bluuebunny/crossref_metadata_2025 huggingface dataset:
L‐carnitine for valproic acid‐induced toxicity
Authors: Gziut Tomasz , Thanacoody Ruben
Published: September 2024

Aims

Review the effectiveness and dosing of L‐carnitine for valproic‐acid induced toxicity.

Methods

A literature review of the pharmacokinetics and clinical use of L‐carnitine was performed.

Results

Valproic acid is a fatty acid used for numerous therapeutic indications ranging from epilepsy to bipolar disorder. The metabolism of valproic acid produces both therapeutic and toxic metabolites. Whilst it has a good safety profile, adverse effects of valproic acid in chronic use include hepatotoxicity ranging from transient elevation of liver enzymes to fulminant liver failure and hyperammonaemia with resultant encephalopathy. L‐carnitine is an essential cofactor for mitochondrial fatty acid metabolism, which is an important source of energy in cardiac and skeletal muscle. Physiological concentrations of L‐carnitine are maintained in man by exogenous dietary intake and endogenous synthesis. Following exogenous oral administration of L‐carnitine, the bioavailability ranges from 14% to 18%. After bolus intravenous administration of L‐carnitine in doses ranging from 20 to 100 mg/kg, the volume of distribution is 0.2–0.3 L/kg, and the fraction excreted unchanged in urine is 0.73–0.95, suggesting that renal clearance of L‐carnitine is dose dependent due to saturable renal reabsorption at supraphysiological concentrations.

Conclusions

There is evidence supporting the use of L‐carnitine in treating hyperammonaemia and hepatotoxicity following chronic therapeutic use and after acute overdose of valproic acid, but the optimal dose and route of administration is unknown. Based on the pharmacokinetics of L‐carnitine, we advocate the administration of L‐carnitine for valproic‐acid induced hyperammonaemia or hepatotoxicity as an intravenous loading dose of 5 mg/kg followed by a continuous intravenous infusion instead of the oral or intravenous boluses that are currently advocated.
Events and entrepreneurial passion: The moderating role of event coping competence
Authors: Li Megan Yuan , Luo Lingli , Makino Shige
Published: September 2024

Few studies have examined how external events that disrupt the economy impact entrepreneurial passion. To address this gap, we focus on two event aspects: event novelty and event disruption. We examine their impact on entrepreneurial passion under two contingencies: innovation capability and future orientation. We conducted a field survey study with government initiatives as the focal event (Study 1) and an online survey study with the COVID‐19 pandemic (Study 2). We supplemented our analysis with interviews of entrepreneurs in two Silicon Alleys of China. Study 1 shows that event novelty and disruption positively affect entrepreneurial passion when ventures have strong innovation capabilities or future‐oriented entrepreneurs. However, Study 2 reveals that, during the COVID‐19 outbreak, innovation capability does not significantly influence passion related to event novelty, and future orientation does not moderate the relationship between event disruption and passion. This study elucidates how and when external events influence entrepreneurial passion.
SELF‐EMPLOYMENT AND LABOR MARKET RISKS
Authors: Audoly Richard
Published: September 2024

I study the labor market risks associated with self‐employment. I document that the self‐employed are subject to larger earnings fluctuations than employees and frequently transition into unemployment. I analyze the provision of benefits targeted at these risks using a calibrated search model with (i) precautionary savings, (ii) work opportunities in paid‐ and self‐employment, and (iii) skill heterogeneity. Extending the U.S. unemployment insurance scheme to the self‐employed increases the transition rate from self‐employment to unemployment and yields an unequal benefits to contributions ratio across skill groups. At the calibrated parameters, the self‐employed in the middle of the skill distribution lose welfare.
α1‐ANTITRYPSIN — COMPLEXATION AND INACTIVATION IN THE UTERINE FLUID OF IUD‐USERS
Authors: Casslén Bertil , Ohlsson Kjell
Published: September 2024

Electrophoretic homogeneity of α1‐antitrypsin (α1‐AT) was studied in the uterine fluid from two groups of normal women; one group was comprised of IUD‐users, the other on non‐users. α1‐AT was found in its free and active form in non‐users. In IUD‐users, one fraction was complexed by granulocyte elastase and neutral proteinase. The other fraction had the same electrophoretic mobility as the native inhibitor, but was inactive, as determined from trypsin inhibition studies. This may explain the finding of elastase activity together with non‐complexed α1‐AT in some samples from IUD‐users. It is concluded that uterine fluid in IUD‐users possesses a minimal, if any, proteinase inhibiting potential. Non‐inhibited activity of granulocyte proteinases in the uterine cavity may incluence hemostasis of the endometrium.
JEJUNO‐ILEAL BYPASS SURGERY IN OBESITY
Authors: Hey H. , Niebuhr‐Jørgensen U.
Published: September 2024

Changes in the quality of life were demonstrated in 38 young women who had undergone intestinal bypass surgery for obesity. After the operation about half the women complained of decreased libido or sexual activity, apparently due to psychological problems related to the development of asthenia secondary to metabolic disturbances.

Bypass surgery resulted in a more regular pattern of menstruation but oral contraception was ineffective because of impaired intestinal absorption, perhaps due to a rapid transit time.

No absolute contraindication to pregnancy was found but there are many risk‐factors for both mother and fetus because of electrolyte disturbances, malnutrition and vitamin deficiency. Infants born to women after bypass surgery were found to have lower birth weights, were shorter, and the placental weight was low. It is necessary for these patients to have close medical supervision.

The results of our study show that intestinal bypass surgery in young women has side effects which should not be ignored.
URINARY BILE ACIDS IN WOMEN TREATED WITH CONTRACEPTIVE STEROIDS
Authors: Thomassen Peter A.
Published: September 2024

Twenty‐five different bile acids were determined by gas chromatography‐mass spectrometry in 24 hour urine specimens before and during treatment with a commercial contraceptive drug. Neither excretion pattern nor individual amounts of bile acids showed any change during treatment of 4 healthy women. One woman with a history of recurrent cholestasis of pregnancy showed a slight increase in the levels of S‐ALAT and total amount of urinary bile acids one day before she stopped taking the pill because of generalized itching. Another patient had a normal pattern of urinary bile acids after one year with a daily intake of 10 mg of estradiol valerate.
A DOUBLE‐BLIND STUDY OF THE VALUE OF TREATMENT WITH A SINGLE DOSE TINIDAZOLE OF PARTNERS TO FEMALES WITH TRICHOMONIASIS
Authors: Lyng Jens , Christensen Jan
Published: September 2024

Tinidazole 2 g single oral dose was given to 137 females with positive trichomonal cultures. On a random basis the same dose of tinidazole was given to half the sexual partners, and matching placebo to the other half. One to two weeks after treatment 5 females had positive cultures, indicating a primary cure rate of 96.4%. At an average of 2 months after treatment and 6 weeks after resuming sexual activity, 118 females were reexamined; 17 had a positive culture, giving an overall relapse rate of 14.4%. The relapse rate with tinidazole‐treated partner was 5.1%, and with placebo‐treated partner 23.7% (p = 0.01). The definitive cure rate after a single dose of tinidazole 2 g was in females with treated partner 91.8% and with untreated partner 72.6%. It is concluded that a single dose of tinidazole is an effective treatment for females with trichomoniasis but to avoid relapse it is necessary to treat the sexual partner too, cond follow‐up, also with trichomonal culture. At this time they were questioned concerning their sexual activity: the date of first intercourse after treatment and the frequency of intercourse.
Sex‐specific effects of PNPLA3 I148M
Authors: Cherubini Alessandro , Rosso Chiara , Della Torre Sara
Published: September 2024

Metabolic dysfunction–associated steatotic liver disease (MASLD, previously termed NAFLD, nonalcoholic fatty liver disease) is a complex multifactorial disease showing generally higher prevalence and severity in men than in women. With respect to women, men are also more prone to develop metabolic dysfunction–associated steatohepatitis, fibrosis and liver‐related complications. Several genetic, hormonal, environmental and lifestyle factors may contribute to sex differences in MASLD development, progression and outcomes. However, after menopause, the sex‐specific prevalence of MASLD shows an opposite trend between men and women, pointing to the relevance of oestrogen signalling in the sexual dimorphism of MASLD. The patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) gene, that encodes a triacylglycerol lipase that plays a crucial role in lipid metabolism, has emerged as a key player in the pathogenesis of MASLD, with the I148M variant being strongly associated with increased liver fat content and disease severity. Recent advances indicate that carrying the PNPLA3 I148M variant can be a risk factor for MASLD especially for women. To elucidate the molecular mechanisms underlying the sex‐specific role of PNPLA3 I148M in the development of MASLD, several in vitro, ex vivo and in vivo models have been developed.
Obesity in Pediatric Hidradenitis Suppurativa: A Scoping Review
Authors: Mehta Shanti , Metko Dea , Lam Joseph M.
Published: September 2024

The relationship between HS and obesity, while well established in adult patients, has drawn increased attention in pediatric patients given the rising prevalence of pediatric obesity worldwide. This review aims to consolidate existing evidence of the relationship between HS and obesity in the pediatric population and to hypothesize about reasons for an association between the two conditions. Our cohort comprised 2911 patients with a mean age of 11.4 years at the age of onset of HS, and based on body mass index (BMI), 42.3% of patients were classified as obese (BMI > 30), and 14% were overweight (BMI 25–29.9). Our findings indicate an association between obesity and HS in pediatric patients, which may be explained through numerous mechanisms, including shared genetic factors, hereditary relationships, and the impact of HS on adolescents’ quality of life.
Be prepared: how does discontinuous hydration in Tabebuia heterophylla seeds induce stress tolerance in seedlings?
Authors: da Silva Dias G. , Chaves J. T. L. , Santos T. R. S. , Garcia Q. S. , Artur M. A. S. , Bicalho E. M.
Published: September 2024

Discontinuous hydration and dehydration (HD) cycles refer to controlled imbibition followed by dehydration before seed germination. Here, we investigated whether the level of imbibition before HD cycles affects the physiology of Tabebuia heterophylla seeds and seedlings.

Seeds were imbibed for 10 h (T1; phase I of imbibition) or 35 h (T2; phase II), dehydrated, and progressively rehydrated one to four times (HD cycles). Germination and biochemical parameters (membrane integrity; total soluble, reducing, and nonreducing (NRS) sugars; proteins, amino acids, proline, H2O2, catalase, ascorbate peroxidase, and glutathione reductase activity) were quantified at the last rehydration step of each cycle. Biometric and biochemical parameters (including pigments) were analysed in seedlings 60 days after germination.

HD cycles at T1 led to reduced seed germination and greater plasma membrane damage, higher enzyme activity (catalase and glutathione reductase) and accumulation of NRS, total amino acids, and proline compared to the controls and T2 treatment. Cellular damage became more severe with more HD cycles. HD cycles at T2 synchronized germination regardless of the number of cycles and also had a priming effect. T2 seeds had less NRS, total amino acids, and proline content than T1. HD cycles at T1 produced seedlings with higher carotenoid and total chlorophyll content than controls and T2, while seedlings from HD cycles at T2 had higher amounts of osmoprotectants.

HD cycles at T2 benefited seeds and seedlings more than at T1. This suggests that the physiological and biochemical effects of HD cycles in seeds modulate seedling plasticity, depending on water availability, potentially promoting increased tolerance to recurrent droughts that will be intensified with ongoing climate changes.
Mathematical topics in compressible flows from single‐phase systems to two‐phase averaged systems
Authors: Bresch Didier , Narbona‐Reina Gladys , Burgisser Alain , Collombet Marielle
Published: September 2024

We review the modeling and mathematical properties of compressible viscous flows, ranging from single‐phase systems to two‐phase systems, with a focus on the occurrence of oscillations and/or concentrations. We explain how establishing the existence of nonlinear weak stability ensures that no such instabilities occur in the solutions because of the system formulation. When oscillation/concentration are inherent to the nature of the physical situation modeled, we explain how the averaging procedure by homogenization helps to understand their effect on the averaged system. This review addresses systems of progressive complexity. We start by focusing on nonlinear weak stability—a crucial property for numerical simulations and well posedness—in single‐phase viscous systems. We then show how a two‐phase immiscible system may be rewritten as a single‐phase system. Conversely, we show then how to derive a two‐phase averaged system from a two‐phase immiscible system by homogenization. As in many homogenization problems, this is an example where physical oscillation/concentration occur. We then focus on two‐phase averaged viscous systems and present results on the nonlinear weak stability necessary for the convergence of numerical schemes. Finally, we review some singular limits frequently developed to obtain drift–flux systems. Additionally, the appendix provides a crash course on basic functional analysis tools for partial differential equation (PDE) and homogenization (averaging procedures) for readers unfamiliar with them. This review serves as the foundation for two subsequent papers (Part I and Part II in this same volume), which present averaged two‐phase models with phase exchange applicable to magma flow during volcanic eruptions. Part I introduces the physical processes occurring in a volcanic conduit and establishes a two‐phase transient conduit flow model ensuring: (1) mass and volatile species conservation, (2) disequilibrium degassing considering both viscous relaxation and volatile diffusion, and (3) dissipation of total energy. The relaxation limit of this model is then used to obtain a drift–flux system amenable to simplification. Part II revisits the model introduced in Part I and proposes a 1.5D simplification that addresses issues in its numerical implementation. Model outputs are compared to those of another well‐established model under conditions typical of an effusive eruption at an andesitic volcano.
GENETIC FEATURES OF ECHINOCOCCOSIS COMMON IN THE REPUBLIC OF KAZAKHSTAN
Authors: Kiyan V.S. , Uakhit R.S. , Smagulova A.M. , Lider L.A.
Published: September 2024

Alveolar and cystic echinococcosis, caused by Echinococcus multilocularis and Echinococcus granulosus sensu lato respectively, are serious zoonotic parasitic diseases infecting humans and animals with a considerable socioeconomic impact. In world practice, the genotypes G1, G3, G4, G5, G6/7 cluster, G8, and G10 within E. granulosus, and the genotypes M1 and M2 within E. multilocularis have been recognized. Despite the high prevalence of echinococcosis in Kazakhstan, data on its genetic origin among humans and animals remains unclear.
Biological material was collected from domestic and farm animals, wild carnivores, as well as people. All protocols were performed in accordance with the International Ethical Guidelines for Biomedical Research. DNA isolation was carried out by phenol-chloroform extraction. Sequencing was performed according to the Sanger method. Phylogenetic analysis was performed using the MEGA v.11 program using the ClustalW and MUSCLE mathematical algorithms.
The data obtained at this stage of the research showed that the invasion among wolves is caused by the species E. granulosus (genotype G1, haplotype H1, H2, H7), in corsacs by the species E. granulosus (genotype G1, haplotype H3, H4, H5, H6), and in foxes, the species E. multilocularis (genotype M1 and M2, haplotype H1, H2, H3). Among farm animals: in cattle, echinococcosis was caused by the species E. granulosus (genotype G1, G3), and in small cattle by the species E. granulosus (genotype G1, G3). Among domestic animals, namely dogs, the species E. granulosus (G1 genotype) was detected. Among people, it was possible to identify the belonging of the causative agent of echinococcosis to the species E. granulosus (G1-G3 genotype).
The establishment of the genetics of the pathogen Echinococcus spp. among wild, domestic, and farm animals, as well as humans, will allow us to show the main ways of transmission, and develop recommendations for controlling the epidemiological situation and preventive measures for this disease.
PRELIMINARY STUDY OF CESTODES GENUS OF TAENIA SPP. AND MESOCESTOIDES SPP. FOUND IN RED FOXES
Authors: Uakhit R.S. , Zhaxylykov A.Zh. , Smagulova A.M. , Kiyan V.S.
Published: September 2024

Tapeworms are parasitic flatworms belonging to the class Cestoda, and the genus Taenia is known to exhibit high variability in morphological traits at the individual level. The variability may be influenced by the host in which the tapeworm resides, and the cestode genus comprises many species that cycle between predator-prey assemblages worldwide. Adult cestodes, which are typically composed of a head or scolex, neck, and a chain of proglottids, live in the small intestine of dogs, cats, and free-ranging carnivores around the world. To accurately identify species of larval tapeworms, it is important to have a comprehensive understanding of the entire life cycle of the worm, which typically includes a definitive host and an intermediate host.
From 2023 to 2024, a comprehensive study was conducted on 18 foxes (Vulpes vulpes) from the Akmola and Karagandy region to investigate the prevalence of parasitic infections. The study's results revealed that six (33.3%) of the studied foxes were positive for the presence of two different species of helminths, namely Taenia spp. and Mesocestoides spp. Further analysis of the morphological and morphometric characteristics of the detected helminths helped to identify the presumably species of the parasites. Morphological analysis is carried out using authoritative sources such as atlases and monographs to identify adult tapeworms.
The identified species, Taenia hydatigena (2/6), Taenia krabbei (1/6), and Mesocestoides sp (3/6), are crucial findings that provide valuable insights into the prevalence and distribution of parasitic infections in fox populations. These insights are not only significant for our understanding of wildlife health but also for the development of effective control and prevention strategies. However, it is important to note that further research, particularly in the area of molecular genetics, is needed to determine the specific species of the detected parasites, underscoring the ongoing importance of this field of study.
Overall, this study highlights the importance of monitoring and controlling parasitic infections in wildlife populations, as these infections can have significant impacts on the health and well-being of both the host and other species in the ecosystem.
Solvent-mediated oxide hydrogenation in layered cathodes
Authors: Wan Gang , Pollard Travis P. , Ma Lin , Schroeder Marshall A. , Chen Chia-Chin , Zhu Zihua , Zhang Zhan , Sun Cheng-Jun , Cai Jiyu , Thaman Harry L. , Vailionis Arturas , Li Haoyuan , Kelly Shelly , Feng Zhenxing , Franklin Joseph , Harvey Steven P. , Zhang Ye , Du Yingge , Chen Zonghai , Tassone Christopher J. , Steinrück Hans-Georg , Xu Kang , Borodin Oleg , Toney Michael F.
Published: September 2024

Self-discharge and chemically induced mechanical effects degrade calendar and cycle life in intercalation-based electrochromic and electrochemical energy storage devices. In rechargeable lithium-ion batteries, self-discharge in cathodes causes voltage and capacity loss over time. The prevailing self-discharge model centers on the diffusion of lithium ions from the electrolyte into the cathode. We demonstrate an alternative pathway, where hydrogenation of layered transition metal oxide cathodes induces self-discharge through hydrogen transfer from carbonate solvents to delithiated oxides. In self-discharged cathodes, we further observe opposing proton and lithium ion concentration gradients, which contribute to chemical and structural heterogeneities within delithiated cathodes, accelerating degradation. Hydrogenation occurring in delithiated cathodes may affect the chemo-mechanical coupling of layered cathodes as well as the calendar life of lithium-ion batteries.
A rockslide-generated tsunami in a Greenland fjord rang Earth for 9 days
Authors: Svennevig Kristian , Hicks Stephen P. , Forbriger Thomas , Lecocq Thomas , Widmer-Schnidrig Rudolf , Mangeney Anne , Hibert Clément , Korsgaard Niels J. , Lucas Antoine , Satriano Claudio , Anthony Robert E. , Mordret Aurélien , Schippkus Sven , Rysgaard Søren , Boone Wieter , Gibbons Steven J. , Cook Kristen L. , Glimsdal Sylfest , Løvholt Finn , Van Noten Koen , Assink Jelle D. , Marboeuf Alexis , Lomax Anthony , Vanneste Kris , Taira Taka’aki , Spagnolo Matteo , De Plaen Raphael , Koelemeijer Paula , Ebeling Carl , Cannata Andrea , Harcourt William D. , Cornwell David G. , Caudron Corentin , Poli Piero , Bernard Pascal , Larose Eric , Stutzmann Eleonore , Voss Peter H. , Lund Bjorn , Cannavo Flavio , Castro-Díaz Manuel J. , Chaves Esteban , Dahl-Jensen Trine , Pinho Dias Nicolas De , Déprez Aline , Develter Roeland , Dreger Douglas , Evers Läslo G. , Fernández-Nieto Enrique D. , Ferreira Ana M. G. , Funning Gareth , Gabriel Alice-Agnes , Hendrickx Marc , Kafka Alan L. , Keiding Marie , Kerby Jeffrey , Khan Shfaqat A. , Dideriksen Andreas Kjær , Lamb Oliver D. , Larsen Tine B. , Lipovsky Bradley , Magdalena Ikha , Malet Jean-Philippe , Myrup Mikkel , Rivera Luis , Ruiz-Castillo Eugenio , Wetter Selina , Wirtz Bastien
Published: September 2024

Climate change is increasingly predisposing polar regions to large landslides. Tsunamigenic landslides have occurred recently in Greenland (
Kalaallit Nunaat
), but none have been reported from the eastern fjords. In September 2023, we detected the start of a 9-day-long, global 10.88-millihertz (92-second) monochromatic very-long-period (VLP) seismic signal, originating from East Greenland. In this study, we demonstrate how this event started with a glacial thinning–induced rock-ice avalanche of 25 × 10
6
cubic meters plunging into Dickson Fjord, triggering a 200-meter-high tsunami. Simulations show that the tsunami stabilized into a 7-meter-high long-duration seiche with a frequency (11.45 millihertz) and slow amplitude decay that were nearly identical to the seismic signal. An oscillating, fjord-transverse single force with a maximum amplitude of 5 × 10
11
newtons reproduced the seismic amplitudes and their radiation pattern relative to the fjord, demonstrating how a seiche directly caused the 9-day-long seismic signal. Our findings highlight how climate change is causing cascading, hazardous feedbacks between the cryosphere, hydrosphere, and lithosphere.
Inherent symmetry and flexibility in hepatitis B virus subviral particles
Authors: Wang Quan , Wang Tao , Cao Lin , Mu An , Fu Sheng , Wang Peipei , Gao Yan , Ji Wenxin , Liu Zhenyu , Du Zhanqiang , Guddat Luke W. , Zhang Wenchi , Li Shuang , Li Xuemei , Lou Zhiyong , Wang Xiangxi , Hu Zhongyu , Rao Zihe
Published: September 2024

Chronic hepatitis B virus (HBV) infection poses a major global health challenge with massive morbidity and mortality. Despite a preventive vaccine, current treatments provide limited virus clearance, necessitating lifelong commitment. The HBV surface antigen (HBsAg) is crucial for diagnosis and prognosis, yet its high-resolution structure and assembly on the virus envelope remain elusive. Utilizing extensive datasets and advanced cryo–electron microscopy analysis, we present structural insights into HBsAg at a near-atomic resolution of 3.7 angstroms. HBsAg homodimers assemble into subviral particles with

D

2
- and

D

4
-like quasisymmetry, elucidating the dense-packing rules and structural adaptability of HBsAg. These findings provide insights into how HBsAg assembles into higher-order filaments and interacts with the capsid to form virions.
Generative AI as a tool for truth
Authors: Bago Bence , Bonnefon Jean-François
Published: September 2024

Conversation with a trained chatbot can reduce conspiratorial beliefs
Patients’ and health professionals’ research priorities for chronic pain associated with inflammatory bowel disease: a co-produced sequential mixed methods Delphi consensus study
Authors: Gordon Morris , Sinopoulou Vassiliki , Mardare Roxana , Abdulshafea Mansour , Grafton-Clarke Ciaran , Vasiliou Jessica
Published: September 2024

Objective

Chronic pain in inflammatory bowel disease (IBD) is common and detrimental to quality of life. Recent Cochrane reviews identified a multitude of randomised controlled trial interventions, but the certainty of the findings is low or very low. We set out to reach a patient and professional co-produced Delphi consensus on treatment priorities, key outcomes and propose a model for understanding our findings.

Methods

An online survey was co-produced with Crohn’s and Colitis UK and sent to patients and healthcare professionals in two phases, for prioritisation of treatments and outcome measures. Phase three consisted of four online group interviews, where patients and healthcare professionals discussed the rationale of their choices. Transcripts were combined with the free text data from the Delphi surveys and analysed through a three-phase qualitative technique.

Results

The phase 1 survey was completed by 128 participants (73 patients, 3 carers and 53 health professionals). Diet was the top priority for both patients (n=26/73, 36.1%) and healthcare professionals (n=29/52, 56.9%). Phase 2 was completed by 68 participants. FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet, stress management therapy and relaxation therapy were the top three consensus priorities. Phase 3 group interviews were attended by 13 patients and 5 healthcare professionals. Key themes included: The patient as an individual, beliefs and experiences, disease activity influencing therapy choice, accessibility barriers and quality of life.

Conclusion

Low FODMAP diet, followed by psychological therapies were the highest-rated research priorities for healthcare professionals and patients. Funding bodies and researchers should consider these findings, alongside the model for understanding our findings, when making research decisions.
Design of TOLERANT: phase I/II safety assessment of intranodal administration of HSP70/mB29a self-peptide antigen-loaded autologous tolerogenic dendritic cells in patients with rheumatoid arthritis
Authors: Stoppelenburg Arie Jan , Schreibelt Gerty , Koeneman Bouke , Welsing Paco , Breman Evert-Jan , Lammers Laureen , de Goede Anna , Duiveman-de Boer Tjitske , van Eden Willem , Leufkens Paul , de Vries I Jolanda M , Broere Femke , van Laar Jacob M
Published: September 2024

Introduction

In rheumatoid arthritis (RA), immunosuppressive therapies may achieve symptomatic relief, but do not induce long-term, drug-free remission. Meanwhile, the lifelong use of immunosuppressive drugs confers increased risk for malignancy and infections. As such, there is an unmet need for novel treatments that selectively target the pathogenic immune response in RA by inducing tolerance to autoantigens. Autologous cell therapy using antigen-loaded tolerogenic dendritic cells (tolDCs) aims to reinstate autoantigen-specific immunological tolerance in RA and could potentially meet this need.

Methods and analysis

We report here the design of the phase I/II, investigator-initiated, open-label, dose-escalation trial TOLERANT. In this study, we will evaluate the intranodal administration of tolDCs in patients with RA that are in remission under immunosuppressive therapy. The tolDCs in this trial are loaded with the heat shock protein 70-derived peptide mB29a, which is an effective surrogate autoantigen in animal models of arthritis. Within this study, three dose-escalation cohorts (two intranodal injections of 5×106, 10×106and 15×106tolDCs), each consisting of three patients, are evaluated to identify the highest safe dose (recommended dose), and an extension cohort of nine patients will be treated with the recommended dose. The (co-)primary endpoints of this study are safety and feasibility, which we assess by the number of AEs and the successful production of tolDCs. The secondary endpoints include the immunological effects of the treatment, which we assess with a variety of high-dimensional and antigen-specific immunological assays. Clinical effects are exploratory outcomes.

Ethics and dissemination

Ethical approval for this study has been obtained from the Netherlands Central Committee on Research Involving Human Subjects. The outcomes of the trial will be disseminated through publications in open-access, peer-reviewed scientific journals, scientific conferences and to patient associations.

Trial registration numbers

NCT05251870; 2019-003620-20 (EudraCT); NL71296.000.20 (CCMO register).
Developing films to support vaccine-hesitant, ethnically diverse parents’ decision-making about the human papillomavirus (HPV) vaccine: a codesign study
Authors: Fisher Harriet , Denford Sarah , Chantler Tracey , Audrey Suzanne , Finn Adam , Hajinur Huda , Hickman Matthew , Mounier-Jack Sandra , Roderick Marion , Tucker Leanne , Yates Julie , Mohamed Asha
Published: September 2024

Objective

To illustrate an evidence-, theory- and person-based approach to codesign the COMMUNICATE films that support parental decision-making about the human papillomavirus (HPV) vaccine for their teenagers.

Design

Codesign study.

Setting

Localities covered by two immunisation teams in London and the south-west of England.

Methods

The intervention planning phase involved combining evidence from a literature review with qualitative interview data to identify barriers and facilitators to HPV vaccine uptake, as well as design features that should be incorporated within the COMMUNICATE films. The intervention development phase involved identifying guiding principles for the COMMUNICATE films, mapping behaviour change techniques onto the behaviour change wheel and codesigning the COMMUNICATE films. Feedback from users informed modifications to maximise acceptability and feasibility and to support behaviour change.

Results

The primary and secondary evidence highlighted important content to include within the COMMUNICATE films: emphasise the benefits of the HPV vaccine, provide transparent information about the safety profile and side effects and emphasise the universality and commonality of HPV infection. A series of scripts were used to guide 4 film shoots to create the content in multiple community languages with 16 participants, including vaccine-hesitant, ethnically diverse parents and professionals. Overall, participants were positive about the films. Potential messengers and ways the films could be distributed, identified by parents, include local social media networks or text messages from general practices. The need for information about the HPV vaccine to be shared by schools ahead of consent being sought was also raised.

Conclusions

By using an integrated approach to intervention development, this study has begun to address the need for an intervention to support vaccine-hesitant, ethnically diverse parents’ decision-making about the HPV vaccination programme. A future study to codesign, implement and evaluate a communication strategy for the COMMUNICATE films is planned.
Association of housing status and cancer diagnosis, care coordination and outcomes in a public hospital: a retrospective cohort study
Authors: Decker Hannah , Colom Sara , Evans Jennifer L , Graham-Squire Dave , Perez Kenneth , Kushel Margot , Wick Elizabeth , Raven Maria C , Kanzaria Hemal K
Published: September 2024

Objectives

Cancer is a leading cause of death in unhoused adults. We sought to examine the association between housing status, stage at diagnosis and all-cause survival following cancer diagnosis at a public hospital.

Design

Retrospective cohort study examining new cancer diagnoses between 1 July 2011 and 30 June 2021.

Setting

A public hospital in San Francisco.

Exposure

Housing status (housed, formerly unhoused, unhoused) was ascertained via a county-wide integrated dataset that tracks both observed and reported homelessness.

Methods

We reported univariate analyses to investigate differences in demographic and clinical characteristics by housing group. We then constructed Kaplan-Meier curves stratified by housing group to examine unadjusted all-cause mortality. Finally, we used multivariable Cox proportional hazards models to compare the hazard rate of mortality for each housing status group, adjusting for demographic and clinical factors.

Results

Our cohort included 5123 patients with new cancer diagnoses, with 4062 (79%) in housed patients, 623 (12%) in formerly unhoused patients and 438 (9%) in unhoused patients. Unhoused and formerly unhoused patients were more commonly diagnosed with stage 4 disease (28% and 27% of the time, respectively, vs 22% of housed patients). After adjusting for demographic and clinical characteristics, unhoused patients with stage 0–3 disease had a 50% increased hazard of death (adjusted HR (aHR) 1.5, 95% CI 1.1 to 1.9; p<0.004) as did formerly unhoused patients (aHR 1.5, 95% CI 1.2 to 1.9; p=0.001) compared with housed individuals 3 months after diagnosis.

Conclusions

Unhoused and formerly unhoused patients diagnosed with non-metastatic cancer had substantially increased hazards of death compared with housed patients cared for in a public hospital setting. Current or former lack of housing could contribute to poor outcomes following cancer diagnoses via multiple mechanisms.
Hospitalised infections and rituximab administration among children and adolescents with systemic lupus erythematosus from 2009 to 2021
Authors: Roberts Jordan E , Faino Anna V , Bryan Mersine A , Cogen Jonathan D , Morgan Esi M
Published: September 2024

Background

Rituximab is associated with high infection rates, but studies of infections following rituximab in youth with childhood-onset SLE (cSLE) are limited. We conducted a retrospective longitudinal cohort study to assess the incidence of hospitalised infections following rituximab among children with cSLE and to assess changes in hospital-based rituximab administration over time.

Methods

Youth ages 2–21 years with an International Classification of Diseases (ICD) code for SLE who received rituximab during admission to a Pediatric Health Information System hospital from 2009 to 2021 were included. Incidence rates for infections requiring hospitalisation over the 12 months following first rituximab administration were calculated. Rituximab use by year of hospital discharge was tabulated.

Results

We identified 1567 children with cSLE who received rituximab. 219 children were admitted with an infection within 1 year after first rituximab administration, for an incidence rate of 140 cases per 1000 patient-years. Seven children (0.44%) died during a hospitalisation with an infection in the year following rituximab administration. The most common hospitalised infections were bacterial pneumonia, sepsis and cellulitis. 12 children were hospitalised with COVID-19, none of whom died. Hospitalisations with rituximab administered decreased from 2019 to 2021.

Conclusions

In this cohort of patients with cSLE who received inpatient treatment with rituximab, we observed a 14% rate of hospitalisation with infection in the year following rituximab administration among youth with cSLE. Rituximab use declined during the COVID-19 pandemic. No fatalities with COVID-19 were observed. Given the lack of outpatient data, including doses of concomitant medications and disease activity measures, further research is needed to identify risk factors for infection following rituximab among children with cSLE.
Topological structural characteristics in patients with systemic lupus erythematosus with and without neuropsychiatric symptoms
Authors: Ao Feng , Su Li , Duan Yunyun , Huang Jing , Qiu Xiaolu , Xu Jun , Zeng Xiaofeng , Zhuo Zhizheng , Liu Yaou
Published: September 2024

Purpose

This study investigated the topological structural characteristics of systemic lupus erythematosus (SLE) with and without neuropsychiatric symptoms (NPSLE and non-NPSLE), and explore their clinical implications.

Methods

We prospectively recruited 50 patients with SLE (21 non-NPSLE and 29 NPSLE) and 32 age-matched healthy controls (HCs), using MRI diffusion tensor imaging. Individual structural networks were constructed using fibre numbers between brain areas as edge weights. Global metrics (eg, small-worldness, global efficiency) and local network properties (eg, degree centrality, nodal efficiency) were computed. Group comparisons of network characteristics were conducted. Clinical correlations were assessed using partial correlation, and differentiation between non-NPSLE and NPSLE was performed using support vector classification.

Results

Patients with oth non-NPSLE and NPSLE exhibited significant global and local topological alterations compared with HCs. These changes were more pronounced in NPSLE, particularly affecting the default mode and sensorimotor networks. Topological changes in patients with SLE correlated with lesion burdens and clinical parameters such as disease duration and the systemic lupus international collaborating clinics damage index. The identified topological features enabled accurate differentiation between non-NPSLE and NPSLE with 87% accuracy.

Conclusion

Structural networks in patients SLE may be altered at both global and local levels, with more pronounced changes observed in NPSLE, notably affecting the default mode and sensorimotor networks. These alterations show promise as biomarkers for clinical diagnosis.
OnabotulinumtoxinA in Resistant Depression: A Randomized Trial Comparing Two Facial Injection Sites (OnaDEP Study)
Authors: Ceolato-Martin Caroline , Chevallier-Collins Claire , Clément Jean-Pierre , Charles Eric , Lacroix Aurélie , Ranoux Danièle
Published: September 2024

Background: OnabotulinumtoxinA (OnaA) injection in glabella area appears to be a promising treatment for major depression. However, one major concern of placebo‐controlled studies on botulinum toxin injections is to ensure adequate blinding.

Patients and Methods: In this context, all subjects of this trial received the active product (OnaA). After randomization, 58 patients with resistant major depressive disorder (MDD) received OnaA either in the glabella area (N = 29) or in the crow’s feet area (N = 29). Subjects were blinded to the supposedly effective area against resistant depression and the examiner was not aware of the injected area. The primary outcome measure was the proportion of responders (50% or greater decrease in MADRS [Montgomery and Asberg Depression Rating Scale] score from baseline) in glabella group versus crow’s feet group at week 6 after the OnaA injection.

Results: The number of responders was significantly higher in the glabella group than in the crow’s feet group with 13 responders out of 29 patients (44.8%) in the glabella group and five out of 28 patients (17.9%) in the crow’s feet group (p = 0.029). The rate of psychomotor agitation as measured by item 9 of the Hamilton Depression Rating Scale (HAM‐D), associated with a shorter span of psychiatric disorder, was a potent positive predictive factor of positive response to treatment.

Conclusion: We conclude that OnaA injected in the glabella muscles is an effective and well‐tolerated treatment for MDD. We suggest that patients with a high score at item 9 of the HAM‐D might be a subgroup of best responders. We assume that OnaA may act as a modulator of the activity of the primary sensorimotor cortex and then of the amygdala.

Trial Registration: ClinicalTrials.gov identifier: NCT03484754
Law Regarding Damage Caused by Repeated Mining in Close Coal Seams
Authors: Wu Fuzhu , Chen Gen , Liu Yanjie , Wu Yonghui , Jin Zidong
Published: September 2024

Coal mining in China is increasingly moving towards deeper resources. In certain Carboniferous–Permian coal fields in North China, there is a typical problem of repeated mining over short distances and multiple coal seams, and the distance between the main coal seam and the mined shallow coal seam is relatively small. This leads to repetitive disturbance damage to the surrounding rock during closed‐coal seam mining. This was followed by more serious threats from water disasters. Therefore, it is particularly important to systematically study the disturbance and failure characteristics of rock masses under repeated mining conditions in multiple coal seams and to investigate repeated mining damage law and characteristics of the overlying rock of a close coal seam. This study focuses on six mining areas in the Jiyang coal mine. This study also predicts the damage height of the top and bottom slabs of mined No. 7 coal and main mined No. 10 coal based on an empirical formula. An on‐site investigation was conducted using downhole drilling and segmental water injection to determine the damage depths of the two seams. A numerical simulation was then conducted to study the height, displacement, and stress of the overlying rock damage caused by mining close to the coal seams. Changes in height, displacement, and stress of the overburden rock mining damage were also studied through numerical simulations. Results indicated the following: (1) The height of the plastic zone of the overburden rock increased by 6.25%, (2) maximum settlement displacement increased by 5.05%, and maximum horizontal displacement increased by 9%. It is important to note that these findings are objective and based solely on presented data. Repetitive disturbances with larger amplitudes caused a 27% change in horizontal displacement. (3) Maximum principal stress in the stress field decreased with the overall value of the vertical stress. The influence range increased slightly and the two sides of the hollow area at the open cutting eye and stopping line were also affected. These findings were obtained through numerical simulations. Stress concentration was more pronounced in the open‐cut eye and near‐the‐stop line.
A Comparative Analysis of the Performance of Leading Countries in Conducting Artificial Intelligence Research
Authors: Al-Marzouqi Ahmed H. , Arabi Alya A.
Published: September 2024

Artificial intelligence (AI) is a rapidly expanding field. Given the dynamic nature of AI research, staying up‐to‐date with this evolving landscape is imperative to guide the global race in this field. Using the world’s largest bibliometric database (SciVal/Scopus), we analyzed the research output of the top 15 countries in AI research productivity between the years 1998 and 2022. Over the past 25 years, the global research output in AI has increased by 26 folds, with China leading the way in the overall number of AI publications (~281,650 articles). During this period, China and India had the highest fold growth (~240–250) and compound annual growth rate (CAGR) (~25). However, when normalized to population size and gross domestic product (GDP), Singapore (250 AI publications per million capita) and India (7.7 AI publications per billion GDP) were the best performers in 2022, respectively. When normalized to the number of researchers and gross expenditures on research and development (GERD), again, India was the best with 36.8 AI publications per thousand researchers and 0.77 AI publications per million GERD in 2020. When the overall quality of AI publications over the past decade was considered, Hong Kong and Singapore performed the best with respect to publications in higher percentile journals (the top 1%, 5%, and 10% journals), and Switzerland performed the best with respect to citations/publication and field‐weighted citation impact (FWCI). Finally, when the quality measures of publications were normalized to country or research metrics, the three best performers were Hong Kong, Singapore, and Switzerland (although India stood out for citations/GERD). These three countries (along with the United States) also had the highest economic impact as measured by the patent citations per scholarly output, which was aligned with the high FWCI values for these countries. Long‐term strategies to help leading countries gain an advantage in the AI frontier have been discussed at the end of the manuscript. These strategies include government initiatives and financial support, talent creation and networking, public awareness, and mindful considerations of rules, guidelines, and ethics.
Reflection of Duplicating Operations in the Graphs Pn and Pn∘K1 Based on the F‐Centroidal Meanness Property
Authors: Kannan A. Rajesh , Loganathan K. , Usha P. , Pattanaik Balachandra
Published: September 2024

A graph admits flooring function of centroidal meanness property if its injective node assignment Λ is from 1 to 1 + q along with bijective link assignment Λ⋆(uv) = ⌊1/3Γ(u, v)[Λ(u)2 + Γ(u, v)2 + Λ(v)2]⌋, where Γ(u, v) = Λ(u) + Λ(v), is from 1 to q. We examined the flooring function of centroidal meanness values of a few duplicates yielded graphs in this context.