bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental investigation of the electromagnetic acceleration mechanisms in an applied-field magnetoplasmadynamic thruster
Authors: Sun Yuzhe , Wang Yibai , Wang Yimeng , Wu Peng , Zhang Guangchuan , Chen Zhiyuan , Gao Yongcheng , Ren Junxue , Tang Haibin
Published: November 2024

The high specific impulse and efficiency of the applied-field magnetoplasmadynamic thruster (AF-MPDT) make it one of the most promising electric thrusters in deep space exploration. However, the crucial electromagnetic acceleration mechanisms are still not clearly investigated, which limits performance improvement. The electromagnetic acceleration mechanism is closely related to the current path and magnetic field distribution in the plume. Experiments are conducted using a water-cooled Hall probe in the steady-state AF-MPDT plume. The radial, azimuthal and axial magnetic fields are measured, then the current density and Lorentz force density are calculated. The results show that the outflow current accounts for 63% to 82% of the thruster discharge current depending on the strength of the applied magnetic field. Moreover, the outflow current can extend the range of electromagnetic force action, which in turn increases the effect of electromagnetic acceleration. The radial Lorentz force is numerically dominant, and the combined effect of the radial Lorentz force and axial Lorentz force is to compress the plasma toward the axis. In electromagnetic acceleration, Self-field contributions are less than 5%, while E× B acceleration constitutes −12.2%–21.2%, and diamagnetic acceleration dominates at approximately 76.7%–90.5%. Finally, a method for evaluating the rotational velocity was presented based on the MHD equations. The centrifugal force was then calculated by combining this with the plasma density. At the thruster outlet, the centrifugal force is significant and cannot be ignored in comparison to the radial Lorentz force.
Testing continuous spontaneous localization model with charged macromolecules
Authors: Lenler-Eriksen Emil , Drewsen Michael , Carlesso Matteo
Published: November 2024

In the last decade, a growing interest has been devoted to models of spontaneous collapse of the wavefunction, known also as collapse models. They coherently solve the well-known quantum measurement problem by suitably modifying the Schrödinger evolution. Quantum experiments are now finally within the reach of testing such models (and thus testing the limits of quantum theory). Here, we propose a method based on a two-ions confined in a linear Paul trap to possibly enhance the testing capabilities of such experiments. The combination of an atomic and a macromolecular ion provide a good match for the cooling of the motional degrees of freedom and a non-negligible insight in the collapse mechanism, respectively.
Electron attachment to CCl3COOH molecule and clusters
Authors: Kocábková Barbora , Schöpfer Gabriel , Ďurana Jozef , Rakovský Jozef , Poterya Viktoriya , Gatt Michael , Jank Dominik , Ončák Milan , Fárník Michal
Published: November 2024

Trichloroacetic acid (TCA) is an integral part of the atmosphere as well as a prototypical small polyhalogenated organic acid. Here, we investigate dissociative electron attachment (DEA) to the TCA molecule and small (TCA)
N
clusters combining cluster beam experiments with quantum chemical calculations exploiting genetic algorithm search and structure clustering. We report negative ion mass spectra at electron energies of 2 eV and 6.8 eV as well as energy dependent ion yields from 2 eV to 10 eV. The chlorine anion Cl− formation is by far the dominating channel at all energies in both isolated molecule and clusters. The calculations suggest that the C–Cl bond breaks spontaneously in the ground state of the transient negative anion. For a single molecule, about an order of magnitude less abundant CCl

2

−

,

CCl2COO−, and CCl3COO−ions are observed. These ions correspond to the HCl + CO2, HCl, and H abstraction reactions, respectively. In the cluster environment, the major cluster ion fragments after the Cl−ion correspond to the H abstraction, with other fragmentation pathways (HCl abstraction) being strongly suppressed or not observed at all (HCl + CO2). Our calculations substantiate the experimental observations and show how the hydrogen bond network efficiently controls the dissociation pathways in molecular clusters.
Non-Gaussian tails without stochastic inflation
Authors: Ballesteros Guillermo , Konstandin Thomas , Rodríguez Alejandro Pérez , Pierre Mathias , Rey Julián
Published: November 2024

We show, both analytically and
numerically,
that
non-Gaussian tails in the probability density function of curvature perturbations arise in ultra-slow-roll inflation from the δN formalism, without invoking stochastic inflation. Previously reported discrepancies between both approaches are a consequence of not correctly accounting for momentum perturbations. Once they are taken into account, both approaches agree to an excellent degree. The shape of the tail depends strongly on the phase space of inflation.
Impact of inhomogeneous diffusion on secondary cosmic ray and antiproton local spectra
Authors: Tovar-Pardo Álvaro , Luque Pedro De La Torre , Sánchez-Conde Miguel A.
Published: November 2024

Recent γ-ray and neutrino observations seem to favor the consideration of non-uniform diffusion of cosmic rays (CRs) throughout the Galaxy.
In this study, we investigate the consequences of spatially-dependent inhomogeneous propagation of CRs on the fluxes of secondary CRs and antiprotons detected at Earth. A comparison is made among different scenarios in search of potential features that may guide us toward favoring one over another in the near future. We also examine both the influence of inhomogeneous propagation in the production of secondary CRs from interactions with the gas, and the effects of this scenario on the local fluxes of antiprotons and light antinuclei produced as final products of dark matter annihilation. Our results indicate that the consideration of an inhomogeneous diffusion model could improve the compatibility of the predicted local antiproton flux with that of B, Be and Li, assuming only secondary origin of these particles. In addition, our model predicts a slightly harder local antiproton spectrum, making it more compatible with the high energy measurements of AMS-02.
Finally, no significant changes are expected in the predicted local flux of antiprotons and antinuclei produced from dark matter among the different considered propagation scenarios.
Shape/properties collaborative intelligent manufacturing of artificial bone scaffold: structural design and additive manufacturing process
Authors: Feng Pei , Liu Lingxi , Yang Feng , Min Rui , Wu Ping , Shuai Cijun
Published: November 2024

Artificial bone graft stands out for avoiding limited source of autograft as well as susceptibility to infection of allograft, which makes it a current research hotspot in the field of bone defect repair. However, traditional design and manufacturing method cannot fabricate bone scaffold that well mimics complicated bone-like shape with interconnected porous structure and multiple properties akin to human natural bone. Additive manufacturing, which can achieve implant’s tailored external contour and controllable fabrication of internal microporous structure, is able to form almost any shape of designed bone scaffold via layer-by-layer process. As additive manufacturing is promising in building artificial bone scaffold, only combining excellent structural design with appropriate additive manufacturing process can produce bone scaffold with ideal biological and mechanical properties. In this article, we sum up and analyze state of art design and additive manufacturing methods for bone scaffold to realize shape/properties collaborative intelligent manufacturing. Scaffold design can be mainly classified into design based on unit cells and whole structure, while basic additive manufacturing and 3D bioprinting are the recommended suitable additive manufacturing methods for bone scaffold fabrication. The challenges and future perspectives in additive manufactured bone scaffold are also discussed.
Open problem in quantum entanglement theory solved after nearly 25 years
Authors: Iannotti Daniele
Published: November 2024

Julio de Vicente from the Universidad Carlos III de Madrid, Spain, has shown that so-called maximally entangled mixed states (MEMS) for a fixed spectrum do not always exist.
NASA at ‘crossroads’ warns panel
Authors: Gwynne Peter
Published: November 2024

A report finds out-of-date infrastructure, budget issues, inefficient management practices, and an unbalanced reliance on commercial partners, as Peter Gwynne reports.
Annular eclipse photograph bags Royal Observatory Greenwich prize
Authors: Banks Michael
Published: November 2024

Ryan Imperio has beaten thousands of amateur and professional photographers from around the world to win the 2024 Astronomy Photographer of the Year.
UK outlines next STEPs towards fusion
Authors: Banks Michael
Published: November 2024

Engineers and physicists have met to discuss the challenges and opportunities of building a practical fusion power plant in the UK. Michael Banks listens in.
Pizza lessons for physicists
Authors: McKenzie James
Published: November 2024

Zume was a $500m start-up company that delivered pizzas cooked by robots on trucks. James McKenzie explains what its failure can teach physicists.
Bayesian optimization for state engineering of quantum gases
Authors: Müller Gabriel , Martínez-Lahuerta Víctor J , Sekulic Ivan , Burger Sven , Schneider Philipp-Immanuel , Gaaloul Naceur
Published: November 2024

State engineering of quantum objects is a central requirement for precision sensing and quantum computing implementations. When the quantum dynamics can be described by analytical solutions or simple approximation models, optimal state preparation protocols have been theoretically proposed and experimentally realized. For more complex systems such as interacting quantum gases, simplifying assumptions do not apply anymore and the optimization techniques become computationally impractical. Here, we propose Bayesian optimization based on multi-output Gaussian processes to learn the physical properties of a Bose–Einstein condensate within few simulations only. We evaluate its performance on an optimization study case of diabatically transporting the quantum gas while keeping it in its ground state. Within a few hundred executions, we reach a competitive performance to other protocols. While restricting this benchmark to the well known Thomas–Fermi approximation for straightforward comparisons, we expect a similar performance when employing more complex theoretical models, which would be computationally more challenging, rendering standard optimal control theory protocols impractical. This paves the way for efficient state engineering of complex quantum systems including mixtures of interacting gases or cold molecules.
MR Corge: sensitivity analysis of Mendelian randomization based on the core gene hypothesis for polygenic exposures
Authors: Zhang Wenmin , Su Chen-Yang , Yoshiji Satoshi , Lu Tianyuan
Published: November 2024

Mendelian randomization is being utilized to assess causal effects of polygenic exposures, where many genetic instruments are subject to horizontal pleiotropy. Existing methods for detecting and correcting for horizontal pleiotropy have important assumptions that may not be fulfilled. Built upon the core gene hypothesis, we developed MR Corge for performing sensitivity analysis of Mendelian randomization. MR Corge identifies a small number of putative core instruments that are more likely to affect genes with a direct biological role in an exposure and obtains causal effect estimates based on these instruments, thereby reducing the risk of horizontal pleiotropy. Using positive and negative controls, we demonstrated that MR Corge estimates aligned with established biomedical knowledge and the results of randomized controlled trials. MR Corge may be widely applied to investigate polygenic exposure-outcome relationships.

Availability and implementation

An open-sourced R package is available at https://github.com/zhwm/MRCorge.
Labile sex allocation and sex ratio in the androdioecious barnacle Octolasmis unguisiformis
Authors: Wijayanti Hendry , Sawada Kota , Yasuda Keiko , Yusa Yoichi
Published: November 2024

Theoretical models predict that the sex allocation of hermaphrodites is affected by the number of individuals who can donate sperm to each other [mating group size (MGS)]. However, theory does not make clear predictions for solitary hermaphrodites (i.e. MGS = 1). Moreover, few empirical studies exist on the sex allocation of hermaphrodites coexisting with males (androdioecy). We studied male function (testis and seminal vesicle volumes), female function (ovary volume), sex allocation [male/(male + female functions)], and the male-to-hermaphrodite ratio in the androdioecious barnacle Octolasmis unguisiformis, with hermaphrodites carrying dwarf males. We analysed the effects of MGS on these traits separately for MGS 1 vs. 2 or larger (i.e., whether hermaphrodites are solitary or gregarious) and for MGS 2–4. The male function of mature hermaphrodites presented a positive relationship with MGS in both MGS 1 vs. 2 or larger and MGS 2–4, and female function presented a negative relationship with MGS when comparing MGS 1 vs. 2 or larger. Moreover, the sex allocation of hermaphrodites was positively related to MGS in the analyses of both MGS 1 vs. 2 or larger and MGS 2–4. Remarkably, we found many ‘hermaphrodites’ lacking sperm in MGS 1, suggesting that they are functional females. In addition, more dwarf males per hermaphrodite were present in small MGS. These results generally agreed with the theoretical predictions and revealed a highly plastic sexual system of this barnacle.
Risk of neurodevelopmental impairment in Swedish preterm children treated for necrotizing enterocolitis: retrospective cohort study
Authors: Brusselaers Nele , Simin Johanna , E. Lilja Helene
Published: November 2024

Background

As the survival of preterm infants has increased, the management of long-term complications, especially neurodevelopmental impairment, becomes increasingly important. The aim of this study was to investigate the risk of neurodevelopmental disorders in preterm babies receiving medical or surgical treatment for necrotizing enterocolitis, compared with other preterm babies and preterm babies who received abdominal surgery for other indications.

Methods

In this nationwide Swedish cohort study, including all liveborn preterm babies born between 1998 and 2019, the risk of attention deficit (and hyperactivity) disorder, autism spectrum disorders, cerebral palsy and intellectual disability was assessed by multivariable Cox regression, expressed as hazard ratios and 95% confidence intervals (c.i.).

Results

Of the surgically (n = 384) and medically (n = 709) treated preterm infants with necrotizing enterocolitis, neurodevelopmental disorders were present in 32% (HR 2.24, 95% c.i. 1.86 to 2.69) and 22% respectively (HR 1.40, 95% c.i. 1.19 to 1.65), compared with 21% (HR 1.63, 95% c.i. 1.40 to 1.91) in the abdominal surgery group (n = 844) and 13% (reference) among other preterm infants (n = 78 972). The highest relative increases were for intellectual disability (HR 3.60, 95% c.i. 2.65 to 4.89) in the surgical necrotizing enterocolitis group and abdominal surgery group (HR 2.84, 95% c.i. 2.12 to 3.80) compared with the control preterm group, and for cerebral palsy (respectively HR 2.74, 95% c.i. 2.04 to 3.68 and HR 2.54, 95% c.i. 1.87 to 3.44). Medically treated necrotizing enterocolitis was associated with autism (HR 1.67, 95% c.i. 1.34 to 2.08), without significant increases for the other specific outcomes. Both surgically treated groups were also strongly associated with both attention deficit (and hyperactivity) disorder and autism.

Conclusion

Surgically treated necrotizing enterocolitis, medically treated necrotizing enterocolitis and abdominal surgery for other indications in preterm infants were all associated with an increased risk of impaired neurodevelopmental outcomes, compared with other preterm infants.
In Response to the Editorial for the BJSW 54(4), Lived versus Living Experience by Dominic Watters
Authors: Cunningham Christopher
Published: November 2024

In applying the concept of living experience to widening participation in higher education, a process of ‘consumption’ that creates profit for powerholders is discussed—while championing social mobility, the widening participation agenda has done little to address the long-standing social and economic inequalities of British society. Yet, through this process, a ‘sector’ of higher education built upon neoliberal principles has been created. Pushing back against the systems of metrification that threaten education’s authenticity, I propose that powerholders apply ethnographic research methods to their decision-making processes.
Redefining pancreatic cancer management with tumor-agnostic precision medicine
Authors: Reddy Neha K , Subbiah Vivek
Published: November 2024

Precision oncology and tumor-agnostic drug development provide hope for enhancing outcomes among patients with pancreatic cancer. Tumor-agnostic therapies have emerged across various tumor types, driven by insights into shared biomarkers. In the case of pancreatic cancer, the prevalence of the KRAS gene mutation is noteworthy. However, there exist other actionable alterations, such as BRCA1/2 mutations and fusion genes (BRAF, FGFR2, RET, NTRK, NRG1, and ALK), which present potential targets for therapy. Notably, tumor-agnostic drugs have demonstrated efficacy in specific subsets of pancreatic cancer patients who harbor these genetic alterations. Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers. Moreover, targeted therapies for BRAF V600, RET fusions, and HER2/neu overexpression have displayed promising results in specific subsets of pancreatic cancer patients. Emerging targets like NRG fusions, FGFR2 fusions, TP53 mutations, and KRAS G12C mutations present potential avenues for targeted therapy. Tumor-agnostic therapies have the potential to revolutionize pancreatic cancer treatment by focusing on specific genetic alterations. It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.
Oculomotor functional connectivity associated with motor sequence learning
Authors: Rubino Cristina , Andrushko Justin W , Rinat Shie , Harrison Adam T , Boyd Lara A
Published: November 2024

Acquisition of learned motor sequences involves saccades directed toward the goal to gather visual information prior to reaching. While goal-directed actions involve both eye and hand movements, the role of brain areas controlling saccades during motor sequence learning is still unclear. This study aimed to determine whether resting-state functional connectivity of oculomotor regions is associated with behavioral changes resulting from motor sequence learning. We investigated connectivity between oculomotor control regions and candidate regions involved in oculomotor control and motor sequence learning. Twenty adults had brain scans before 3 days of motor task practice and after a 24-hour retention test, which was used to assess sequence-specific learning. During testing, both saccades and reaches were tracked. Stronger connectivity in multiple oculomotor regions prior to motor task practice correlated with greater sequence-specific learning for both saccades and reaches. A more negative connectivity change involving oculomotor regions from pre- to post-training correlated with greater sequence-specific learning for both saccades and reaches. Overall, oculomotor functional connectivity was associated with the magnitude of behavioral change resulting from motor sequence learning, providing insight into the function of the oculomotor system during motor sequence learning.
miR-24-3p secreted as extracellular vesicle cargo by cardiomyocytes inhibits fibrosis in human cardiac microtissues
Authors: Senesi Giorgia , Lodrini Alessandra M , Mohammed Shafeeq , Mosole Simone , Hjortnaes Jesper , Veltrop Rogier J A , Kubat Bela , Ceresa Davide , Bolis Sara , Raimondi Andrea , Torre Tiziano , Malatesta Paolo , Goumans Marie-José , Paneni Francesco , Camici Giovanni G , Barile Lucio , Balbi Carolina , Vassalli Giuseppe
Published: November 2024

Aims

Cardiac fibrosis in response to injury leads to myocardial stiffness and heart failure. At the cellular level, fibrosis is triggered by the conversion of cardiac fibroblasts (CF) into extracellular matrix-producing myofibroblasts. miR-24-3p regulates this process in animal models. Here, we investigated whether miR-24-3p plays similar roles in human models.

Methods and results

Gain- and loss-of-function experiments were performed using human induced pluripotent stem cell-derived cardiomyocytes (hCM) and primary hCF under normoxic or ischaemia-simulating conditions. hCM-derived extracellular vesicles (EVs) were added to hCF. Similar experiments were performed using three-dimensional human cardiac microtissues and ex vivo cultured human cardiac slices. hCF transfection with miR-24-3p mimic prevented TGFβ1-mediated induction of FURIN, CCND1, and SMAD4—miR-24-3p target genes participating in TGFβ1-dependent fibrogenesis—regulating hCF-to-myofibroblast conversion. hCM secreted miR-24-3p as EV cargo. hCM-derived EVs modulated hCF activation. Ischaemia-simulating conditions induced miR-24-3p depletion in hCM-EVs and microtissues. Similarly, hypoxia down-regulated miR-24-3p in cardiac slices. Analyses of clinical samples revealed decreased miR-24-3p levels in circulating EVs in patients with acute myocardial infarction (AMI), compared with healthy subjects. Post-mortem RNAScope analysis showed miR-24-3p down-regulation in myocardium from patients with AMI, compared with patients who died from non-cardiac diseases. Berberine, a plant-derived agent with miR-24-3p-stimulatory activity, increased miR-24-3p contents in hCM-EVs, down-regulated FURIN, CCND1, and SMAD4, and inhibited fibrosis in cardiac microtissues.

Conclusion

These findings suggest that hCM may control hCF activation through miR-24-3p secreted as EV cargo. Ischaemia impairs this mechanism, favouring fibrosis.
At a Remove: The Curious State(lessness) of Migrant Mothering in Novels by Shumona Sinha and Nathacha Appanah
Authors: Lee Mark D
Published: November 2024

This article orchestrates a critical conversation between novels by contemporary French writers Shumona Sinha and Nathacha Appanah around the question of mothering, space, and migration. Whether mothers by choice, by default, or childless, the outwardly dissimilar women of the novels studied arrive at a shared poetic interrogation of a remove in migrant motherhood, culminating in a curious spectral statelessness. Rethinking this odd form of mothering at a distance, I identify the performance of a dispossession as both perilous and salutary. Finally, I articulate how this ghostly remove is reinscribed in Appanah’s remarks about how Sinha and she—as non-native, non-European writers of French—are disjointedly situated in French literature, which they re-imagine as a contested, stateless space for their literary expression.
Peptipedia v2.0: a peptide sequence database and user-friendly web platform. A major update
Authors: Cabas-Mora Gabriel , Daza Anamaría , Soto-García Nicole , Garrido Valentina , Alvarez Diego , Navarrete Marcelo , Sarmiento-Varón Lindybeth , Sepúlveda Yañez Julieta H , Davari Mehdi D , Cadet Frederic , Olivera-Nappa Álvaro , Uribe-Paredes Roberto , Medina-Ortiz David
Published: November 2024

In recent years, peptides have gained significant relevance due to their therapeutic properties. The surge in peptide production and synthesis has generated vast amounts of data, enabling the creation of comprehensive databases and information repositories. Advances in sequencing techniques and artificial intelligence have further accelerated the design of tailor-made peptides. However, leveraging these techniques requires versatile and continuously updated storage systems, along with tools that facilitate peptide research and the implementation of machine learning for predictive systems. This work introduces Peptipedia v2.0, one of the most comprehensive public repositories of peptides, supporting biotechnological research by simplifying peptide study and annotation. Peptipedia v2.0 has expanded its collection by over 45% with peptide sequences that have reported biological activities. The functional biological activity tree has been revised and enhanced, incorporating new categories such as cosmetic and dermatological activities, molecular binding, and antiageing properties. Utilizing protein language models and machine learning, more than 90 binary classification models have been trained, validated, and incorporated into Peptipedia v2.0. These models exhibit average sensitivities and specificities of 0.877±0.0530 and 0.873±0.054, respectively, facilitating the annotation of more than 3.6 million peptide sequences with unknown biological activities, also registered in Peptipedia v2.0. Additionally, Peptipedia v2.0 introduces description tools based on structural and ontological properties and user-friendly machine learning tools to facilitate the application of machine learning strategies to study peptide sequences.

Database URL: https://peptipedia.cl/
Move out of the land: certification and migration in China
Authors: Huangfu Bingyu , Gao Xuwen , Shi Xinjie , Jin Songqing
Published: November 2024

Motivated by the emphasis on securing property rights as an important tool for the efficient allocation of resources, including land and labour, we use three rounds of China Rural Household Panel Survey data to assess the impact of a land certification programme (LCP) on the labour and land allocation in rural China. We find that the LCP results in increased rural–urban migration, more active land rental markets, as well as higher household income and consumption in rural China. These effects vary with age and are larger for younger individuals and households with heads aged 50 years or younger. Improving property rights could be a central task for the Chinese government to tackle issues related to labour and land misallocation.
Regulators of aerobic and anaerobic methane oxidation in two pristine temperate peatland types
Authors: Nweze Justus Amuche , Tláskal Vojtěch , Wutkowska Magdalena , Meador Travis B , Picek Tomáš , Urbanová Zuzana , Daebeler Anne
Published: November 2024

Despite covering <5% of Earth's terrestrial area, peatlands are crucial for global carbon storage and are hot spots of methane cycling. This study examined the dynamics of aerobic and anaerobic methane oxidation in two undisturbed peatlands: a fen and a spruce swamp forest. Using microcosm incubations, we investigated the effect of ammonium addition, at a level similar to current N pollution processes, on aerobic methane oxidation. Our findings revealed higher methane consumption rates in fen compared to swamp peat, but no effect of ammonium amendment on methane consumption was found. Members of Methylocystis and Methylocella were the predominant methanotrophs in both peatlands. Furthermore, we explored the role of ferric iron and sulfate as electron acceptors for the anaerobic oxidation of methane (AOM). AOM occurred without the addition of an external electron acceptor in the fen, but not in the swamp peat. AOM was stimulated by sulfate and ferric iron addition in the swamp peat and inhibited by ferric iron in the fen. Our findings suggest that aerobic methane oxidizers are not N-limited in these peatlands and that there is an intrinsic potential for AOM in these environments, partially facilitated by ferric iron and sulfate acting as electron acceptors.
Efficacy of Janus Kinase Inhibitors (JAKi) in the treatment of biologic-naive and biologic-experienced patients with ulcerative colitis
Authors: Yeung K , Al-Zarrad D , Chana A , Dyall L , Kamperidis N , Arebi N
Published: November 2024

Introduction

Janus kinase inhibitors (JAKi) are an orally available treatment for patients with moderately to severe ulcerative colitis (UC). There are currently 3 JAKi for UC: tofacitinib, filgotinib and upadacitinib with variable selectivity to JAK-11. There is limited data comparing the outcomes between biologic-naive and biologic-experienced patients. This study describes the effectiveness of JAKi according to biologic exposure.

Aim

To investigate the effectiveness of 3 the JAKi’s, tofacitinib, filgotinib and upadacitinib according to biologic exposure.

Method

We undertook a retrospective study of UC patients treated with JAKi within a tertiary hospital. Clinical endpoints were assessed at week 8-12. Baseline disease activity, previous advanced therapies and use of corticosteroids were documented. Clinical response was defined as reduction in SCCAI score by ≥3 points from baseline or a sustained score of <2.5. Clinical remission was defined as a SCCAI score of < 2.5, and/ or a calprotectin level of <250 mg/g with a CRP of < 5mg/L.

Ethical approval has been granted by HRA and Health and Care Research Wales (HCRW) (REC ref: 24/HRA/1198)

Results

52 patients were reviewed at week 8-12 following their first dose. 15, 15 and 22 patients were on tofacitinib, filgotinib, and upadacitinib respectively. 3 (20%) of patient in the tofacitinib group were exposed to at least 3 biologics prior to initiating the JAK Inhibitor, followed by upadacitinib which was 3 (14%) of patients. In the tofacitinib group, most patients were exposed to 2 previous biologics (n=7, 47%), whereas majority of patients on filgotinib and upadacitinib had exposure to 1 previous biologic, 7 (47%) and 8 (36%) patients respectively. For the patient group exposed to 3 or more biologics (n=7, 14%), 100% patients on tofacitinib (n=3) and upadacitinib (n=3) achieved clinical remission by week 8-12, whereas none of the patients on filgotinib achieve clinical remission. In biologic naïve patients, filgotinib demonstrated the greatest improvement in calprotectin score with a reduction in 30% from baseline (n=2, 100%). In patients exposed to ≥3 biologics, upadacitinib achieved higher rates of improvement in faecal calprotectin score (n=2, 100%).

Conclusion

Our observations suggest that patients exposed to at least 3 biologics, tofacitinib and upadacitinib were the most effective, whereas filgotinib seems to be more effective in biologic naïve patients. Our patient cohort is small. We will continue to collect data and undertake further statistical analysis to examine the significance of the observations and factors associated with effectiveness.

Reference

1. Goetsch, A et al. Advances in pharmacotherapy for ulcerative colitis: a focus on JAK1 inhibitors. Expert Opinion on Pharmacotherapy, 2023, 24(7), 849–861.
New insights on extramedullary granulopoiesis and neutrophil heterogeneity in the spleen and its importance in disease
Authors: Guo Rongxia , Xie Xuemei , Ren Qian , Liew Pei Xiong
Published: November 2024

Neutrophils are traditionally viewed as uncomplicated exterminators that arrive quickly at sites of infection, kill pathogens, and then expire. However, recent studies employing modern transcriptomics coupled with novel imaging modalities have discovered that neutrophils exhibit significant heterogeneity within organs and have complex functional roles ranging from tissue homeostasis to cancer and chronic pathologies. This has revised the view that neutrophils are simplistic butchers, and there has been a resurgent interest in neutrophils. The spleen was described as a granulopoietic organ more than 4 decades ago, and studies indicate that neutrophils are briefly retained in the spleen before returning to circulation after proliferation. Transcriptomic studies have discovered that splenic neutrophils are heterogeneous and distinct compared with those in blood. This suggests that a unique hematopoietic niche exists in the splenic microenvironment, i.e., capable of programming neutrophils in the spleen. During severe systemic inflammation with an increased need of neutrophils, the spleen can adapt by producing neutrophils through emergency granulopoiesis. In this review, we describe the structure and microanatomy of the spleen and examine how cells within the splenic microenvironment help to regulate splenic granulopoiesis. A focus is placed on exploring the increase in splenic granulopoiesis to meet host needs during infection and inflammation. Emerging technologies such as single-cell RNA sequencing, which provide valuable insight into splenic neutrophil development and heterogeneity, are also discussed. Finally, we examine how tumors subvert this natural pathway in the spleen to generate granulocytic suppressor cells to promote tumor growth.
Association between glucagon-like peptide-1 receptor agonist use and progression of monoclonal gammopathy of uncertain significance to multiple myeloma among patients with diabetes
Authors: Grandhi Nikhil , Liu Lawrence , Wang Mei , Thomas Theodore , Schoen Martin , Sanfilippo Kristen , Gao Feng , Colditz Graham A , Carson Kenneth R , Janakiram Murali , Chang Su-Hsin
Published: November 2024

Background

In patients with diabetes and monoclonal gammopathy of uncertain significance (MGUS), the impact of glucagon-like peptide-1 (GLP-1) receptor agonists on the natural history of MGUS is unknown. We aimed to assess the association of GLP-1 receptor agonist use in the progression of MGUS to multiple myeloma in patients with diabetes.

Methods

This is a population-based cohort study of veterans diagnosed with MGUS from 2006 to 2021 with a prior diagnosis of diabetes. A validated natural language processing algorithm was used to confirm MGUS and progression to multiple myeloma. We performed 1:2 matching for individuals with and without GLP-1 receptor agonist exposure. The Gray test was performed to detect the difference in cumulative incidence functions for progression by GLP-1 receptor agonist use status. The association between time-varying GLP-1 receptor agonist use and progression was estimated through multivariable-adjusted hazard ratio using a stratified Fine-Gray distribution hazard model, with death as a competing event and stratum for the matched patient triad.

Results

Our matched cohort included 1097 individuals with MGUS who had ever used GLP-1 receptor agonists and the matched 2194 patients who had never used GLP-1 receptor agonists. Overall, 2.6% of individuals progressed in the GLP-1 receptor agonist ever use group compared with 5.0% in the GLP-1 receptor agonist never use group. Cumulative incidence functions were statistically significantly different between the exposed and unexposed groups (P = .02). GLP-1 receptor agonist use vs no use was associated with decreased progression to multiple myeloma (hazard ratio = 0.45, 95% confidence interval = 0.22 to 0.93, P = .03).

Conclusions

For patients with diabetes and MGUS, GLP-1 receptor agonist use is associated with a 55% reduction in risk of progression from MGUS to multiple myeloma compared with no use.
Systematic review and meta-analysis of combined cognitive-behavioral therapy and physical activity and exercise interventions for pediatric chronic disease
Authors: Black William R , von Klinggraeff Lauren , White David A ,   ACSM-CEP, Forseth Bethany , Jackson Jamie L , Bates Carolyn R , Pfledderer Christopher D , Dobbins Sidney , Hoskinson Kristen R , Gehred Alison , Davis Ann M
Published: November 2024

Objective

Cognitive-behavioral (CBT) interventions combined with either a physical activity (CBT+PA) or exercise intervention (CBT+Ex) are becoming more common in pediatric populations. Considering the independent effects of PA and exercise on health and psychological outcomes, it is unclear whether CBT alone differs from CBT+PA or CBT+Ex in efficacy. The main objective of this systematic review and meta-analysis of randomized clinical trials (RCTs) was to assess the efficacy of CBT+PA and CBT+Ex interventions in pediatric chronic disease.

Method

This review included RCTs in children (≤18 years) with a chronic condition, a CBT+Ex or CBT+PA intervention, and an objective measure of PA&Ex. Seven databases were searched using MeSH terms and key terms and included studies published before July 1, 2023. Abstracts were reviewed for inclusion by two independent reviewers, data was extracted by three independent reviewers. Risk of bias (RoB 2) and study quality were coded. Random effect meta-analyses of differences in between-group change in PA&Ex were conducted.

Results

Eligible studies (k = 5) reported outcomes for a combined 446 children. A small, nonsignificant overall effect was found (d = 0.10, 95% CI −0.16, 0.35) indicating intervention groups (CBT+PA or CBT+Ex) increased engagement in PA&Ex more than comparator groups (CBT). Additional analyses were inconclusive due to the small number of eligible studies.

Discussion

Additional RCTs are needed with integrated PA&Ex interventions targeting pediatric chronic disease. Future trials should report more detailed PA&Ex data. The full protocol for this analysis was prospectively registered in Open Science Framework (project ID: osf.io/m4wtc).
Breach of Confidence
Authors: Rushbrooke Justin , Speker Adam , Hamer Ben
Published: November 2024

Chapter 4 focuses on breach of confidence. Section B provides an overview of this cause of action through looking at its origins and development, juridical basis, and key components. The section also looks at the elements of ‘hybrid’ breach of confidence, the position of third parties who acquire information that is subject to a duty of confidence, defences, and remedies. Section C considers the four primary classes of information that are associated with breach of confidence, namely: trade secrets, personal confidences, government information, and artistic and literary confidences. Section D examines the criteria for identifying confidentiality in non-contractual matters as well as the factors negating confidentiality. Section E sets out the circumstances in which a duty of confidence will be imposed, the factors that amount to a breach of that duty, and who has a right to bring an action for breach of confidence.
Defamation
Authors: Speker Adam
Published: November 2024

Chapter 8 considers the relationship between defamation law and the protection of personal privacy. The introduction begins with an analysis of the impact of ZXC v Bloomberg LP [2022] UKSC 5 on the development of other causes of action to protect reputation. It then goes on to consider the relationship between defamation, privacy and confidentiality, the essential features of defamation and malicious falsehood, the value of reputation, and the value of freedom of expression. Section B sets out the various protections of privacy afforded by defamation law, including the test for determining what is defamatory, the pre-2013 defence of fair comment on a matter of public interest, the defence of publication on a matter of public interest (now found in s 4 Defamation Act 2013), the statutory privilege defences, and the principles relating to defamation damages. In Section C, the conflict between defamation and privacy is addressed by examining truth as an absolute defence in defamation, the rule against prior restraint, and the impact of Article 8 ECHR rights on the substantive defences in defamation.
Intrusion into Physical Privacy
Authors: Moreham N A , Hamer Clara
Published: November 2024

By contrast with informational privacy, which is protected in England and Wales primarily through the bespoke tort of misuse of private information, intrusions into people’s homes, space, or property are limited by a wide range of statutory and tortious actions, but no single specialized cause of action. This chapter is divided principally between statutory measures which protect physical privacy on the one hand (Section B), and protections deriving from the common law on the other (Section C). It ends in Section D with a brief overview of how physical privacy is preserved in other common law jurisdictions, often through legislation or torts specifically targeted at intrusion, and how it could be better protected in England and Wales.
Privacy, the Internet, and Social Media
Authors: Busuttil Godwin , McMahon Felicity , de Wilde Gervase
Published: November 2024

This chapter considers the legal means of protecting individuals against unwarranted infringements of privacy in the context of the ever-expanding media through which information is shared online. The Online Safety Act 2023 imposes significant new responsibilities on Internet Service Providers (ISPs), including apps and social media platforms, though the explanatory codes of practice to be produced by Ofcom as regulator are yet to be released. Without significant guidance or jurisprudence on the Act, the causes of action discussed elsewhere in this book remain the key means of legal redress. Section B offers practical advice on preliminary considerations when an online privacy breach is alleged, and Section C briefly discusses potential criminal liability for such breaches. Sections D to F consider questions about who bears responsibility for privacy-infringing material posted online, particularly, the novel means of republishing online (eg through hyperlinks), difficulties identifying anonymous online authors, and the extent of ISPs’ liability. Section G addresses statutory defences available in cases of online publication, particularly for web hosts and search engine operators under the e-Commerce Regulations 2002. Section H considers the key common law actions which protect online privacy, particularly harassment which is a flexible tool for addressing multi-faceted online abuse. Section I ends by describing the remedies available to online privacy claimants, including damages and injunctions.
Impact of survey spatial variability on galaxy redshift distributions and the cosmological 3 × 2-point statistics for the Rubin Legacy Survey of Space and Time (LSST)
Authors: Hang Qianjun , Joachimi Benjamin , Charles Eric , Crenshaw John Franklin , Larsen Patricia , Malz Alex I , Schmidt Sam , Yan Ziang , Zhang Tianqing ,   the LSST Dark Energy Science Collaboration, Leistedt Boris , Rau Markus , Bianco Federica , Burchat Pat , Hearin Andrew , Kovacs Eve , Lahav Ofer , Mandelbaum Rachel , Nicola Andrina , Yoachim Peter
Published: November 2024

We investigate the impact of spatial survey non-uniformity on the galaxy redshift distributions for forthcoming data releases of the Rubin Observatory Legacy Survey of Space and Time (LSST). Specifically, we construct a mock photometry data set degraded by the Rubin OpSim observing conditions, and estimate photometric redshifts of the sample using a template-fitting photo-z estimator, BPZ, and a machine learning method, FlexZBoost. We select the Gold sample, defined as $i\lt 25.3$ for 10 yr LSST data, with an adjusted magnitude cut for each year and divide it into five tomographic redshift bins for the weak lensing lens and source samples. We quantify the change in the number of objects, mean redshift, and width of each tomographic bin as a function of the coadd i-band depth for 1-yr (Y1), 3-yr (Y3), and 5-yr (Y5) data. In particular, Y3 and Y5 have large non-uniformity due to the rolling cadence of LSST, hence provide a worst-case scenario of the impact from non-uniformity. We find that these quantities typically increase with depth, and the variation can be $10\!-\!40~{{\rm per\ cent}}$ at extreme depth values. Using Y3 as an example, we propagate the variable depth effect to the weak lensing $3\times 2$ pt analysis, and assess the impact on cosmological parameters via a Fisher forecast. We find that galaxy clustering is most susceptible to variable depth, and non-uniformity needs to be mitigated below 3 per cent to recover unbiased cosmological constraints. There is little impact on galaxy–shear and shear–shear power spectra, given the expected LSST Y3 noise.
Combination therapy as a new standard of care in diabetic and non-diabetic chronic kidney disease
Authors: Neuen Brendon L , Yeung Emily K , Rangaswami Janani , Vaduganathan Muthiah
Published: November 2024

PLAIN ENGLISH SUMMARY

 

Combination therapy, involving the use of multiple medications together, is becoming a new standard of care for chronic kidney disease (CKD). For people with CKD, combination therapy offers the promise of preventing kidney failure and reducing the risk of heart problems. This approach is appealing because different drugs target distinct mechanisms involved in CKD progression. For instance, some target immune responses, others reduce kidney inflammation and scarring, while others improve blood pressure within the kidneys. Data from large clinical trials suggest that each treatment works effectively on its own, regardless of other medications people are taking. Combining therapies can also reduce the risk of side effects of individual medications. This review highlights the evidence for combination therapy in CKD, explores how to improve its use, and discusses how future studies may answer remaining questions.

A range of therapies now exists to reduce the risk of kidney failure and cardiovascular events in people with type 2 diabetes, including renin–angiotensin system blockade, sodium-glucose cotransporter 2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists. With multiple clinical trials underway, it is likely that at least some of these therapies—as well as additional agents such as endothelin receptor antagonists—will further demonstrate kidney-protective effects in people with CKD who do not have diabetes in the near future. For conditions such as IgA nephropathy, several therapies have recently been approved or are being evaluated in late phase trials. Thus combination therapy is emerging as a new standard for diabetic and non-diabetic chronic kidney disease (CKD). This approach is supported by randomized data suggesting that each therapeutic class offers independent and additive benefits in diabetic kidney disease, regardless of background therapy. Notably, the reduction in hyperkalaemia and fluid retention with SGLT2 inhibitors may enhance the tolerability and safety of other treatments. In this review, we present the rationale for combination therapy with evidence-based kidney therapies in diabetic and non-diabetic CKD. We also summarize randomized evidence supporting a multi-medicine approach, address safety considerations, review ongoing trials, and propose frameworks for implementing treatments aligned with patient risk to optimize person-centred care and reduce long-term risks of kidney failure and related complications.