-cell lymphoma with immune checkpoint inhibitors
Authors: Scheuerpflug Anne , Ahmetlić Fatima , Bauer Vera , Riedel Tanja , Röcken Martin , Mocikat Ralph
Published: November 2020

Immune checkpoint blocking (ICB) is a promising new tool of cancer treatment. Yet, the underlying therapeutic mechanisms are not fully understood. Here we investigated the role of dendritic cells (DCs) for the therapeutic effect of ICB in a λ-MYC-transgenic mouse model of endogenously arising B-cell lymphoma. The growth of these tumors can be effectively delayed by antibodies against CTLA-4 and PD-1. Tumor-infiltrating DCs from mice having received therapy showed an upregulation of costimulatory molecules as well as an augmented IL-12/IL-10 ratio as compared to untreated controls. Both alterations seemed to be induced by interferon-γ (IFN-γ), which is upregulated in T cells and natural killer cells upon ICB. Furthermore, the enhanced IL-12/IL-10 ratio, which favors Th1-prone antitumor T-cell responses, was a consequence of direct interaction of ICB antibodies with DCs. Importantly, the capability of tumor-infiltrating DCs of stimulating peptide-specific or allogeneic T-cell responses in vitro was improved when DCs were derived from ICB-treated mice. The data indicate that ICB therapy is not only effective by directly activating T cells, but also by triggering a complex network, in which DCs play a pivotal role at the interface between innate and adaptive antitumor responses.
The influence of social-grouping on territorial defense behavior in the black-crested titmouse (Baeolophus atricristatus)
Authors: Borger Mirjam J. , Johnson Lauren E. , Salazar Nathaly O. , Dreghorn Cameron L. , Komdeur Jan , Murphy Troy G.
Published: November 2020

Status signals have evolved for individuals to avoid energetic and physical costs of resource defense. These signals reflect an individual’s competitive ability and therefore influence competitors’ decisions on how to invest in a fight. We hypothesized that the response of receivers to status signals will depend on the social context. During territorial defense, group members may provide support to a territory owner by participating in defense. We investigated whether the presence of juveniles—who group together with territorial males—alters the territorial male’s attack decisions and level of aggression in the black-crested titmouse (Baeolophus atricristatus). Crest-length in this species functions as status signal. We simultaneously presented two taxidermic male models in a territory: one with an unmanipulated crest and one with a modified shortened crest. Models were presented to males that had resident juveniles cohabiting on their territory, and to males without juveniles. During intrusions, juveniles actively defended against the simulated intruders by approaching and sometimes attacking. The presence of juveniles affected how territorial males responded to the status signals of the intruders: when juveniles were present, males were more likely to first attack the model with the unmanipulated crest (i.e., longer, and more threatening), compared to males residing without juveniles. This suggests that juvenile support alters the risk-taking decision of the territorial male. To our knowledge, this is the first indication that behavioral responses to a status signal depends on the presence of supportive group members.

Significance statement

Status signals can indicate relative quality of animals and can therefore be used to evaluate a competitor when deciding whether or not to fight over resources. The black-crested titmouse has been shown to use its crest length as a status signal during fights over food. In our study, we assessed if this status signal is also used in territorial defense, by conducting an experiment where we presented two taxidermic male models with different crest sizes to a territorial male. We also investigated whether juvenile presence influenced which model was attacked. In trials where juveniles were present, territorial males attacked the longer crested model significantly more often than in trials where territorial males were alone. This suggests that the presence of juveniles, which help the male defend the territory, allows the male to attack the more aggressive-appearing intruder.
Digital Variance Angiography in Lower-Limb Angiography with Metal Implants
Authors: Bastian M. B. , König A. M. , Viniol S. , Gyánó M. , Szöllősi D. , Góg I. , Kiss J. P. , Osvath S. , Szigeti K. , Mahnken A. H. , Thomas R. P.
Published: November 2020

Purpose

The presence of metal implants may reduce angiographic image quality due to automated beam adjustments. Digital variance angiography (DVA) is reported to be superior to digital subtraction angiography (DSA) with increased contrast-to-noise ratio (CNR) and better image quality. The aim of the study was to evaluate whether DVA could counterbalance the image quality impairment of lower-limb angiographies with metal implants.

Materials and Methods

From November 2019 to January 2020, 85 raw lower-limb iodine contrast angiograms of 12 patients with metal implants were processed retrospectively with DVA analyses. For objective comparison, CNR of DSA and DVA images was calculated and the ratio CNRDVA/CNRDSA was determined. Visual image quality was evaluated in a paired comparison and by a five-grade Likert scale by three experienced radiologists.

Results

The CNR was calculated and compared in 1252 regions of interest in 37 image pairs containing metal implants. The median ratio of CNRDVA/CNRDSA was 1.84 with an interquartile range of 1.35–2.32. Paired comparison resulted in 84.5% in favour of DVA with an interrater agreement of 83.2% (Fleiss κ 0.454, p < 0.001). The overall image quality scores for DSA and DVA were 3.64 ± 0.08 and 4.43 ± 0.06, respectively (p < 0.001, Wilcoxon signed-rank test) with consistently higher individual ratings for DVA.

Conclusion

Our small-sample pilot study shows that DVA provides significantly improved image quality in lower-limb angiography with metal implants, compared to DSA imaging. The improved CNR suggest that this approach could reduce radiation exposure for lower-limb angiography with metal implants.

Level of Evidence

Level 4, case studies
Population pharmacokinetics of ATR inhibitor berzosertib in phase I studies for different cancer types
Authors: Terranova Nadia , Jansen Mendel , Falk Martin , Hendriks Bart S.
Published: November 2020

Purpose

Berzosertib (formerly M6620) is the first-in-class inhibitor of ataxia–telangiectasia and Rad3-related protein, a key component of the DNA damage response, and being developed in combination with chemotherapy for the treatment of patients with advanced cancers. The objectives of this analysis were to characterize the pharmacokinetics (PK) of berzosertib across multiple studies and parts, estimate inter-individual variability, and identify covariates that could explain such variability.

Methods

A population PK analysis was performed using the combined dataset from two phase I clinical studies (NCT02157792, EudraCT 2013-005100-34) in patients with advanced cancers receiving an intravenous infusion of berzosertib alone or in combination with chemotherapy. The analysis included data from 240 patients across 11 dose levels (18–480 mg/m2). Plasma concentration data were modeled with a non-linear mixed-effect approach and clinical covariates were evaluated.

Results

PK data were best described by a two-compartment linear model. For a typical patient, the estimated clearance (CL) and intercompartmental CL were 65 L/h and 295 L/h, respectively, with central and peripheral volumes estimated to be 118 L and 1030 L, respectively. Several intrinsic factors were found to influence berzosertib PK, but none were considered clinically meaningful due to a very limited effect. Model simulations indicated that concentrations of berzosertib exceeded p-Chk1 (proximal pharmacodynamic biomarker) IC50 at recommended phase II doses in combination with carboplatin, cisplatin, and gemcitabine.

Conclusions

There was no evidence of a clinically significant PK interaction between berzosertib and evaluated chemo-combinations. The covariate analysis did not highlight any need for dosing adjustments in the population studied to date.

Clinical Trial information

NCT02157792, EudraCT 2013-005100-34
The prevalence and locations of bone metastases using whole-body MRI in treatment-naïve intermediate- and high-risk prostate cancer
Authors: Ottosson Fredrik , Baco Eduard , Lauritzen Peter M. , Rud Erik
Published: November 2020

Objective

The aim of this study was to assess the prevalence and distribution of bone metastases in treatment-naïve prostate cancer patients eligible for a metastatic workup using whole-body MRI, and to evaluate the results in light of current guidelines.

Methods

This single-institution, retrospective study included all patients with treatment-naïve prostate cancer referred to whole-body MRI during 2016 and 2017. All were eligible for a metastatic workup according to the guidelines: PSA > 20 ng/ml and/or Gleason grade group ≥ 3 and/or cT ≥ 2c and/or bone symptoms. The definition of a metastasis was descriptive and based on the original MRI reports. The anatomical location of metastases was registered.

Results

We included 161 patients with newly diagnosed prostate cancer of which 36 (22%) were intermediate-risk and 125 (78%) were high-risk. The median age and PSA were 71 years (IQR 64–76) and 13 ng/ml (IQR 8–28), respectively. Bone metastases were found in 12 patients (7%, 95% CI: 4–13), and all were high-risk with Gleason grade group ≥ 4. The pelvis was affected in 4 patients, and the spine + pelvis in the remaining 8. No patients demonstrated metastases to the spine without concomitant metastases in the pelvis. Limitations are the small number of metastases and retrospective design.

Conclusion

This study suggests that the overall prevalence of bone metastases using the current guidelines for screening is quite low. No metastases were seen in the case of Gleason grade group ≤ 3, and further studies should investigate if it necessary to screen non-high-risk patients.

Key Points

• The overall prevalence of bone metastases was 7% in the case of newly diagnosed intermediate- and high-risk prostate cancer.

• The prevalence in high-risk patients was 10%, and no metastases were seen in patients with Gleason grade group ≤ 3.

• The pelvic skeleton is the main site, and no metastases occurred in the spine without concomitant pelvic metastases.
Consciously processing balance leads to distorted perceptions of instability in older adults
Authors: Ellmers Toby J. , Kal Elmar C. , Young William R.
Published: November 2020

Background

Persistent dizziness without a clear cause is common in older adults. We explored whether an anxiety-driven preoccupation with consciously processing balance may underpin the distorted perceptions of unsteadiness that characterises ‘unexplained’ dizziness in older adults.

Methods

We experimentally induced anxiety about losing one’s balance (through a postural threat manipulation) in a cohort of asymptomatic older adults and evaluated associated changes in perceived stability, conscious movement processing and postural control. These outcomes were also assessed when performing a distracting cognitive task designed to prevent anxiety-related conscious movement processing, in addition to during baseline conditions (ground level).

Results

Despite a lack of increase in postural sway amplitude (p = 0.316), participants reported reductions in perceived stability during postural threat compared to baseline (p < 0.001). A multiple linear regression revealed that anxiety-related conscious movement processing independently predicted perceptions of instability during this condition (p = 0.006). These changes were accompanied by alterations in postural control previously associated with functional dizziness, namely high-frequency postural sway and disrupted interaction between open- and closed-loop postural control (ps < 0.014). While the distraction task successfully reduced conscious processing (p = 0.012), leading to greater perceived stability (p = 0.010), further increases in both postural sway frequency (p = 0.002) and dominance of closed-loop control (p = 0.029) were observed.

Conclusion

These findings implicate the role of conscious movement processing in the formation of distorted perceptions of unsteadiness, suggesting that such perceptions may be modifiable by reducing an over-reliance on conscious processes to regulate balance.
Spectral-domain OCT changes in retina and optic nerve in children with hypoxic–ischaemic encephalopathy
Authors: Grego L. , Pignatto S. , Busolini E. , Rassu N. , Samassa F. , Prosperi R. , Pittini C. , Cattarossi L. , Lanzetta Paolo
Published: November 2020

Purpose

To evaluate the effect of neonatal hypoxic–ischaemic injury on the retina and the optic nerve and to correlate ocular damage with systemic parameters, laboratory tests, neurological imaging and therapeutic hypothermia at birth.

Methods

Forty-one children with hypoxic–ischaemic encephalopathy (HIE) at birth (9.09 ± 3.78 years) and a control group of 38 healthy subjects (9.57 ± 3.47 years) were enrolled in a cohort study. The HIE population was divided into three subgroups, based on the degree of encephalopathy according to Sarnat score and the treatment with therapeutic hypothermia (TH): Sarnat score I not treated with hypothermia, Sarnat score II-III treated with TH and Sarnat score II-III not subjected to TH. Total macular thickness, individual retinal layers and peripapillary nerve fibre layer thickness were measured with spectral-domain optical coherence tomography. Clinical data of perinatal period of HIE children were collected: APGAR score, pH and base excess of funiculus blood at birth, apnoea duration, brain ultrasound, cerebral MRI ischaemic lesions and blood chemistry tests.

Results

Children with Sarnat score I did not show a reduction of peripapillary nerve fibres and ganglion cell layer compared to the control group (p = 0.387, p = 0.316). Peripapillary nerve fibre layer was 109.06 ± 7.79 μm in children with Sarnat score II-III treated with TH, 108.31 ± 7.83 μm in subjects with Sarnat score II-III not subjected to TH and 114.27 ± 6.81 μm in the control group (p = 0.028, p = 0.007). Ganglion cell layer was thinner in children with Sarnat score II-III treated with TH (50.31 ± 5.13 μm) compared to the control group (54.04 ± 2.81 μm) (p = 0.01). Inner retinal layers damage correlated with C-reactive protein and lactate dehydrogenase increase, while higher levels of total bilirubin were protective against retinal impairment (p < 0.05). Cerebral oedema was related to peripapillary nerve fibre layer damage (p = 0.046).

Conclusions

Thickness reduction of inner retinal layer and peripapillary nerve fibre impairment was related to encephalopathy severity. Ocular damage was associated with inflammation and cerebral oedema following hypoxic–ischaemic damage.
Neuronal tangential migration from Nkx2.1-positive hypothalamus
Authors: Murcia-Ramón Raquel , Company Verónica , Juárez-Leal Iris , Andreu-Cervera Abraham , Almagro-García Francisca , Martínez Salvador , Echevarría Diego , Puelles Eduardo
Published: November 2020

During the development of the central nervous system, the immature neurons suffer different migration processes. It is well known thatNkx2.1-positive ventricular layer give rise to critical tangential migrations into different regions of the developing forebrain. Our aim was to study this phenomenon in the hypothalamic region. With this purpose, we used a transgenic mouse line that expresses thetdTomatoreporter driven by the promotor ofNkx2.1. Analysing theNkx2.1-positive derivatives at E18.5, we found neural contributions to the prethalamic region, mainly in the zona incerta and in the mes-diencephalic tegmental region. We studied the developing hypothalamus along the embryonic period. From E10.5 we detected that theNkx2.1expression domain was narrower than the reporter distribution. Therefore, theNkx2.1expression fades in a great number of the early-born neurons from theNkx2.1-positive territory. At the most caudal positive part, we detected a thin stream of positive neurons migrating caudally into the mes-diencephalic tegmental region using time-lapse experiments on open neural tube explants. Late in development, we found a second migratory stream into the prethalamic territory. All these tangentially migrated neurons developed a gabaergic phenotype. In summary, we have described the contribution of interneurons from theNkx2.1-positive hypothalamic territory into two different rostrocaudal territories: the mes-diencephalic reticular formation through a caudal tangential migration and the prethalamic zona incerta complex through a dorsocaudal tangential migration.