bluuebunny/crossref_metadata_2025 huggingface dataset:
IsoTools: a flexible workflow for long-read transcriptome sequencing analysis
Authors: Lienhard Matthias , van den Beucken Twan , Timmermann Bernd , Hochradel Myriam , Börno Stefan , Caiment Florian , Vingron Martin , Herwig Ralf
Published: June 2023

Motivation

Long-read transcriptome sequencing (LRTS) has the potential to enhance our understanding of alternative splicing and the complexity of this process requires the use of versatile computational tools, with the ability to accommodate various stages of the workflow with maximum flexibility.

Results

We introduce IsoTools, a Python-based LRTS analysis framework that offers a wide range of functionality for transcriptome reconstruction and quantification of transcripts. Furthermore, we integrate a graph-based method for identifying alternative splicing events and a statistical approach based on the beta-binomial distribution for detecting differential events. To demonstrate the effectiveness of our methods, we applied IsoTools to PacBio LRTS data of human hepatocytes treated with the histone deacetylase inhibitor valproic acid. Our results indicate that LRTS can provide valuable insights into alternative splicing, particularly in terms of complex and differential splicing patterns, in comparison to short-read RNA-seq.

Availability and implementation

IsoTools is available on GitHub and PyPI, and its documentation, including tutorials, CLI, and API references, can be found at https://isotools.readthedocs.io/.
Cdc42GAP deficiency contributes to the Alzheimer’s disease phenotype
Authors: Zhu Mengjuan , Xiao Bin , Xue Tao , Qin Sifei , Ding Jiuyang , Wu Yue , Tang Qingqiu , Huang Mengfan , Zhao Na , Ye Yingshan , Zhang Yuning , Zhang Boya , Li Juan , Guo Fukun , Jiang Yong , Zhang Lin , Zhang Lu
Published: May 2023

Alzheimer’s disease, the most common cause of dementia, is a chronic degenerative disease with typical pathological features of extracellular senile plaques and intracellular neurofibrillary tangles and a significant decrease in the density of neuronal dendritic spines. Cdc42 is a member of the small G protein family that plays an important role in regulating synaptic plasticity and is regulated by Cdc42GAP, which switches Cdc42 from active GTP-bound to inactive GDP-bound states regulating downstream pathways via effector proteins. However, few studies have focused on Cdc42 in the progression of Alzheimer’s disease.

In a heterozygous Cdc42GAP mouse model that exhibited elevated Cdc42-GTPase activity accompanied by increased Cdc42-PAK1-cofilin signalling, we found impairments in cognitive behaviours, neuron senescence, synaptic loss with depolymerization of F-actin and the pathological phenotypes of Alzheimer’s disease, including phosphorylated tau (p-T231, AT8), along with increased soluble and insoluble Aβ1–42 and Aβ1–40, which are consistent with typical Alzheimer’s disease mice. Interestingly, these impairments increased significantly with age. Furthermore, the results of quantitative phosphoproteomic analysis of the hippocampus of 11-month-old GAP mice suggested that Cdc42GAP deficiency induces and accelerates Alzheimer’s disease-like phenotypes through activation of GSK-3β by dephosphorylation at Ser9, Ser389 and/or phosphorylation at Tyr216. In addition, overexpression of dominant-negative Cdc42 in the primary hippocampal and cortical neurons of heterozygous Cdc42GAP mice reversed synaptic loss and tau hyperphosphorylation. Importantly, the Cdc42 signalling pathway, Aβ1–42, Aβ1–40 and GSK-3β activity were increased in the cortical sections of Alzheimer’s disease patients compared with those in healthy controls.

Together, these data indicated that Cdc42GAP is involved in regulating Alzheimer’s disease-like phenotypes such as cognitive deficits, dendritic spine loss, phosphorylated tau (p-T231, AT8) and increased soluble and insoluble Aβ1–42 and Aβ1–40, possibly through the activation of GSK-3β, and these impairments increased significantly with age. Thus, we provide the first evidence that Cdc42 is involved in the progression of Alzheimer’s disease-like phenotypes, which may provide new targets for Alzheimer’s disease treatment.
MAITs and their mates: “Innate-like” behaviors in conventional and unconventional T cells
Authors: Hackstein Carl-Philipp , Klenerman Paul
Published: May 2023

Most CD4 and CD8 T cells are restricted by conventional major histocompatibility complex (MHC) molecules and mount TCR-dependent adaptive immune responses. In contrast, MAIT, iNKT, and certain γδ TCR bearing cells are characterized by their abilities to recognize antigens presented by unconventional antigen-presenting molecules and to mount cytokine-mediated TCR-independent responses in an “innate-like” manner. In addition, several more diverse T-cell subsets have been described that in a similar manner are restricted by unconventional antigen-presenting molecules but mainly depend on their TCRs for activation. Vice versa, innate-like behaviour was reported in defined subpopulations of conventional T cells, particularly in barrier sites, showing that these two features are not necessarily linked. The abilities to recognize antigens presented by unconventional antigen-presenting molecules or to mount TCR-independent responses creates unique niches for these T cells and is linked to wide range of functional capabilities. This is especially exemplified by unconventional and innate-like T cells present at barrier sites where they are involved in pathogen defense, tissue homeostasis as well as in pathologic processes.
Outcome of immunotherapy in adrenocortical carcinoma: a retrospective cohort study
Authors: Remde Hanna , Schmidt-Pennington Laura , Reuter Miriam , Landwehr Laura-Sophie , Jensen Marie , Lahner Harald , Kimpel Otilia , Altieri Barbara , Laubner Katharina , Schreiner Jochen , Bojunga Joerg , Kircher Stefan , Kunze Catarina Alisa , Pohrt Anne , Teleanu Maria-Veronica , Hübschmann Daniel , Stenzinger Albrecht , Glimm Hanno , Fröhling Stefan , Fassnacht Martin , Mai Knut , Kroiss Matthias
Published: May 2023

Objective

Clinical trials with immune checkpoint inhibitors (ICI) in adrenocortical carcinoma (ACC) have yielded contradictory results. We aimed to evaluate treatment response and safety of ICI in ACC in a real-life setting.

Design

Retrospective cohort study of 54 patients with advanced ACC receiving ICI as compassionate use at 6 German reference centres between 2016 and 2022.

Methods

Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAE) were assessed.

Results

In 52 patients surviving at least 4 weeks after initiation of ICI, ORR was 13.5% (6-26) and DCR was 24% (16-41). PFS was 3.0 months (95% CI, 2.3-3.7). In all patients, median OS was 10.4 months (3.8-17). 17 TRAE occurred in 15 patients, which was associated with a longer PFS of 5.5 (1.9-9.2) vs 2.5 (2.0-3.0) months (HR 0.29, 95% CI, 0.13-0.66, P = 0.001) and OS of 28.2 (9.5-46.8) vs 7.0 (4.1-10.2) months (HR 0.34, 95% CI, 0.12-0.93). Positive tissue staining for programmed cell death ligand 1 (PD-L1) was associated with a longer PFS of 3.2 (2.6-3.8) vs 2.3 (1.6-3.0, P < 0.05) months. Adjusted for concomitant mitotane use, treatment with nivolumab was associated with lower risk of progression (HR 0.36, 0.15-0.90) and death (HR 0.20, 0.06-0.72) compared to pembrolizumab.

Conclusions

In the real-life setting, we observe a response comparable to other second-line therapies and an acceptable safety profile in ACC patients receiving different ICI. The relevance of PD-L1 as a marker of response and the potentially more favourable outcome in nivolumab-treated patients require confirmation.
Biological characteristics of microRNAs secreted by exosomes of periodontal ligament stem cells due to mechanical force
Authors: Zheng Xiaowen , Zhao Ning , Peng Liying , Li Zhenxia , Liu Chao , You Qingling , Fang Bing
Published: June 2023

Background

Orthodontic tooth movement (OTM) has previously been considered an inflammatory process. However, recent studies suggest that exosomes may play an important role in the cellular microenvironment of OTM. microRNAs (miRNAs) are one of the major constituents of exosomes. This study aims to investigate the biological characteristics of miRNAs secreted by exosomes of periodontal ligament stem cells (PDLSCs) due to mechanical forces.

Materials and methods

First, we established a mechanical stress model. The PDLSCs were loaded under different force values and exosomes were extracted after 48 h. High-throughput sequencing of exosomal miRNAs was performed to further evaluate their biological functions and underlying mechanisms.

Results

The morphology and functions of exosomes were not significantly different between the loading and non-loading PDLSC groups. The optimal loading time and force were 48 h and 1 g/cm2, respectively. After sequencing, gene ontology (GO) and Kyoto encyclopaedia of genes and genomes (KEGG) pathway and network analyses were performed and 10 differentially expressed miRNAs were identified according to a literature search. These are miR-99a-5p, miR-485-3P, miR-29a-3p,miR-21-5p, miR-146a-5p, miR140-3p, miR-1306-5p, miR-126-5p, miR-125a-5p, and miR-23a-3p.

Limitations

Extracting exosomes needs a large amount of PDLSCs. More functional experiments need to be done to confirm the exact mechanism of exosomal miRNAs of PDLSCs due to mechanical force.

Conclusions

The expression levels of miRNAs secreted by PDLSC-derived exosomes due to mechanical force were very different compared to PDLSC-derived exosomes under nonmechanical stress. The function of many of the identified exosomal miRNAs was found to be related to osteoblasts and osteoclasts. Further validation is required. A functional investigation of these miRNA could provide novel insights into their mechanism.
The accuracy of photographic soft-tissue profile analysis to determine Class II and vertical skeletal relationships in children
Authors: Becking Bibi E , Fledderus Anne C , van Merkesteyn J P Richard , Jonkman Ronald E G
Published: May 2023

Background

Lateral cephalometric analysis (LCA) is the reference standard for identifying common skeletal relationships in orthodontics, such as Cl II and hyperdivergent skeletal discrepancies, but it entails radiation exposure. Therefore, photographic soft-tissue profile analysis (PSPA) could be a useful alternative for these diagnoses, particularly for paediatric patients. This study aims to estimate the accuracy of PSPA for determining common skeletal discrepancies in children.

Methods

Cephalometric radiographs and profile photographs of a consecutive series of 100 children (8.0–17.6 years old) made on the same day were included. The validity of PSPA was verified against comparable LCA. First, by assessing the Pearson correlation and then estimating the sensitivity, specificity, receiver operating characteristic (ROC) curves and area under the curve (AUC) in sample A (n = 50). After external validation in a new sample B (n = 50), the ROC–AUC, diagnostic odds ratio, best cut-off points and discriminative validity were assessed in the total sample. Interrater reliability was estimated using the intraclass correlation coefficient, the standard error of measurement and Bland–Altman plots.

Results

The measurement properties of the PSPA angles A’N’B’, Gl’-Sn-Pog, N’-Sn-Pog’, and N’-Tra-Me’ were valid (ROC–AUC > 0.7) and reliable (ICCs > 0.92). The angles A’N’B’, Gl’-Sn-Pog’, and N’-Sn-Pog’, with the respective cut-off points ≥7.7’, ≥12.8’, and ≤163.5’, were accurate values for determining Cl II discrepancy. The N’-Tra-Me’-angle (≥63’) was an accurate estimate for a hyperdivergent discrepancy.

Conclusions

These validated PSPA angles could be used in clinical settings as a minimally invasive diagnostic tool to screen children suspected of having skeletal Cl II and hyperdivergent discrepancies.
Evolution of reproductive isolation in a long-term evolution experiment with Drosophila melanogaster: 30 years of divergent life-history selection
Authors: Robinson Chloe E , Thyagarajan Harshavardhan , Chippindale Adam K
Published: May 2023

We ask if three decades and over 1,500 generations of divergent life-history selection on age at reproduction has resulted in the evolution of reproductive isolation (RI) between laboratory populations of Drosophila melanogaster. We tested for premating, postmating-prezygotic, and postzygotic reproductive isolation between three replicate population pairs. Large, evolved differences in body size between selection treatments suggested the potential for prezygotic barriers driven by sexual selection or physical incompatibilities between the sexes. Although a simple prediction would be preference for larger size, creating directional isolation, our results from individual mate choice trials indicate that populations from both selection treatments show a marked bias towards homotypic mate choice; indicative of prezygotic RI driven by sexual selection or sexual conflict. Hybridization between the focal populations resulted in the production of viable adult flies with intermediate size and developmental traits. We observed a suggestive but statistically nonsignificant trend of fitness decline in the F2 generation of hybrids, but no significant evidence suggesting the evolution of postmating-prezygotic or postzygotic RI. Our findings are in accord with extant literature that posits that premating RI evolves before postmating forms of RI.
VqMAPK3/VqMAPK6, VqWRKY33, and VqNSTS3 constitute a regulatory node in enhancing resistance to powdery mildew in grapevine
Authors: Liu Wandi , Yan Chaohui , Li Ruimin , Chen Guanyu , Wang Xinqi , Wen Yingqiang , Zhang Chaohong , Wang Xiping , Xu Yan , Wang Yuejin
Published: May 2023

Grapevine powdery mildew is caused by Erysiphe necator, which seriously harms grape production in the world. Stilbene synthase makes phytoalexins that contribute to the resistance of grapevine against powdery mildew. A novel VqNSTS3 was identified and cloned from Chinese wild Vitis quinquangularis accession Danfeng-2. The novel VqNSTS3 was transferred into susceptible ‘Thompson Seedless’ by Agrobacterium-mediated transformation. The transgenic plants showed resistance to the disease and activated other resistance-related genes. VqNSTS3 expression in grapevine is regulated by VqWRKY33, and which binds to TTGACC in the VqNSTS3 promoter. Furthermore, VqWRKY33 was phosphorylated by VqMAPK3/VqMAPK6 and thus led to enhanced signal transduction and increased VqNSTS3 expression. ProVqNSTS3::VqNSTS3-GFP of transgenic VqNSTS3 in Arabidopsis thaliana was observed to move to and wrap the pathogen’s haustoria and block invasion by Golovinomyces cichoracearum. These results demonstrate that stilbene accumulation of novel VqNSTS3 of the Chinese wild Vitis quinquangularis accession Danfeng-2 prevented pathogen invasion and enhanced resistance to powdery mildew. Therefore, VqNSTS3 can be used in generating powdery mildew-resistant grapevines.
Impact of Inflammatory Bowel Disease on Patients’ Caregivers: Results From a French Survey
Authors: El Hajj Weam , Buisson Anne , Olympie Alain , Ravel Marie Hélène , Devos Corinne , Trang-Poisson Caroline , Macaigne Gilles , Nahon Stéphane
Published: June 2023

Background

The impact of inflammatory bowel disease (IBD) on caregivers has rarely been investigated. Our work aims to explore the burden of IBD on the different aspects of caregivers’ lives.

Methods

We conducted an online survey via the social network of the French IBD patient organization addressed to patients’ caregivers who were asked to fill in a questionnaire covering the impact of the disease on different aspects of their lives. Impacts were measured by a visual analog scale (VAS). A VAS score ≥5 of 10 was considered significantly high. We then performed uni- and multivariate analyses of predictors of higher impact on parents and partners, separately.

Results

A total of 853 caregivers participated, predominantly women (77%). The mean age was 48.5 years. Their relationship with the patient was mainly parents in 57.1% and partners in 30.6%. The type of IBD was Crohn’s disease in 63% and ulcerative colitis in 35%. The psychological burden was the highest among parents and was mainly correlated with a lack of knowledge about IBD and professional compromise (P < .05). The impact on leisure was the highest among partners and was affected by psychological, sexual, and professional burdens (P < .05). About 50% of partners experienced an absent sexual relationship for weeks/months and decreased libido regardless of IBD type. Professional impact was greater in parents compared with partners, and 36% of caregivers needed work arrangements.

Conclusions

IBD has a high impact on different aspects of life of patients’ caregivers. Therefore, interventions to reduce the disease burden in this population are needed.
One-Year Clinical Outcomes of Subcutaneous Infliximab Maintenance Therapy Compared With Intravenous Infliximab Maintenance Therapy in Patients With Inflammatory Bowel Disease: A Prospective Cohort Study
Authors: Hong Sung Noh , Hye Song Joo , Jin Kim Sung , Ha Park Yoon , Wan Choi Chang , Eun Kim Ji , Ran Kim Eun , Kyung Chang Dong , Kim Young-Ho
Published: June 2023

Background

Although the pharmacokinetic profile of subcutaneous (SC) infliximab (IFX) is superior to conventional intravenous (IV) IFX, long-term efficacy and safety of SC IFX in patients with inflammatory bowel disease (IBD) have not been reported yet. This study aimed to evaluate long-term clinical outcomes of IBD patients treated with SC IFX compared with those of IBD patients treated with IV IFX during maintenance therapy.

Methods

This prospective cohort study enrolled 61 IBD patients in clinical remission who received scheduled IFX maintenance therapy. Of them, 38 patients were switched to SC IFX, while 23 patients continued IV IFX with dose optimization. Enrolled patients were followed up for 1 year. The primary outcome was durable remission defined as clinical remission (Crohn’s disease, Harvey-Bradshaw index <5; ulcerative colitis, partial Mayo score <2) and biochemical remission (C-reactive protein <0.5 mg/dL) with IFX trough level ≥3 µg/mL throughout the follow-up period.

Results

One-year clinical remission, 1-year biochemical remission, and mucosal healing did not differ between the IV and SC IFX groups (n = 20 of 23 vs 33 of 38; P = 1.000; n = 22 of 23 vs 34 of 38; P = .641; and n = 10 of 18 vs 17 of 25; P = .414, respectively). During follow-up, the number of patients with IFX trough level <3 μg/mL was significantly lower in the SC IFX group (n = 0 of 38, 0%) than in the IV IFX group (n = 10 of 23, 43%) (P < .001). The SC IFX group showed higher 1-year durable remission than the IV IFX group (n = 31 of 38, 82% vs n = 11 of 23, 48%; P = .013). The incidence of IFX-related adverse events did not differ significantly between both groups (26% vs 39%; P = .446).

Conclusion

The SC IFX switch induced a higher 1-year durable remission rate than continuing IV IFX in patients with IBD during scheduled maintenance therapy, showing similar safety.
Use of Immune Checkpoint Inhibitors in Patients With Inflammatory Bowel Disease After Ileal Pouch-Anal Anastomosis
Authors: Karime Christian , Farraye Francis A , Hashash Jana G
Published: June 2023

Lay Summary

It is unknown if immune checkpoint inhibitor therapy increases risk of pouch-related complications in patients with inflammatory bowel disease after ileal-pouch anal anastomosis. In our study, pembrolizumab therapy was not associated with significant gastrointestinal immune-related adverse events or pouch-related complications.
Halāl Habichuelas: Food, Belonging, and the Conundrums of Being a Puerto Rican Muslim
Authors: Chitwood Ken
Published: May 2023

Based on multiple years of ethnographic fieldwork alongside Puerto Rican Muslims in Puerto Rico and the United States, this article explores issues of identification and belonging among Puerto Rican converts to Islam, as expressed in their food practices. As “quadruple minorities”—Muslim among Puerto Ricans, Puerto Rican among Muslims, and both Puerto Rican and Muslim in the shadow of American empire—I suggest that Puerto Rican converts seek ways to restore a sense of coherence and selfhood through cooking, consuming, and forming community around food. For Puerto Rican Muslim converts, halāl consumption practices are about more than making their food, drink, or actions permissible; they are also about making their very identifications permissible, what one interlocutor called “Boricua halāl.” This focus on religious actors’ food practices showcases affective encounters with what we call religion in the everyday, showing matter’s ability to reflect the quotidian complexity of late-modern lifeworlds.
Evaluation of integrase resistance in individuals who failed a regimen containing dolutegravir in French and Italian clinical settings
Authors: Armenia Daniele , Santoro Maria M , Charpentier Charlotte , Bertoli Ada , Forbici Federica , Calvez Vincent , Descamps Diane , Ceccherini-Silberstein Francesca , Marcelin Anne-Genevieve , Flandre Philippe
Published: June 2023

Background

This work aims to evaluate integrase resistance and its predictors in HIV-1 infected combined antiretroviral therapy (cART) experienced individuals failing a dolutegravir-based regimen.

Methods

Major resistance mutations (MRM) and genotypic susceptibility score (GSS) of dolutegravir companion drugs were evaluated on plasma genotypic resistance test (GRT) performed at dolutegravir failure. Logistic regression was used to evaluate factors associated to the risk of integrase strand-transfer inhibitors (INSTI)-resistance at dolutegravir failure.

Results

We retrospectively analysed 467 individuals. At failure GRT, individuals had been under dolutegravir for a median (IQR) time of 11 (5–20) months; around half of them had never been exposed to INSTI (52%) and 10.7% were at first-line regimen. Fifty-eight (12.4%) individuals showed ≥1 INSTI MRM. Among them, people INSTI-exposed showed significantly higher prevalence of INSTI resistance compared to those who were INSTI naïve [46 (21.2%) versus 9 (3.9%), P < 0.001].

N155H was the most prevalent MRM (5.4%), followed by G140S (4.5%) and Q148H (4.3%). These MRM were more probably present in INSTI-experienced individuals compared to those INSTI naïve. Despite failure, 89.5% of individuals harboured viral strains fully susceptible to dolutegravir and bictegravir and 85.0% to all INSTI. No INSTI exposure before receiving dolutegravir [OR: 0.35 (0.16–0.78), P < 0.010] and a GSS for companion drugs ≥2 (OR: 0.09 [0.04–0.23], P < 0.001) were negatively associated with INSTI resistance at failure.

Conclusions

In a large set of individuals failing dolutegravir in real-life, INSTI resistance was low and mainly related to previous first-generation INSTI exposure. Surveillance of integrase resistance remains crucial to preserve efficacy of INSTI class in the future.
Mechanism of tRNA recognition by heterotetrameric glycyl-tRNA synthetase from lactic acid bacteria
Authors: Nagato Yasuha , Yamashita Seisuke , Ohashi Azusa , Furukawa Haruyuki , Takai Kazuyuki , Tomita Kozo , Tomikawa Chie
Published: June 2023

Glycyl-tRNA synthetases (GlyRSs) have different oligomeric structures depending on the organisms. While a dimeric α2 GlyRS species is present in archaea, eukaryotes and some eubacteria, a heterotetrameric α2β2 GlyRS species is found in most eubacteria. Here, we present the crystal structure of heterotetrameric α2β2 GlyRS, consisting of the full-length α and β subunits, from Lactobacillus plantarum (LpGlyRS), gram-positive lactic bacteria. The α2β2LpGlyRS adopts the same X-shaped structure as the recently reported Escherichia coli α2β2 GlyRS. A tRNA docking model onto LpGlyRS suggests that the α and β subunits of LpGlyRS together recognize the L-shaped tRNA structure. The α and β subunits of LpGlyRS together interact with the 3′-end and the acceptor region of tRNAGly, and the C-terminal domain of the β subunit interacts with the anticodon region of tRNAGly. The biochemical analysis using tRNA variants showed that in addition to the previously defined determinants G1C72 and C2G71 base pairs, C35, C36 and U73 in eubacterial tRNAGly, the identification of bases at positions 4 and 69 in tRNAGly is required for efficient glycylation by LpGlyRS. In this case, the combination of a purine base at Position 4 and a pyrimidine base at Position 69 in tRNAGly is preferred.
Differential developmental rates and demographics in Red Kangaroo (Osphranter rufus) populations separated by the dingo barrier fence
Authors: Mitchell D Rex , Cairns Stuart C , Körtner Gerhard , Bradshaw Corey J A , Saltré Frédérik , Weisbecker Vera
Published: May 2023

Decommissioning the dingo barrier fence has been suggested to reduce destructive dingo control and encourage a free transfer of biota between environments in Australia. Yet the potential impacts that over a century of predator exclusion might have had on the population dynamics and developmental biology of prey populations has not been assessed. We here combine demographic data and both linear and geometric morphometrics to assess differences in populations among 166 red kangaroos (Osphranter rufus)—a primary prey species of the dingo—from two isolated populations on either side of the fence. We also quantified the differences in aboveground vegetation biomass for the last 10 years on either side of the fence. We found that the age structure and growth patterns, but not cranial shape, differed between the two kangaroo populations. In the population living with a higher density of dingoes, there were relatively fewer females and juveniles. These individuals were larger for a given age, despite what seems to be lower vegetation biomass. However, how much of this biomass represented kangaroo forage is uncertain and requires further on-site assessments. We also identified unexpected differences in the ontogenetic trajectories in relative pes length between the sexes for the whole sample, possibly associated with male competition or differential weight-bearing mechanics. We discuss potential mechanisms behind our findings and suggest that the impacts of contrasting predation pressures across the fence, for red kangaroos and other species, merit further investigation.
The resolution of professional tennis disputes
Authors: Bantekas Ilias
Published: June 2023

The regulatory landscape of professional tennis is scattered across several entities, each administering its own tournaments. This article focuses on disputes involving professional tennis players. In this context, it identifies two major areas of disputes, namely regulatory (encompassing disciplinary, doping and corruption offences) and contractual. The latter are chiefly resolved through litigation. Regulatory disputes are administered through distinct judicial and quasi-judicial institutions set up by the various tennis entities. The International Tennis Federation’s (ITF) international adjudication panel and its independent tribunal are the key institutions in this respect, with the independent tribunal possessing all the attributes of arbitral tribunals. The Court of Arbitration for Sport (CAS) has been conferred a limited appellate jurisdiction over decisions of these two entities. Overall, the ITF’s dispute resolution architecture has been effective and has created a significant body of precedent, further supplemented by that of the CAS.
Global Neurosurgery Advances From Trenches to Bedside: Lessons From Neurosurgical Care in War, Humanitarian Assistance, and Disaster Response
Authors: Asfaw Zerubabbel K , Greisman Jacob D , Comuniello Briana , Shlobin Nathan A , Etienne Mill , Zuckerman Scott L , Laeke Tsegazeab , Al-Sharshahi Zahraa F , Barthélemy Ernest J
Published: June 2023

Introduction

War has influenced the evolution of global neurosurgery throughout the past century. Armed conflict and mass casualty disasters (MCDs), including Humanitarian Assistance Disaster Relief missions, require military surgeons to innovate to meet extreme demands. However, the military medical apparatus is seldom integrated into the civilian health care sector. Neurosurgeons serving in the military have provided a pragmatic template for global neurosurgeons to emulate in humanitarian disaster responses. In this paper, we explore how wars and MCD have influenced innovations of growing interest in the resource-limited settings of global neurosurgery.

Methods

We performed a narrative review of the literature examining the influence of wars and MCD on contemporary global neurosurgery practices.

Results

Wartime innovations that influenced global neurosurgery include the development of triage systems and modernization with airlifts, the implementation of ambulance corps, early operation on cranial injuries in hospital camps near the battlefield, the use of combat body armor, and the rise of damage control neurosurgery. In addition to promoting task-shifting and task-sharing, workforce shortages during wars and disasters contributed to the establishment of the physician assistant/physician associate profession in the USA. Low- and middle-income countries (LMICs) face similar challenges in developing trauma systems and obtaining advanced technology, including neurosurgical equipment like battery-powered computed tomography scanners. These challenges—ubiquitous in low-resource settings—have underpinned innovations in triage and wound care, rapid evacuation to tertiary care centers, and minimizing infection risk.

Conclusion

War and MCDs have catalyzed significant advancements in neurosurgical care both in the pre-hospital and inpatient settings. Most of these innovations originated in the military and subsequently spread to the civilian sector as military neurosurgeons and reservist civilian neurosurgeons returned from the battlefront or other low-resource locations. Military neurosurgeons have utilized their experience in low-resource settings to make volunteer global neurosurgery efforts in LMICs successful. LMICs have, by necessity, responded to challenges arising from resource shortages by developing innovative, context-specific care paradigms and technologies.
Correlates of the Veterans Visiting Emergency Departments in Taiwan: A Comparison Before and After the Coronavirus Disease 2019 Pandemic
Authors: Lin Pei-Ying , Lee Yen-Han , Wang Ren-Siang , Chen Tze-Yin , Li Yi-Jing , Wu Yu-Hsuan , Hsu Teh-Fu , Chang Yen-Chang
Published: May 2023

Background

Taiwan has a substantial number of veterans, but knowledge regarding their emergency department (ED) visits during the coronavirus disease 2019 (COVID-19) pandemic remains limited. This study examined the characteristics of veterans’ ED visits during Taiwan’s COVID-19 epidemic.

Methods

This was a cross-sectional study conducted at the ED of a large veteran medical center located in Taipei, Taiwan, from May 2018 to October 2021. We analyzed the numbers and features of visits in summer and autumn according to the first wave of the COVID-19 epidemic in Taiwan in 2021.

Results

Medical institutions were positively associated with veteran status. Emergency department complaints of trauma (adjusted odds ratio [AOR] = 1.15, 95% CI: 1.06-1.25; summer P < .01) and chest pain/tightness (AOR = 1.65, 95% CI: 1.45-1.87; summer P < .01; AOR = 1.4, 95% CI: 1.26-1.55; P < .01) were associated with increased odds of being a veteran. Triage levels above 2 were positively associated with veteran status in the autumn model (AOR = 1.14, 95% CI: 1.07-1.22; P < .01). Patients hospitalized after ED visits were associated with reduced odds of veteran status (P < .01). Those who spent a long time in the ED were more likely to be veterans than those who spent a shorter time in the ED (P < .01). Veterans were less likely to visit the ED regardless of the time frame of the study period (P < .01), except during the COVID-19 outbreak in the autumn (2019-2020).

Conclusions

The distinctions in ED visits highlighted the individuality of veterans’ medical needs. Our findings suggest that the veteran medical system can add to the focus on improving senior-friendly care, fall prevention, quality of life of institutionalized veterans, access for homeless veterans, and care for ambulatory care–sensitive conditions.
Dark matter profiles of SPARC galaxies: a challenge to fuzzy dark matter
Authors: Khelashvili M , Rudakovskyi A , Hossenfelder S
Published: May 2023

Stellar and gas kinematics of galaxies are a sensitive probe of the dark matter distribution in the halo. The popular fuzzy dark matter models predict the peculiar shape of density distribution in galaxies: specific dense core with sharp transition to the halo. Moreover, fuzzy dark matter predicts scaling relations between the dark matter particle mass and density parameters. In this work, we use a Bayesian framework and several dark matter halo models to analyse the stellar kinematics of galaxies using the Spitzer Photometry and Accurate Rotation Curves data base. We then employ a Bayesian model comparison to select the best halo density model. We find that more than half of the galaxies prefer the fuzzy dark model against standard dark matter profiles (NFW, Burkert, and cored NFW). While this seems like a success for fuzzy dark matter, we also find that there is no single value for the particle mass that provides a good fit for all galaxies.
A photometric study of centaurs 29P/Schwassmann–Wachmann and (2060) Chiron
Authors: Betzler Alberto S
Published: May 2023

This study presents the analysis of forced photometry data in the o and c filters of centaurs 29P/Schwassmann–Wachmann and (2060) Chiron obtained by the ATLAS network between 2015 and 2022. Centaur 29P had 24 outbursts with a median peak brightness of −3.0 and a range of −3.7 mag, regardless of spectral band. Some of these outbursts exhibited an asymmetric light curve with respect to peak brightness, with brightness decreases ranging from −0.22 to −7.6 mag h−1 and durations from 2.8 min to 1.4 d. The slope m of the photometric profile of the coma after/before and during an outburst was ≤1 and >1, respectively, reflecting an increase in brightness at the optocenter of the object. Without the outbursts, 29P has an absolute magnitudes H0 of 9.3 ± 0.2 and 9.10 ± 0.01 in the c and o filters, respectively, and activity indices of n = 11.56 ± 0.08 and 2.1 ± 0.1. Using the Lomb–Scargle periodogram, a periodicity of 0.97 d was found in the c magnitudes after perihelion, probably related to nuclear rotation. The absolute magnitude of Chiron in the HG1G2 system in the o filter is nearly constant between 2017 and 2020, with a weighted mean of 5.35 ± 0.03. In 2021, the brightness increases to H = 4.54 ± 0.03 and decreases to 5.04 ± 0.04 in 2022. This increase in 2021 is not due to outbursts that did not occur during the entire observing campaign, but is related to the increase in opposition effect.
Regulation of T7 gp2.5 binding dynamics by its C-terminal tail, template conformation and sequence
Authors: Xu Longfu , Cabanas-Danés Jordi , Halma Matthew T J , Heller Iddo , Stratmann Sarah A , van Oijen Antoine M , Lee Seung-Joo , Peterman Erwin J G , Wuite Gijs J L
Published: May 2023

Bacteriophage T7 single-stranded DNA-binding protein (gp2.5) binds to and protects transiently exposed regions of single-stranded DNA (ssDNA) while dynamically interacting with other proteins of the replication complex. We directly visualize fluorescently labelled T7 gp2.5 binding to ssDNA at the single-molecule level. Upon binding, T7 gp2.5 reduces the contour length of ssDNA by stacking nucleotides in a force-dependent manner, suggesting T7 gp2.5 suppresses the formation of secondary structure. Next, we investigate the binding dynamics of T7 gp2.5 and a deletion mutant lacking 21 C-terminal residues (gp2.5-Δ21C) under various template tensions. Our results show that the base sequence of the DNA molecule, ssDNA conformation induced by template tension, and the acidic terminal domain from T7 gp2.5 significantly impact on the DNA binding parameters of T7 gp2.5. Moreover, we uncover a unique template-catalyzed recycling behaviour of T7 gp2.5, resulting in an apparent cooperative binding to ssDNA, facilitating efficient spatial redistribution of T7 gp2.5 during the synthesis of successive Okazaki fragments. Overall, our findings reveal an efficient binding mechanism that prevents the formation of secondary structures by enabling T7 gp2.5 to rapidly rebind to nearby exposed ssDNA regions, during lagging strand DNA synthesis.
Staphylococcus aureus Bacteremia in Pediatric Patients: Uncovering a Rural Health Challenge
Authors: Whittington Kyle J , Malone Sara M , Hogan Patrick G , Ahmed Faria , Flowers JessieAnn , Milburn Grace , Morelli John J , Newland Jason G , Fritz Stephanie A
Published: May 2023

Background

Staphylococcus aureus bacteremia poses significant risk for morbidity and mortality. This may be exacerbated in rural populations facing unique health challenges.

Methods

To investigate factors influencing S. aureus bacteremia outcomes, we conducted a retrospective cohort study of children admitted to St. Louis Children's Hospital (SLCH) from 2011 to 2019. Exposures included rurality (defined by the Rural-Urban Continuum Code), Area Deprivation Index, and outside hospital (OSH) admission before SLCH admission. The primary outcome was treatment failure, a composite of 90-day all-cause mortality and hospital readmission.

Results

Of 251 patients, 69 (27%) were from rural areas; 28 (11%) were initially admitted to an OSH. Treatment failure occurred in 39 (16%) patients. Patients from rural areas were more likely to be infected with methicillin-resistant S. aureus (45%) vs urban children (29%; P = .02). Children initially admitted to an OSH, vs those presenting directly to SLCH, were more likely to require intensive care unit–level (ICU) care (57% vs 29%; P = .002), have an endovascular source of infection (32% vs 12%; P = .004), have a longer duration of illness before hospital presentation (4.1 vs 3.0 days; P = .04), and have delayed initiation of targeted antibiotic therapy (3.9 vs 2.6 days; P = .01). Multivariable analysis revealed rural residence (adjusted odds ratio [aOR], 2.3; 95% CI, 1.1–5.0), comorbidities (aOR, 2.9; 95% CI, 1.3–6.2), and ICU admission (aOR, 3.9; 95% CI, 1.9–8.3) as predictors of treatment failure.

Conclusions

Children from rural areas face barriers to specialized health care. These challenges may contribute to severe illness and worse outcomes among children with S. aureus bacteremia.
Place of Death for Israeli Cancer Patients Over a 20-Year Period: Reducing Hospital Deaths, but Barriers Remain
Authors: Shalev Many Yuval , Shvartzman Pesach , Wolf Ido , Silverman Barbara G
Published: June 2023

Background

Cancer remains a leading cause of mortality worldwide. While the main focus of palliative care (PC) is quality of life, the elements that comprise the quality of death are often overlooked. Dying at home, with home-hospice-care (HHC) support, rather than in-hospital, may increase patient satisfaction and decrease the use of invasive measures. We examined clinical and demographic characteristics associated with out-of-hospital death among patients with cancer, which serves as a proxy measure for HHC deaths.

Methods

Using death certification data from the Israel Central Bureau of Statistics, we analyzed 209,158 cancer deaths between 1998 and 2018 in Israel including demographic information, cause of death, and place of death (POD). A multiple logistic regression model was constructed to identify factors associated with out-of-hospital cancer deaths.

Results

Between 1998 and 2018, 69.1% of cancer deaths occurred in-hospital, and 30.8% out-of-hospital. Out-of-hospital deaths increased by 1% annually during the study period. Older patients and those dying of solid malignancies were more likely to die out-of-hospital (OR = 2.65, OR = 1.93, respectively). Likelihood of dying out-of-hospital varied with area of residency; patients living in the Southern district were more likely than those in the Jerusalem district to die out-of-hospital (OR = 2.37).

Conclusion

The proportion of cancer deaths occurring out-of-hospital increased during the study period. We identified clinical and demographic factors associated with POD. Differences between geographical areas probably stem from disparity in the distribution of PC services and highlight the need for increasing access to primary EOL care. However, differences in age and tumor type probably reflect cultural changes and suggest focusing on educating patients, families, and physicians on the benefits of PC.
A Phase I Trial of the Dual MET Kinase/OCT-2 Inhibitor OMO-1 in Metastatic Solid Malignancies Including MET Exon 14 Mutated Lung Cancer
Authors: Pruis Melinda A , Krebs Matthew G , Plummer Ruth , De Vos Filip , Angevin Eric , Prenen Hans , Forster Martin D , Clack Glen , Van der Aa Annegret , Tjwa Marc , Jansen Ellen , Perera Timothy , Lolkema Martijn P
Published: June 2023

Introduction

Targeted therapy in non-small cell lung cancer (NSCLC) patients with mesenchymal epithelial transition (MET) exon 14 skipping mutations (METex14) and MET amplifications has improved patients’ outcomes. The development of more potent MET kinase inhibitors could further benefit these patients. The aim of this trial is to determine the safety and recommended phase 2 dose (RP2D) of OMO-1 (an oral dual MET kinase/OCT-2 inhibitor) and to assess preliminary clinical efficacy in METex14-positive NSCLC and other MET-positive solid tumors.

Materials and Methods

This was a first-in-patient, open-label, multicenter study of OMO-1 in patients with locally advanced or metastatic solid malignancies. A standard 3 + 3 dose escalation design was utilized starting at a dose level of 100 mg BID continuously. Preliminary efficacy was investigated in patients with METex14-positive NSCLC, and MET amplified NSCLC and other solid tumors (MET basket).

Results

In the dose-escalation part, 24 patients were included in 5 dose levels ranging from 100 mg twice daily (BID) to 400 mg BID. Most common adverse events (≥ 20%) were nausea, fatigue, vomiting, increased blood creatinine, and headache. The RP2D was determined at 250 mg BID. In the expansion cohorts, 15 patients were included (10 in METex14-positive NSCLC cohort and 5 in MET basket cohort) and received either 200 or 250 mg BID. Eight out of the 10 patients with METex14 positive NSCLC had stable disease as the best response.

Conclusion

OMO-1 was tolerated at the dose of 250 mg BID and shows initial signs of MET inhibition and anti-tumor activity in METex14 mutated NSCLC patients.
The Decline of the Traditional Model of European Constitutional Jurisdiction
Authors: Requejo Pagés Juan Luis
Published: May 2023

The comparative study of the legal orders examined in this text proves that there is a genuinely European type of constitutional jurisdiction. Its specific task is to review statutes under privileged conditions. However, constitutional courts are beginning to see themselves as dysfunctional institutions: increasingly, they appear to be an obstacle to the proper functioning of legal orders, which no longer can be solely understood by means of the categories of validity and nullity and are no longer strictly hierarchical and constitution-centred. In another paradox of the history of the European integration process, it is possible that the constitutional courts will find a new raison d’être in EU law, since Article 4 para 2 TEU logically presupposes the participation of national communication partners that, together with the ECJ, bring the concept of ‘national identity’ to life. Thus, constitutional courts are required to play a crucial role in this open and permanent process of loyal judicial cooperation.
Leaf starch metabolism sets the phase of stomatal rhythm
Authors: Westgeest Adrianus J , Dauzat Myriam , Simonneau Thierry , Pantin Florent
Published: June 2023

In leaves of C3 and C4 plants, stomata open during the day to favor CO2 entry for photosynthesis and close at night to prevent inefficient transpiration of water vapor. The circadian clock paces rhythmic stomatal movements throughout the diel (24–h) cycle. Leaf transitory starch is also thought to regulate the diel stomatal movements, yet the underlying mechanisms across time (key moments) and space (relevant leaf tissues) remain elusive. Here, we developed PhenoLeaks, a pipeline to analyze the diel dynamics of transpiration, and used it to screen a series of Arabidopsis (Arabidopsis thaliana) mutants impaired in starch metabolism. We detected a sinusoidal, endogenous rhythm of transpiration that overarches days and nights. We determined that a number of severe mutations in starch metabolism affect the endogenous rhythm through a phase shift, resulting in delayed stomatal movements throughout the daytime and diminished stomatal preopening during the night. Nevertheless, analysis of tissue-specific mutations revealed that neither guard-cell nor mesophyll-cell starch metabolisms are strictly required for normal diel patterns of transpiration. We propose that leaf starch influences the timing of transpiration rhythm through an interplay between the circadian clock and sugars across tissues, while the energetic effect of starch-derived sugars is usually nonlimiting for endogenous stomatal movements.
Validity, Reliability, and Measurement Error of the Remote Fugl-Meyer Assessment by Videoconferencing: Tele-FMA
Authors: Liz Larissa , da Silva Tayara Gaspar , Michaelsen Stella Maris
Published: May 2023

Objective

The objective of this study was to investigate the validity, reliability, and measurement error of the Fugl-Meyer Assessment (FMA) when it was remotely administered by videoconferencing (Tele-FMA) and to describe barriers to remote administration of the FMA.

Methods

Forty-five participants who had strokes and had a smartphone or laptop computer with a camera and internet access were included. An in-person assessment was compared with a remote assessment in 11 participants, and 34 participants completed only the remote assessment. Rater 1 (R1) remotely administered, recorded, and scored the items of the FMA, after which the recording was forwarded to be scored by Rater 2. At least 7 days later, R1 rated the videorecording of the remote assessment a second time for the evaluation of intrarater reliability. In-person assessment was completed by R1 at the participant’s home. Criterion validity was analyzed using the Bland–Altman limits of agreement, and convergent validity was analyzed using Spearman correlation coefficient. The intrarater and interrater reliability was analyzed using the intraclass correlation coefficient, and individual items were analyzed using the weighted kappa. The standard error of measurement and minimal detectable change were calculated to evaluate the measurement error.

Results

Bland–Altman plots showed adequate agreement of in-person FMA and tele-FMA. A moderate positive correlation was found between Tele-FMA lower extremity (LE) scores and step test results, and a strong positive correlation was found between Tele-FMA-upper extremity (UE) and Stroke Impact Scale hand function domain. Significant and excellent (0.96 ≤ ICC ≤ 0.99) interrater and intrarater reliabilities of the Tele-FMA, Tele-FMA-UE, and tele-FMA-LE were found. Regarding the individual items, most showed excellent reliability (weighted kappa > 0.70). The standard error of measurement for both reliabilities was small (≤3.1 points). The minimal detectable change with 95% CI for both the Tele-FMA and Tele-FMA-UE was 2.5 points, whereas it was 1.3 points for the Tele-FMA-LE.

Conclusion

Tele-FMA has excellent intrarater and interrater reliability and should be considered as a valid measurement.

Impact

The FMA is widely used in clinical practice. However, the measurement properties of the remote version applied by videoconferencing were unknown. This study’s results demonstrate the validity and reliability of the Tele-FMA for assessing poststroke motor impairment remotely via videoconferencing. The Tele-FMA may be used to implement telerehabilitation in clinical practice.