bluuebunny/crossref_metadata_2025 huggingface dataset:
UHPLC–MS/MS method for simultaneous quantification of doripenem, meropenem, ciprofloxacin, levofloxacin, pazufloxacin, linezolid, and tedizolid in filtrate during continuous renal replacement therapy
Authors: Kai Makoto , Tanaka Ryota , Suzuki Yosuke , Goto Koji , Ohchi Yoshifumi , Yasuda Norihisa , Tatsuta Ryosuke , Kitano Takaaki , Itoh Hiroki
Published: December 2022

Background

Since severe infections frequently cause acute kidney injury (AKI), continuous renal replacement therapy (CRRT) is often initiated for regulation of inflammatory mediators and renal support. Thus, it is necessary to decide the antibiotic dosage considering the CRRT clearance in addition to residual renal function. Some of the hemofilters used in CRRT are known to adsorb antibiotics, and clearance of antibiotics may differ depending on the adsorptive characteristics of hemofilters. Although assay systems for blood and CRRT filtrate concentrations are required, no method for measuring antibiotics concentrations in filtrate has been reported. We developed a UHPLC–MS/MS method for simultaneous quantification of antibiotics commonly used in ICU, comprising carbapenems [doripenem (DRPM) and meropenem (MEPM)], quinolones [ciprofloxacin (CPFX), levofloxacin (LVFX) and pazufloxacin (PZFX)] and anti‐MRSA agents [linezolid (LZD), and tedizolid (TZD)] in CRRT filtrate samples.

Methods

Filtrate samples were pretreated by protein precipitation. The analytes were separated with an ACQUITY UHPLC CSH C18 column under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate.

Results

The method showed good linearity over wide ranges. Within‐batch and batch‐to‐batch accuracy and precision for each drug fulfilled the criteria of the US Food and Drug Administration guidance. The recovery rate was more than 87.20%. Matrix effect ranged from 99.57% to 115.60%. Recovery rate and matrix effect did not differ remarkably between quality control samples at different concentrations.

Conclusion

This is the first report of a simultaneous quantification method of multiple antibiotics in filtrate of CRRT circuit.
Dysregulated ceRNA network modulated by copy number variation‐driven lncRNAs in breast cancer: A comprehensive analysis
Authors: Zhu Xiaotao , Song Jialu , Wang Mingzheng , Wang Xiaohui , Lv Lin
Published: December 2022

Breast cancer is a malignancy harmful to physical and mental health in women, with quite high mortality. Copy number variations (CNVs) are vital factors affecting the progression of breast cancer. Detecting CNVs in breast cancer to predict the prognosis of patients has become a promising approach to accurate treatment in recent years. The differential analysis was performed on CNVs of long noncoding RNAs (lncRNAs) as well as the expression of lncRNAs, microRNAs (miRNAs) and mRNAs in normal tissue and breast tumor tissue based on The Cancer Genome Atlas (TCGA) database. The CNV‐driven lncRNAs were identified by the Kruskal–Wallis test. Meanwhile, a competitive endogenous RNA (ceRNA) network regulated by CNV‐driven lncRNA was constructed. As the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed, the mRNAs in the dysregulated ceRNA network were mainly enriched in the biological functions and signaling pathways, including the Focal Adhesion‐PI3K‐Akt–mTOR‐signaling pathway, the neuronal system, metapathway biotransformation Phase I and II and blood circulation, etc. The relationship between the CNVs of five lncRNAs and their gene expression in the ceRNA network was analyzed via a chi‐square test, which confirmed that except for LINC00243, the expression of four lncRNAs was notably correlated with the CNVs. The survival analysis revealed that only the copy number gain of LINC00536 was evidently related to the poor prognosis of patients. The CIBERSORT algorithm showed that five lncRNAs were correlated with the abundance of immune cell infiltration and immune checkpoints. In a word, by analyzing CNV‐driven lncRNAs and the ceRNA network regulated by these lncRNAs, this study explored the mechanism of breast cancer and provided novel insights into new biomarkers.
Bone marrow necrosis and fat embolism syndrome in sickle cell disease during COVID‐19 infection treated successfully with sequential red cell and plasma exchange
Authors: Rizvi Syed , Khakwani Muhammad , Pancham Shivan , Tsitsikas Dimitris , Rudzki Zbigniew , Hassan‐Smith Ghaniah , Bowen Michael , Wright Christine , Park Daniel
Published: December 2022

Fat embolism syndrome (FES) is a rare life‐threatening condition that is particularly seen in milder forms of sickle cell disease (SCD). Widespread systemic fat emboli are generated in the context of extensive bone marrow necrosis. Multi‐organ failure with a high morbidity and mortality may quickly develop. Infection with Parvovirus B19 is a common precipitant.

Here, the authors report the case of a 35‐year‐old Afro‐Caribbean man with HbSC disease who presented with FES having tested positive for SARS‐COV‐2. He rapidly became critically ill and required admission to the intensive care unit for organ support. He was treated with red cell exchange and plasma exchange and made a good recovery to leave hospital at week 7.
The effect of post‐brew holding time and carafe type on the sensory properties of drip brew coffee
Authors: Batali Mackenzie E. , Cotter Andrew R. , Lim Lik Xian , Ristenpart William D. , Guinard Jean‐Xavier
Published: December 2022

Background

Coffee quality is believed to degrade quickly after brewing, and retail establishments discard unsold brewed coffee after a specified holding time period, sometimes as short as 30 min. We used trained sensory panels to evaluate the flavor profiles of light, medium, and dark roast coffees held in three different carafe types (glass on hot plate, thermal jacket, and vacuum insulated) for times ranging from 15 min to 3 h. Furthermore, a panel of 93 coffee‐industry professionals performed a blind evaluation of fresh (30 min) versus held (180 min) coffee for overall liking and attribute level adequacy.

Results

Sourness increased over time, consistent with acidity increasing over time (i.e., higher titratable acidity, lower pH), but only for the light and medium roasts. Dark roasted coffee became significantly more acidic over 3 h post‐brew but was not perceived as more sour over time by the sensory panel. Variations were observed between the thermal jacket and vacuum carafes for the light and dark roast, but few differences were observed with storage type in the medium roast. Surprisingly, the panel of coffee industry professionals showed no preference for fresh over held.

Conclusions

More sensory attributes decreased than increased over time, suggesting that the primary concern with loss of quality during coffee holding may be the loss of volatile aroma compounds. Hedonic ratings suggest that even if the changes over time are noticeable, they may not negatively impact overall liking. © 2022 Society of Chemical Industry.
Postoperative opioid‐prescribing practices in otolaryngology: Evidence‐based guideline outcomes
Authors: Rana Tanvi , Daniels Kelly , Dang Sophia , Li Jonathan C. , Freeman Cecilia G. , Duffy Alexander , Curry Joseph , Luginbuhl Adam , Cottrill Elizabeth , Cognetti David
Published: December 2022

Objectives

We previously reported that >50% of postoperative opioids prescribed at our institution went unused for common otolaryngologic procedures. Based on these findings, we instituted multimodal, evidence‐based guidelines for postoperative pain management. In the second part of our multiphasic study, we evaluated the effects of these guidelines on (1) quantity of unused opioids, (2) patient satisfaction, and (3) institutional perceptions toward the opioid epidemic and prescribing guidelines.

Methods

Standardized, procedure‐specific opioid prescription guidelines were created using prospective data from the first phase of our study and evidence from current literature. Again, we examined sialendoscopy, parotidectomy, parathyroidectomy/thyroidectomy, and transoral robotic surgery (TORS). Patients were surveyed at their first postoperative appointment. Groups from Phases I and II were compared. Attending physicians were surveyed before the start of the multiphasic project and after prescribing guidelines were implemented.

Results

Prescribing guidelines led to an average reduction in prescribed morphine milligram equivalents (MME) per patient by: 48% (sialendoscopy), 63% (parotidectomy), 60% (para/thyroidectomy), and 42% (TORS). Average used MME per patient for parotidectomy was significantly reduced (64%). The proportion of unused MME per patient and patient satisfaction scores did not significantly change after guidelines were implemented.

Conclusion

Implementation of opioid‐prescribing guidelines and the use of multimodal analgesia substantially reduced the amount of opioids prescribed across all procedures without impacting patient satisfaction.

Level of Evidence

2
Development of 3D‐Printed, Biodegradable, Conductive PGSA Composites for Nerve Tissue Regeneration
Authors: Huang Wei‐Jia , Wang Jane
Published: December 2022

Nerve conduits are used to reconnect broken nerve bundles and provide protection to facilitate nerve regeneration. However, the low degradation rate and regeneration rate, as well as the requirement for secondary surgery are some of the most criticized drawbacks of existing nerve conduits. With high processing flexibility from the photo‐curability, poly (glycerol sebacate) acrylate (PGSA) is a promising material with tunable mechanical properties and biocompatibility for the development of medical devices. Here, polyvinylpyrrolidone (PVP), silver nanoparticles (AgNPs), and graphene are embedded in biodegradable PGSA matrix. The polymer composites are then assessed for their electrical conductivity, biodegradability, three‐dimensional‐printability (3D‐printability), and promotion of cell proliferation. Through the four‐probe technique, it is shown that the PGSA composites are identified as highly conductive in swollen state. Furthermore, biodegradability is evaluated through enzymatic degradation and facilitated hydrolysis. Cell proliferation and guidance are significantly promoted by three‐dimensional‐printed microstructures and electrical stimulation on PGSA composites, especially on PGSA‐PVP. Hence, microstructured nerve conduits are 3D‐printed with PGSA‐PVP. Guided cell growth and promoted proliferation are subsequently demonstrated by Schwann cell culture combined with electrical stimulation. Consequently, 3D‐printed nerve conduits fabricated with PGSA composites hold great potential in nerve tissue regeneration through electrical stimulation.
Photosensitive Benzoxazines Derived from Divanillidene Cyclopentanone/Cyclohexanone for Hydrophobic and Optical Applications
Authors: Appasamy Subasri , Arumugam Hariharan , Krishnasamy Balaji , Muthukaruppan Alagar
Published: December 2022

An attempt is made to synthesize two series of photosensitive benzoxazines using a divanillidene cyclopentanone/divanillidene cyclohexanone (DVCP/DVCH) core containing structurally different amines such as aniline, cyclohexylamine, 4‐aminobenzonitrile, furfurylamine, and stearylamine with paraformaldehyde through Mannich condensation reaction. The molecular structure of the synthesized benzoxazines is confirmed from Fourier transform infrared and proton nuclear magnetic resonance (1H‐NMR) spectroscopic analyses. The curing behavior and thermal stability of the benzoxazines are analyzed using differential scanning calorimetry and thermogravimetric analysis, respectively. Both DVCP and DVCH core benzoxazines are cured by thermal and photocuring methods. Cyclopentanone core containing benzoxazines exhibit higher thermal stability when compared with that of most of the cyclohexanone core containing benzoxazines. The DVCP and DVCH core benzoxazines exhibit excellent hydrophobic behavior and good self‐extinguishing properties. The photolysis of DVCP‐ and DVCH‐based benzoxazines indicates that the α,β‐unsaturated ketone moiety in the main chain dimerizes through 2π+2π cycloaddition reaction to form a cyclobutane derivative and leads to crosslinking. The photosensitivity of the benzoxazine decreases with an increase in the size of the cycloalkanone ring. The band gap energy (Eg) calculated from absorption spectra is found between 3.0 and 3.29 eV.
Michigan bills would boost MH care, telehealth service access
Authors: Canady Valerie A.
Published: December 2022

Bipartisan legislation that passed in the Michigan House and Senate would allow psychologists to practice in certain states even if they are not licensed there. Although the bills are set to be sent to Gov. Gretchen Whitmer, psychologists hope that this time it will be signed after similar legislation had been vetoed by her two years ago.
International Society for Prenatal Diagnosis 2022 DEBATE: There should be formal accreditation and ongoing quality assurance/review for units offering fetal therapy that includes public reporting of outcomes
Authors: Moldenhauer Julie S. , Johnson Anthony , Van Mieghem Tim
Published: December 2022

The field of fetal therapy has so far escaped from formal accreditation and quality control. Despite that, current published evidence shows that outcomes of interventions in younger fetal therapy centers are similar to what is achieved in more experienced centers and outcomes of interventions have improved over time. The question however remains what is not being published and what should be the standard of care, given the lack of level 1 evidence from randomized controlled trials for many interventions. Formal collaborative networks such as NAFTnet and others allow for anonymized benchmarking of center outcomes, without publicly shaming (and financially punishing) underperforming centers. Large registries also allow for tracking of rare complications and may result in improved patient outcomes over time. Core outcome sets, which could serve as a basis for outcome reporting, are available for some conditions, but certainly not for all, resulting in communication difficulties between centers. Formal accreditation, quality control, and outcome reporting are hard to implement, expensive, and may result in decreasing access to care by pushing smaller centers out of the market. Despite the existing difficulties, international societies have committed to quality improvement, and fetal therapy programs are strongly recommended to participate in voluntary outcome tracking.
ATAC‐seq exposes differences in chromatin accessibility leading to distinct leaf shapes in mulberry
Authors: Wang Lei , Feng Yuming , Wang Jiangying , Jin Xin , Zhang Qiaonan , Ackah Michael , Wang Yuhua , Xu Dayong , Zhao Weiguo
Published: December 2022

Mulberry leaf shape is an important agronomic trait indicating yield, growth, development, and habitat variation. China was the earliest country in the world to grow mulberry for sericulture, and it is also one of the great contributions of the Chinese nation to human civilization. ATAC‐seq (Assay for Transposase Accessible Chromatin using sequencing) is a recently developed technique for genome‐wide analysis of chromatin accessibility. The samples used for ATAC sequencing in this study were divided into two groups of whole leaves (CK‐1 and CK‐2) and lobed leaves (HL‐1 and HL‐2), with two replicates in each group. The related motif analysis, differential expression motif screening, and functional annotation of mulberry leaf shape differences were performed by raw letter analysis to finally obtain the transcription factors (TFs) that lead to the production of heteromorphic leaves. These transcription factors are common in plants, especially the TCP family, shown to be associated with leaf development and growth in other woody plants and are a potential transcription factor responsible for leaf shape differences in mulberry. Dissecting the regulatory mechanisms of leaf shape of different forms of mulberry leaves by ATAC‐seq is an important way to protect mulberry germplasm resources and improve mulberry yield. It is conducive to cultivating mulberry varieties with high resistance to adversity, promoting the sustainable development of sericulture, and protecting and improving the ecological environment.
An experimental vibrational spectroscopic and density functional theory computational study on 2,4‐dioxopyrimidine in solvation phase
Authors: Badoğlu Serdar , Yurdakul Şenay
Published: December 2022

In this study, experimental ATR FTIR spectrum of 2,4‐dioxopyrimidine is recorded in solid phase. Its vibrational frequencies and modes were determined. Density functional theory calculations are employed to determine the ground‐state geometry and vibrational frequencies of the title compound. Possible dimeric forms of the molecule were investigated theoretically. A solvation phase experimental ATR FTIR spectrum is recorded in dimethyl sulfoxide (DMSO) solution and vibrational frequencies together with the modes are determined. Solvent effects are included in our calculations by using polarizable continuum model in DMSO. Solid phase and solvation phase experimental spectra are compared with each other.
Current and future opportunities for satellite remote sensing to inform rewilding
Authors: Pettorelli Nathalie , Schulte to Bühne Henrike
Published: December 2022

Rewilding has been suggested as an effective strategy for addressing environmental challenges such as the intertwined biodiversity and climate change crises, but there is little information to guide the monitoring of rewilding projects. Since rewilding focuses on enhancing ecosystem functionality, with no defined endpoint, monitoring strategies used in restoration are often inappropriate, as they typically focus on assessing species composition, or the ecological transition of an ecosystem towards a defined desired state. We here discuss how satellite remote sensing can provide an opportunity to address existing knowledge and data gaps in rewilding science. We first discuss how satellite remote sensing is currently being used to inform rewilding initiatives and highlight current barriers to the adoption of this type of technology by practitioners and scientists involved with rewilding. We then identify opportunities for satellite remote sensing to help address current knowledge gaps in rewilding, including gaining a better understanding of the role of animals in ecosystem functioning; improving the monitoring of landscape‐scale connectivity; and assessing the impacts of rewilding on the conservation status of rewilded sites. Though significant barriers remain to the widespread use of satellite remote sensing to monitor rewilding projects, we argue that decisions on monitoring approaches and priorities need to be part of implementation plans from the start, involving both remote sensing experts and ecologists. Making use of the full potential of satellite remote sensing for rewilding ultimately requires integrating species and ecosystem perspectives at the monitoring, knowledge‐producing and decision‐making levels. Such an integration will require a change in know‐how, necessitating increased inter‐disciplinary interactions and collaborations, as well as conceptual shifts in communities and organizations traditionally involved in biodiversity conservation.
Deep learning for sustainable agriculture needs ecology and human involvement
Authors: Ryo Masahiro , Schiller Josepha , Stiller Stefan , Rivera Palacio Juan Camilo , Mengsuwan Konlavach , Safonova Anastasiia , Wei Yuqi
Published: December 2022

Deep learning is an emerging data analytic tool that can improve predictability, efficiency and sustainability in agriculture. With a bibliometric analysis of 156 articles, we show how deep learning methods have been applied in the context of sustainable agriculture. As a general publication trend, China and India are leading countries for publication, international collaboration is still minor. Deep learning has been popularly applied in the context of smart agriculture across scales for individual plant monitoring, field monitoring, field operation and robotics, predicting soil, water and climate conditions and landscape‐level monitoring of land use and crop types. We identified that the potential of deep learning had been investigated mainly for predicting soil (abiotic), water, climate and vegetation dynamics, but ecological characteristics are critically understudied. We also highlight key themes that can be better addressed with deep learning for fostering sustainable agriculture: (i) including above‐ and belowground ecological dynamics such as ecosystem functioning and ecotone, (ii) evaluating agricultural impacts on other ecosystems and (iii) incorporating the knowledge and opinions of domain experts and stakeholders into artificial intelligence. We propose that deep learning needs to go beyond automatic data analysis by integrating ecological and human knowledge to foster sustainable agriculture.
Temporal variability in soil organic matter accretion rates in coastal deltaic wetlands under changing depositional environments
Authors: Sapkota Yadav , Xu Kehui , Maiti Kanchan , Inglett Patrick , White John R.
Published: December 2022

The Mississippi River Deltaic Plain experiences high relative sea level rise, limited sediment supply, and high marsh edge erosion, leading to the substantial coastal wetland and stored soil organic matter (SOM) loss. The objective of this study was to understand the SOM accumulation rates over the past 1000 years related to the changes in the depositional environment in these highly eroding coastal wetlands. Soil cores (2 m) were collected from four sites in Barataria Basin, LA and analyzed for proportion of organic and mineral matter, total C, N, P, particle size, and stable isotopic composition (δ13C and δ15N), as well as 14C and 137Cs dating. The soil carbon stock in the 2 m depth (62.4 ± 2 kg m−2) was approximately 88% greater than the carbon stock in just the 1 m depth (33.1 ± 0.6 kg m−2) indicating a need for considering deeper soil profiles (up to 2 m) to estimate blue carbon stock in deltaic environments. The average vertical accretion rate for Barataria Basin was 8.1 ± 0.6 mm year−1 over 50 years. The long‐term (1000‐year time scale) C accumulation rate (39 g C m−2 year−1) was ∼14% of the short‐term accumulation rate (254 ± 19 g C m−2 year−1). Wetlands in Barataria Basin started as fresh marsh and transitioned over time to intermediate to brackish. These marshes were able to maintain relative elevation through the accumulation of organic matter and mud despite high relative rates of sea‐level rise. However, the high rates of edge erosion may limit these marshes to continue to sequester atmospheric carbon under accelerating sea level in the absence of restoration efforts.
Current landscape in antiviral drug development against herpes simplex virus infections
Authors: Frejborg Fanny , Kalke Kiira , Hukkanen Veijo
Published: December 2022

Herpes simplex viruses (HSV) are common human pathogens with a combined global seroprevalence of 90% in the adult population. HSV‐1 causes orofacial herpes but can cause severe diseases, such as the potentially fatal herpes encephalitis and herpes keratitis, a prevalent cause of infectious blindness. The hallmark of HSV is lifelong latent infections and viral reactivations, leading to recurrent lesions or asymptomatic shedding. HSV‐1 and HSV‐2 can cause recurrent, painful, and socially limiting genital lesions, which predispose to human immunodeficiency virus infections, and can lead to neonatal herpes infections, a life‐threatening condition for the newborn. Despite massive efforts, there is no vaccine against HSV, as both viruses share the capability to evade the antiviral defenses of human and to establish lifelong latency. Recurrent and primary HSV infections are treated with nucleoside analogs, but the treatments do not completely eliminate viral shedding and transmission. Drug‐resistant HSV strains can emerge in relation to long‐term prophylactic treatment. Such strains are likely to be resistant to other chemotherapies, justifying the development of novel antiviral treatments. The importance of developing new therapies against HSV has been recognized by the World Health Organization. In this review, we discuss the current approaches for developing novel antiviral therapies against HSV, such as small molecule inhibitors, biopharmaceuticals, natural products, gene editing, and oligonucleotide‐based therapies. These approaches may have potential in the future to answer the unmet medical need. Furthermore, novel approaches are presented for potential eradication of latent HSV.
Bacterial infection microenvironment‐responsive porous microspheres by microfluidics for promoting anti‐infective therapy
Authors: Gao Yang , Ma Qingming
Published: December 2022

The overuse of antibiotics for treating bacterial infection has caused severe bacterial resistance and become a public health threat worldwide. It is desired to develop novel antibiotic delivery systems as efficient antibacterial strategies for promoting anti‐infective therapy. Herein, the AgNPs‐loaded N‐[(2‐hydroxy‐3‐trimethyl ammonium) propyl] chitosan (HTCC)/hyaluronic acid (HA) porous microspheres (HHPMs) by microfluidics have been developed as novel bacterial infection microenvironment (IME)‐responsive antibiotic delivery systems for promoting antimicrobial therapy. The release of AgNPs can respond explicitly to the IME with acidic pH values and relatively high hyaluronidase concentration. The unique porous structures of HHPMs can effectively facilitate the capture and enrichment of bacteria, thus exerting synergistic antibacterial effects, which can be more efficient in instant bacteria inhibiting and killing. The excellent biocompatibility of HHPMs is revealed by investigating their hemolytic activity and cytotoxicity. In vivo assays demonstrate that the fabricated AgNPs‐loaded HHPMs can effectively resist bacterial infection and promote wound healing and tissue regeneration at infected wound sites by inhibition of the bacterial survival. This work indicates that fabricated HHPMs are ideal bacterial infection microenvironment‐responsive materials for antibiotic delivery and show great promises for promoting anti‐infective therapy in clinics.
Tuning the Kinetic Trapping in Chemically Fueled Self‐Assembly
Authors: Kriebisch Brigitte A. K. , Kriebisch Christine M. E. , Bergmann Alexander M. , Wanzke Caren , Tena‐Solsona Marta , Boekhoven Job
Published: December 2022

The front cover artwork is provided by BoekhovenLab at TU Munich. The image shows an energy landscape of kinetically trapped chemically fueled supramolecular fibers, which reminds of a mountain landscape. Read the full text of the Research Article at 10.1002/syst.202200035.
Dog attacks: why was 2022 so bad?
Authors: Loeb Josh , Gray Arabella
Published: December 2022

A higher than usual number of human deaths attributed to dog attacks in 2022 has prompted renewed focus on questions relating to ‘dangerous dogs’, but as Josh Loeb and Arabella Gray find out, answers appear scarce.
Species, God, and Dominion
Authors: Wilkins John S.
Published: December 2022

Species as a concept is the outcome of theological and philosophical considerations, not empirical or scientific need. It still holds political import for the religious movement of dominionism, with great impact on environmentalist and conservationist politics in the United States and elsewhere in the world. This chapter will argue that having a “theoretical” notion of species is inimical to science and polity. It is not needed, as it retains much of its original essentialistic religious origins and emphasizes human exceptionalism to the detriment of ecological stewardship.
Dilepton Decays of Vector Particles
Authors: Faccioli Pietro , Lourenço Carlos
Published: December 2022

This chapter introduces the basic notions used in the measurement of the polarization of a particle and in its interpretation.We use, as a prototype, the case of a vector particle (the $$\text{J}/\psi$$meson,a virtual photon, the Z boson, etc.) decaying into a lepton-antilepton pair.In particular, we address the general shape of the decay angular distribution, its relation to the particle polarization, the meaning of the relevant parameters, and the main difficulties usually encountered in polarization measurements.
Correction to: Doing Indefinite Time
Authors: Marti Irene
Published: December 2022

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Die nationale Begleitgesetzgebung zum Genehmigungsverfahren klinischer Prüfungen mit Humanarzneimitteln im Rahmen der Verordnung (EU) Nr. 536/2014
Authors: Frech Marion , Dexel Florian , Burgard Margareta , Seibel Yvonne
Published: December 2022

Die Verordnung (EU) Nr. 536/2014 (Clinical Trials Regulation [CTR]) über klinische Prüfungen mit Humanarzneimitteln stellt nicht nur die Sponsoren, sondern auch die Behörden und Ethik-Kommissionen vor Herausforderungen. So waren grundlegende strukturelle Veränderungen für die Etablierung des neuartigen Genehmigungsverfahrens erforderlich. Die dazu notwendige Begleitgesetzgebung wurde 2016 mit dem Vierten Gesetz zur Änderung arzneimittelrechtlicher und anderer Vorschriften (4. AMGÄndG) sowie 2017 mit der Klinische Prüfung-Bewertungsverfahren-Verordnung (KPBV) geschaffen.

Das 4. AMGÄndG sah Änderungen des Arzneimittelgesetzes (AMG) vor, die bereits vor Geltungsbeginn der CTR in Kraft getreten sind. Ganz wesentlich betrifft das die Einführung einer Registrierungspflicht für Ethik-Kommissionen beim Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM). Daneben enthält das 4. AMGÄndG Regelungen, die parallel zum Geltungsbeginn der CTR Anfang 2022 in Kraft getreten sind. Die Verordnung über die Anwendung der guten klinischen Praxis bei der Durchführung von klinischen Prüfungen mit Arzneimitteln zur Anwendung an Menschen (GCP-Verordnung) wurde aufgehoben. Der 6. Abschnitt des AMG über den Schutz des Menschen bei klinischen Prüfungen wurde neu gefasst, um die Vorgaben der CTR zu ergänzen und den Verfahrensablauf in das nationale Rechtssystem einzupassen. Insbesondere betrifft das Regelungen über die Zusammenarbeit zwischen Bundesoberbehörden und Ethik-Kommissionen, wie zu Zuständigkeiten, Fristen, Verfahrensabläufen und auch Gebühren. Auch wurden Regelungen für das nationale Verfahren der Freisetzungsgenehmigung bei klinischen Prüfungen mit Arzneimitteln, die gentechnisch veränderte Organismen (GVO) enthalten, getroffen sowie besondere Schutzvorschriften für spezielle Teilnehmergruppen geschaffen.
Land-use Suitability is Not an Intrinsic Property of a Land Parcel
Authors: Snelder Ton , Lilburne Linda , Booker Doug , Whitehead Amy , Harris Simon , Larned Scott , Semadeni-Davies Anette , Plew David , McDowell Richard
Published: December 2022

Agricultural production has economic, environmental, social and cultural consequences beyond farm boundaries, but information about these impacts is not readily available to decision makers. This study applied the land use suitability concept by carrying out an assessment of a region that has the potential for intensification of agricultural production, but where eutrophication of river and estuary receiving environments due to nitrogen enrichment is a significant issue. The assessment evaluated three indicators for each farmable land parcel in the region: productive potential (the inherent productive and economic potential of the parcel), relative contribution (the potential for the parcel to contribute nitrogen to receiving environments compared to other land parcels), and pressure (the load of nitrogen delivered to receiving environments compared to the loads that ensure environmental objectives are achieved). The assessment indicated that land with high suitability for land-use intensification in Southland is limited because areas with high productive potential and low relative contribution rarely coincide with receiving environments with low pressure. Existing data, methods and models can be used to calculate the indicators under different choices for regional land-use intensity and receiving environment objectives. However, the spatial resolution and accuracy that is achievable may preclude using assessment outputs to make land use decisions at small spatial scales such as individual farms. The study highlighted that land use suitability is not an intrinsic property of a land parcel because it is dependent on choices about land use elsewhere in the landscape and the environmental objectives, and that land use suitability is inherently subjective because of decisions that concern how indicators are combined and weighted.
Impact of physical activity on postural stability and coordination in children with posterior fossa tumor: randomized control phase III trial
Authors: Usama Mahmoud , Abdelaziem Faten , Rashed Wafaa M. , Maher Eslam , El Beltagy Mohamed , Zekri Wael
Published: December 2022

Background

Posterior fossa tumor is a type of brain tumor that is located at the borders of both the brain stem and cerebellum. The cerebellum is the brain region in charge of balance and coordination. Pediatric patients diagnosed with posterior fossa tumor have been reported to fall frequently.

Objectives

The aim of this study is to investigate the effectiveness of balance and coordination training in these children.

Methods

This randomized control clinical trial (ClinicalTrials.gov Identifier: NCT04528316) was carried out between September 2020 and April 2021 at Children’s Cancer Hospital-57357. The inclusion criteria were patients with posterior fossa tumor in maintenance phase and, age between 5 and 12 years. The exclusion criteria were patients who had a genetic disorder or suffer from mental retardation, a chronic lung disease, severe cardiomyopathy, or a neuromuscular disease that does not relate to tumor. The study participants were randomly assigned into three groups: Group I/Control group: they received Pilates core stability exercises program, Group II/Postural stability group: they received the same program plus HUMAC balance program, and Group III/Coordination group: they received the same program plus coordination exercises of BOT-2. The semi-parametric proportional odds model was used to compare follow-up scores of the Postural stability group vs Control, and Coordination group vs Control, while adjusting for baseline values. All tests were two sided, with alpha set to 0.05.

Results

Sixty children including 38 boys and 22 girls were enrolled in this study. In all three groups, postural stability and coordination improved significantly in terms of modified clinical test of sensory integration of balance, center of pressure, limits of stability, bilateral coordination, and upper-limb coordination.

Conclusion

The current study supports the value of adding postural stability and coordination training to the physiotherapy plan for children with posterior fossa tumor.

Trial registration number and date of registration

ClinicalTrials.gov Identifier: NCT04528316 on August 27, 2020.
Social Support, social ties, and cognitive function of women with breast cancer: findings from the Women’s Health Initiative (WHI) Life and Longevity After Cancer (LILAC) Study
Authors: Yang Yesol , McLaughlin Eric M. , Naughton Michelle J. , Lustberg Maryam B. , Nolan Timiya S. , Kroenke Candyce H. , Weitlauf Julie C. , Saquib Nazmus , Shadyab Aladdin H. , Follis Shawna , Pan Kathy , Paskett Electra D.
Published: December 2022

Purpose

This study examined associations between self-reported cognitive functioning and social support as well as social ties among women with breast cancer.

Methods

The study included 3351 women from the Women’s Health Initiative Life and Longevity After Cancer cohort who were diagnosed with breast cancer stages I–III. Social support was assessed using a modified Medical Outcomes Study (MOS) Social Support Survey, and marital status was obtained from the baseline questionnaire. We also assessed social ties (e.g., number of friends, relatives, living children) and cognitive function (Functional Assessment of Cancer Therapy-Cognitive Function [FACT-COG]) on the year-1-follow up questionnaire. Multivariable quantile regression was used to estimate the changes in median cognitive scores. Kruskal–Wallis tests were used to assess the association of cognitive function with social ties.

Results

The majority of participants were non-Hispanic White (93.3%), presently married (49%), with at least a 4-year college degree (53.2%), and had been diagnosed with localized breast cancer (79%). A 10-point higher social support score correlated to a 0.32 higher (better) median cognitive score (p < 0.001). Women who were presently married tended to have better cognition than women who were divorced/separated or widowed (p = 0.01). Significant associations were also present for having close relatives (p < 0.001) or friends (p < 0.001), with cognitive scores being higher in those with at least one close relative or friend compared to none.

Conclusion

Women reporting higher social support and greater numbers of friends or relatives have higher cognitive functioning. Compared to divorced or separated women, married women were likely to have higher cognitive functioning. These findings suggest that social support assessments have the potential to help identify women at higher risk of cognitive decline.
Untersuchungen zur Vergleichbarkeit der statischen und dynamischen Überdruckprüfung von druckfesten Kapselungen
Authors: Spörhase Stefanie , Brombach Falk Marian , Eckhardt Felix , Krause Tim , Markus Detlev , Küstner Bernd , Walch Otto
Published: December 2022

Der Einsatz von elektrischen Geräten in explosionsgefährdeten Bereichen erfordert besondere Schutzmaßnahmen, um eine Zündung der explosionsfähigen Atmosphäre zu verhindern. Eine mögliche Schutzmaßnahme ist die Zündschutzart „Druckfeste Kapselung“. Hierfür müssen die Gehäuse nach den Vorgaben der Norm IEC 60079‑1 ausgelegt und geprüft werden. Neben anderen Prüfungen muss das Gehäuse entweder einer statischen oder einer dynamischen Überdruckprüfung unterzogen werden. Diese basieren auf dem maximalen Druck einer Explosion, dem sogenannten Bezugsdruck. Auf Grundlage der Überdruckprüfung wird die Festigkeit des Gehäuses beurteilt.

Dieser Beitrag beschäftigt sich mit der Frage, ob eine dieser beiden Prüfmethoden das Material stärker beansprucht als die andere. Es wurden Gehäuse aus verschiedenen Materialien und Wandstärken statisch und dynamisch belastet. Die dynamischen Explosionsversuche wurden mit verschiedenen Gasen, Vordrücken und Gehäusegeometrien durchgeführt. Hierbei wurden der Innendruck mit piezoelektrischen Drucksensoren und die Dehnung des Materials mit Hilfe von Dehnungsmessstreifen gemessen und die Ergebnisse verglichen.

Bei einfachen Geometrien treten unterhalb der Dehn- bzw. Streckgrenze bei der dynamischen und bei der statischen Prüfung vergleichbar große Dehnungen des Materials auf. Bei Geometrien, bei denen Drucküberhöhungen, pressure piling, auftreten, kommt es zusätzlich zu einer Schwingungsanregung, welches sich in erhöhten Dehnungswerten zeigt. Es kann dennoch in diesem Fall keine Aussage darüber getroffen werden, welche Prüfmethode zu einer höheren Belastung des Prüfmusters führt.
Reshoring by Decree? The Effects of Decoupling Europe from Global Value Chains
Authors: Sandkamp Alexander
Published: December 2022

Overall, decoupling from certain countries may be both politically necessary and economically feasible, at least in the long run. However, a general shift of production back to Europe would be accompanied by significant losses in real income.
The End of the End of History: A Political-Economy Perspective
Authors: Zissimos Ben
Published: December 2022

From the standpoint of the focus of this article, we need to find a better way to compensate the losers from globalisation so that voters re-engage through the democratic process with openness and benefit from the potential for increased prosperity that this holds.
Multi-fidelity Surrogate Modelling of Wall Mounted Cubes
Authors: Mole Andrew , Skillen Alex , Revell Alistair
Published: December 2022

This paper focuses on the application of multi-fidelity surrogate modelling to characteristics of a flow as it changes with a parameter. This provides insight into the potential of combining multi-fidelity modelling approaches with varying fidelities of computational fluid dynamics methods to a parameter space exploration. A limited number of trusted high-fidelity large eddy simulation data points, in combination with an extended study using lower-fidelity Reynolds averaged Navier–Stokes modelling is used as the input for the surrogate model. Multi-fidelity surrogate models are implemented to bridge the low-fidelity and high-fidelity models providing an improved surrogate model over using a single fidelity alone. The flow around tandem wall mounted cubes at varying inlet yaw angle is used as an aerodynamic test case for this methodology. Results presented show that the multi-fidelity surrogate modelling provides a significant improvement over single fidelity modelling for the prediction of global flow properties. This methodology is then extended to combine multiple local flow features into the multi-fidelity model to build up fuller descriptions of the flow at angles not included in the training data for the model. The results of this are presented for both one-dimensional line plots at a range of locations along the center line of the flow and for two-dimensional slices of the velocity field. The multi-fidelity surrogate model produces results at locations in the parameter space away from the high fidelity training data that match closely to large eddy simulation results.
Robust and continuous metric subregularity for linear inequality systems
Authors: Camacho J. , Cánovas M. J. , López M. A. , Parra J.
Published: December 2022

This paper introduces two new variational properties, robust and continuous metric subregularity, for finite linear inequality systems under data perturbations. The motivation of this study goes back to the seminal work by Dontchev, Lewis, and Rockafellar (2003) on the radius of metric regularity. In contrast to the metric regularity, the unstable continuity behavoir of the (always finite) metric subregularity modulus leads us to consider the aforementioned properties. After characterizing both of them, the radius of robust metric subregularity is computed and some insights on the radius of continuous metric subregularity are provided.
Extracellular adenosine 5ʹ-diphosphate promotes MCP-1/CCL2 expression via the P2Y13 purinergic receptor/ERK signaling axis in temporomandibular joint-derived mouse fibroblast-like synoviocytes
Authors: Yokota Seiji , Chosa Naoyuki , Matsumoto Shikino , Satoh Kazuro , Ishisaki Akira
Published: December 2022

Background

Temporomandibular joint osteoarthritis (TMJ-OA) causes cartilage degeneration, bone cavitation, and fibrosis of the TMJ. However, the mechanisms underlying the fibroblast-like synoviocyte (FLS)-mediated inflammatory activity in TMJ-OA remain unclear.

Methods and results

Reverse transcription-quantitative polymerase chain reaction analysis revealed that the P2Y1, P2Y12, and P2Y13 purinergic receptor agonist adenosine 5ʹ-diphosphate (ADP) significantly induces monocyte chemotactic protein 1 (MCP-1)/ C–C motif chemokine ligand 2 (CCL2) expression in the FLS1 synovial cell line. In contrast, the uracil nucleotide UTP, which is a P2Y2 and P2Y4 agonist, has no significant effect on MCP-1/CCL2 production in FLS1 cells. In addition, the P2Y13 antagonist MRS 2211 considerably decreases the expression of ADP-induced MCP-1/CCL2, whereas ADP stimulation enhances extracellular signal-regulated kinase (ERK) phosphorylation. Moreover, it was found that the mitogen-activated protein kinase/ERK kinase (MEK) inhibitor U0126 reduces ADP-induced MCP-1/CCL2 expression.

Conclusion

ADP enhances MCP-1/CCL2 expression in TMJ FLSs via P2Y13 receptors in an MEK/ERK-dependent manner, thus resulting in inflammatory cell infiltration in the TMJ. Collectively, the findings of this study contribute to a partial clarification of the signaling pathway underlying the development of inflammation in TMJ-OA and can help identify potential therapeutic targets for suppressing ADP-mediated purinergic signaling in this disease.
Quality of life outcomes in incidental and operated meningiomas (QUALMS): a cross-sectional cohort study
Authors: Keshwara Sumirat M. , Gillespie Conor S. , Mustafa Mohammad A. , George Alan M. , Richardson George E. , Clynch Abigail L. , Wang Justin Z. , Lawson David D. A. , Gilkes Catherine E. , Farah J. Osman , Yousaf Jawad , Chavredakis Emmanuel , Mills Samantha J. , Brodbelt Andrew R. , Zadeh Gelareh , Millward Christopher P. , Islim Abdurrahman I. , Jenkinson Michael D.
Published: December 2022

Introduction:

Few studies have evaluated meningioma patients’ longer-term health-related quality of life (HRQoL) following diagnosis and treatment, particularly in those with incidental, actively monitored tumours.

Methods:

A single-center, cross-sectional study was completed. Adult patients with surgically managed or actively monitored meningioma with more than five years of follow-up were included. The patient-reported outcome measures RAND SF-36, EORTC QLQ-C30 and QLQ-BN20 were used to evaluate HRQoL. HRQoL scores were compared to normative population data. Outcome determinants were evaluated using multivariate linear regression analysis.

Results:

243 patient responses were analyzed, and the mean time from diagnosis was 9.8 years (range 5.0–40.3 years). Clinically relevant, statistically significant HRQoL impairments were identified across several SF-36 and QLQ-C30 domains. Increasing education level (β = 2.9, 95% CI 0.9 to 4.9), P = .004), employment (β = 7.7, 95% CI 2.2 to 13.1, P = .006) and absence of postoperative complications (β=-6.7, 95% CI -13.2 to (-)0.3, P = .041) were associated with a better QLQ-C30 summary score. Other tumour and treatment variables were not.

Conclusion:

This study highlights the longer-term disease burden of patients with meningioma nearly one decade after diagnosis or surgery. Patients with actively monitored meningioma have similar HRQoL to operated meningioma patients. Healthcare professionals should be mindful of HRQoL impairments and direct patients to sources of support as needed.