bluuebunny/crossref_metadata_2025 huggingface dataset:
“Under the hood”: artificial intelligence in personalized radiotherapy
Authors: Gianoli Chiara , De Bernardi Elisabetta , Parodi Katia
Published: July 2024

This review presents and discusses the ways in which artificial intelligence (AI) tools currently intervene, or could potentially intervene in the future, to enhance the diverse tasks involved in the radiotherapy workflow. The radiotherapy framework is presented on 2 different levels for the personalization of the treatment, distinct in tasks and methodologies. The first level is the clinically well-established anatomy-based workflow, known as adaptive radiation therapy. The second level is referred to as biology-driven workflow, explored in the research literature and recently appearing in some preliminary clinical trials for personalized radiation treatments. A 2-fold role for AI is defined according to these 2 different levels. In the anatomy-based workflow, the role of AI is to streamline and improve the tasks in terms of time and variability reductions compared to conventional methodologies. The biology-driven workflow instead fully relies on AI, which introduces decision-making tools opening uncharted frontiers that were in the past deemed challenging to explore. These methodologies are referred to as radiomics and dosiomics, handling imaging and dosimetric information, or multiomics, when complemented by clinical and biological parameters (ie, biomarkers). The review explicitly highlights the methodologies that are currently incorporated into clinical practice or still in research, with the aim of presenting the AI’s growing role in personalized radiotherapy.
Voices of Refugee Families from Ukraine Currently Living in the Czech Republic
Authors: Racko Veronika , Mikulcová Kateřina
Published: July 2024

The living situation of Ukrainian refugees in the Czech Republic can be explored from various perspectives. However, the currently available data are not able to provide a sufficient view of the refugee situation. These data are rather economic (related to financial situation, employment, wage disadvantage, use of state aid, etc) and do not provide, for example, information on daily needs. Our goal is therefore to give a voice to refugees from Ukraine to describe their current perception of their life situation and based on this establish implications for social work. The data were created through the perspective of participatory research using the photovoice method (individual and group) interviews (n = 13), online responsive questionnaire survey (n = 41) and a final photo exhibition. According to the available data, the context of life situation was created by economic well-being. But the key theme of life situation of Ukrainian refugees was loneliness. An interesting aspect is the gender dimension of activities coping with loneliness, which especially includes the ‘typically female role’ of childcare.
The rich information hidden in misspoken discourse
Authors: Hillis Argye E
Published: July 2024

This scientific commentary refers to ‘Artificial intelligence classifies primary progressive aphasia from connected speech’ by Rezaii et al. (https://doi.org/10.1093/brain/awae196).
The involvement of the piriform cortex in non-lesional temporal lobe epilepsy: an uncommon component of the epileptogenic network
Authors: Pedersen Nigel P , Raghu Ashley , Shivamurthy Veeresh Kumar N , Chern Joshua J , Gross Robert E , Willie Jon T , Dingledine Raymond J , Kheder Ammar
Published: July 2024

The piriform cortex is recognized as highly epileptogenic in rodents, yet its electrophysiological role in human epilepsy remains understudied. Recent surgical outcomes have suggested potential benefits in resecting the piriform cortex for cases of medial temporal lobe epilepsy. However, little is known about its electrophysiological activity in human epilepsy. This case-series study aimed to explore the electrophysiological role of the piriform cortex within the epileptogenic network among patients with suspected temporal lobe epilepsy. Participants were recruited from Emory University Hospital or Children’s Healthcare of Atlanta, with non-lesional frontotemporal or temporal lobe hypotheses, undergoing stereoelectroencephalographic studies. Specifically, focus was placed on patients with one or more electrode contacts in the piriform cortex. Primary objectives included determining piriform cortex involvement within the electrophysiologically defined epileptogenic network and assessing the effects of electrical stimulation. Twenty-two patients were included in the study. Notably, only one patient exhibited piriform cortex involvement at seizure onset, associated with an olfactory aura. Two patients showed early piriform cortex involvement, while others displayed late or no involvement. Electrical stimulation of the piriform cortex induced after-discharges in three patients and replicated a habitual seizure in one. These findings present a contrast to surgical outcome studies, suggesting that the piriform cortex may not typically play a significant role in the epileptogenic network among patients with non-lesional temporal lobe epilepsy.
Patterns of brain volume and metabolism predict clinical features in the progressive supranuclear palsy spectrum
Authors: Ali Farwa , Clark Heather , Machulda Mary , Senjem Matthew L , Lowe Val J , Jack Clifford R , Josephs Keith A , Whitwell Jennifer , Botha Hugo
Published: July 2024

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy that presents with highly heterogenous clinical syndromes. We perform cross-sectional data-driven discovery of independent patterns of brain atrophy and hypometabolism across the entire PSP spectrum. We then use these patterns to predict specific clinical features and to assess their relationship to phenotypic heterogeneity. We included 111 patients with PSP (60 with Richardson syndrome and 51 with cortical and subcortical variant subtypes). Ninety-one were used as the training set and 20 as a test set. The presence and severity of granular clinical variables such as postural instability, parkinsonism, apraxia and supranuclear gaze palsy were noted. Domains of akinesia, ocular motor impairment, postural instability and cognitive dysfunction as defined by the Movement Disorders Society criteria for PSP were also recorded. Non-negative matrix factorization was used on cross-sectional MRI and fluorodeoxyglucose-positron emission tomography (FDG-PET) scans. Independent models for each as well as a combined model for MRI and FDG-PET were developed and used to predict the granular clinical variables. Both MRI and FDG-PET were better at predicting presence of a symptom than severity, suggesting identification of disease state may be more robust than disease stage. FDG-PET predicted predominantly cortical abnormalities better than MRI such as ideomotor apraxia, apraxia of speech and frontal dysexecutive syndrome. MRI demonstrated prediction of cortical and more so sub-cortical abnormalities, such as parkinsonism. Distinct neuroanatomical foci were predictive in MRI- and FDG-PET-based models. For example, vertical gaze palsy was predicted by midbrain atrophy on MRI, but frontal eye field hypometabolism on FDG-PET. Findings also differed by scale or instrument used. For example, prediction of ocular motor abnormalities using the PSP Saccadic Impairment Scale was stronger than with the Movement Disorders Society Diagnostic criteria for PSP oculomotor impairment designation. Combination of MRI and FDG-PET demonstrated enhanced detection of parkinsonism and frontal syndrome presence and apraxia, cognitive impairment and bradykinesia severity. Both MRI and FDG-PET patterns were able to predict some measures in the test set; however, prediction of global cognition measured by Montreal Cognitive Assessment was the strongest. MRI predictions generalized more robustly to the test set. PSP leads to neurodegeneration in motor, cognitive and ocular motor networks at cortical and subcortical foci, leading to diverse yet overlapping clinical syndromes. To advance understanding of phenotypic heterogeneity in PSP, it is essential to consider data-driven approaches to clinical neuroimaging analyses.
Synthesis of cyclic organosilicon compounds by palladium-catalyzed reactions of 2-silylaryl triflates
Authors: Shintani Ryo
Published: July 2024

2-Silylaryl triflates are widely employed as effective aryne precursors in organic synthesis, but their use as substrates for the synthesis of organosilicon compounds by retaining their silicon substituents is another attractive usage of these reagents. In particular, cyclic compounds with a silicon atom in the ring are promising candidates for various biologically active substances and optoelectronic functional materials. In this context, new synthetic methods for silicon-containing cyclic compounds have been actively investigated through the development of palladium-catalyzed reactions of 2-silylaryl triflates without generating aryne intermediates. As a result, selective synthesis of various silacyclic compounds has been achieved via C–H and/or C–Si bond activations as well as intramolecular exchange between these bonds and C–Pd bonds that are formed as reaction intermediates. An overview of this topic is described, including the mechanistic insights.
Right atrial and right ventricular strain: prognostic value depends on the severity of tricuspid regurgitation
Authors: Curtis Elizabeth , Lemarchand Léo , Lee K Charlotte , Galli Elena , L’Official Guillaume , Auffret Vincent , Leurent Guillaume , Oger Emmanuel , Donal Erwan
Published: July 2024

Aims

Assessing right heart function is challenging, particularly when significant tricuspid regurgitation (TR) is present. Amongst available echocardiographic techniques for assessment, literatures suggest that strain imaging may be more reliable and less susceptible to loading conditions. Thus, we aimed to assess the validity of right atrial (RA) and right ventricular (RV) strain relative to conventional metrics as well as their utility in predicting patient outcomes in TR.

Methods and results

We studied 262 consecutive patients (mean age 74 ± 11.2 years, 53% male) who underwent same-day echocardiography and right heart catheterization between 2018 and 2023. We compared right heart strain to traditional metrics of RV function and subsequently correlated RA and RV strain to heart failure (HF)-related death or hospitalization, whichever came first. Over a mean follow-up of 34 ± 15 months, there were 103 deaths and HF hospitalizations. Both RA strain and RV strain were correlated with echocardiographic and invasive measures of right heart function. Across all patients, preserved RA strain was associated with lower risk of adverse outcomes [hazard ratio (HR) 0.763, 95% confidence interval (CI) 0.618–0.943]. Similarly, preserved RV strain was correlated with better outcomes, although this was only statistically significant in patients without severe TR or pulmonary hypertension (HR 2.450, 95% CI 1.244–4.825). Moreover, abnormal ratios of RV strain to pulmonary pressures and RV size were significantly correlated with adverse outcomes (P < 0.05 each).

Conclusion

RA and RV strain are independently correlated with echocardiographic and invasive measures of cardiac function. Moreover, preserved RA and RV strain is likely associated with better clinical outcomes.
Regulatory role of VvsB protein on serine protease activity of VvsA in Vibrio vulnificus
Authors: Kawase Tomoka , Debnath Anusuya , Okamoto Keinosuke
Published: July 2024

Background: Vibrio vulnificus NCIMB2137, a Gram-negative, metalloprotease negative estuarine strain was isolated from a diseased eel. A 45 kDa chymotrypsin-like alkaline serine protease known as VvsA has been recently reported as one of the major virulence factor responsible for the pathogenesis of this strain. The vvsA gene along with a downstream gene vvsB, whose function is still unknown constitute an operon designated as vvsAB. Objective: This study examines the contribution of VvsB to the functionality of VvsA. Method: In this study, VvsB was individually expressed using Rapid Translation System (RTS system), followed by an analysis of its role in regulating the serine protease activity of VvsA. Result: The proteolytic activity of VvsA increased upon the addition of purified VvsB to the culture supernatant of V. vulnificus. However, the attempts of protein expression using an E. coli system revealed a noteworthy observation that protein expression from the vvsA gene exhibited higher protease activity compared to that from the vvsAB gene within the cytoplasmic fraction. These findings suggest an intricate interplay between VvsB and VvsA, where VvsB potentially interacts with VvsA inside the bacterium and suppress the proteolytic activity. While outside the bacterial milieu, VvsB appears to stimulate the activation of inactive VvsA. Conclusion: The findings suggest that Vibrio vulnificus regulates VvsA activity through the action of VvsB, both intracellularly and extracellularly, to ensure its survival.
Chromosome-Level Genome Assembly of the Viviparous Eelpout Zoarces viviparus
Authors: Fuhrmann Nico , Brasseur Marie V , Bakowski Christina E , Podsiadlowski Lars , Prost Stefan , Krehenwinkel Henrik , Mayer Christoph
Published: July 2024

The viviparous eelpout Zoarces viviparus is a common fish across the North Atlantic and has successfully colonized habitats across environmental gradients. Due to its wide distribution and predictable phenotypic responses to pollution, Z. viviparus is used as an ideal marine bioindicator organism and has been routinely sampled over decades by several countries to monitor marine environmental health. Additionally, this species is a promising model to study adaptive processes related to environmental change, specifically global warming. Here, we report the chromosome-level genome assembly of Z. viviparus, which has a size of 663 Mb and consists of 607 scaffolds (N50 = 26 Mb). The 24 largest represent the 24 chromosomes of the haploid Z. viviparus genome, which harbors 98% of the complete Benchmarking Universal Single-Copy Orthologues defined for ray-finned fish, indicating that the assembly is highly contiguous and complete. Comparative analyses between the Z. viviparus assembly and the chromosome-level genomes of two other eelpout species revealed a high synteny, but also an accumulation of repetitive elements in the Z. viviparus genome. Our reference genome will be an important resource enabling future in-depth genomic analyses of the effects of environmental change on this important bioindicator species.
Testing times: disentangling admixture histories in recent and complex demographies using ancient DNA
Authors: Williams Matthew P , Flegontov Pavel , Maier Robert , Huber Christian D
Published: July 2024

Our knowledge of human evolutionary history has been greatly advanced by paleogenomics. Since the 2020s, the study of ancient DNA has increasingly focused on reconstructing the recent past. However, the accuracy of paleogenomic methods in resolving questions of historical and archaeological importance amidst the increased demographic complexity and decreased genetic differentiation remains an open question. We evaluated the performance and behavior of two commonly used methods, qpAdm and the f3-statistic, on admixture inference under a diversity of demographic models and data conditions. We performed two complementary simulation approaches—firstly exploring a wide demographic parameter space under four simple demographic models of varying complexities and configurations using branch-length data from two chromosomes—and secondly, we analyzed a model of Eurasian history composed of 59 populations using whole-genome data modified with ancient DNA conditions such as SNP ascertainment, data missingness, and pseudohaploidization. We observe that population differentiation is the primary factor driving qpAdm performance. Notably, while complex gene flow histories influence which models are classified as plausible, they do not reduce overall performance. Under conditions reflective of the historical period, qpAdm most frequently identifies the true model as plausible among a small candidate set of closely related populations. To increase the utility for resolving fine-scaled hypotheses, we provide a heuristic for further distinguishing between candidate models that incorporates qpAdm model P-values and f3-statistics. Finally, we demonstrate a significant performance increase for qpAdm using whole-genome branch-length f2-statistics, highlighting the potential for improved demographic inference that could be achieved with future advancements in f-statistic estimations.
Psychological safety is associated with better work environment and lower levels of clinician burnout
Authors: de Lisser Rosalind , Dietrich Mary S , Spetz Joanne , Ramanujam Rangaraj , Lauderdale Jana , Stolldorf Deonni P
Published: July 2024

Burnout is attributed to negative work environments and threatens patient and clinician safety. Psychological safety is the perception that the work environment is safe for interpersonal risk-taking and may offer insight into the relationship between the work environment and burnout. In this cross-sectional analysis of survey data from 621 nurse practitioners in California, we found that one-third (34%) experienced high burnout. Four factors in the work environment were negatively associated with burnout and positively associated with psychological safety. Significant mediation effects of psychological safety were observed on the relationships between each work environment factor and both emotional exhaustion and depersonalization. The largest mediation effects were observed on the total effects of Nurse Practitioner–Physician Relations and Practice Visibility on Emotional Exhaustion (37% and 32%, respectively) and Independent Practice and Support and NP-Administration Relations on Depersonalization (32% and 29%, respectively). We found, overall, that psychological safety decreased the strength of the negative relationship between work environment and burnout. We argue that research, practice, and policy efforts to mitigate burnout and improve the work environment should consider psychological safety as a metric for system-level well-being.
The influence of threat and right-wing authoritarianism on the selection of online (dis)information—a conceptual replication and extension of Lavine et al. (2005)
Authors: Klebba Lea-Johanna , Winter Stephan
Published: July 2024

Over the decades, communication research has investigated the situational and personal conditions under which people particularly prefer attitude-consistent over attitude-inconsistent content (confirmation bias). In a central study, Lavine et al. (2005) [Lavine, H., Lodge, M., & Freitas, K. (2005). Authoritarianism, threat, and motivated reasoning. Political Psychology, 26(2), 219–244.] examined how right-wing authoritarianism (RWA) and threat cause bias when processing political information. Their laboratory experiment suggested that right-wing authoritarians prefer attitude-consistent information in the presence of a threat. Given new crisis environments accompanied by various threats, we re-examined this interaction effect and conceptually replicated Lavine et al.'s central hypothesis in a contemporary media environment. In an online experiment (N = 1,118), we focused on selective exposure to verified news and disinformation and tracked participants’ selection unobtrusively. Contrary to expectations, the interaction between different threats and RWA did not increase selective exposure to attitude-consistent (dis)information. The results challenge the hypothesis’ underlying framework and make it necessary to consider new ways of advancing the theoretical model.
Predicting Adverse Events to Thiopurines in IBD: Are We a Step Closer?
Authors: Sharip Mohmmed Tauseef , Parkes Miles , Subramanian Sreedhar
Published: July 2024

Thiopurines remain an important option in the treatment of IBD. However, the unpredictable and sometimes serious side effects and intolerance remain a major challenge. Pretreatment of extended genetic panel analysis, identification of novel variants, and monitoring of intermediate metabolites will help improve the overall outcome and reduce the toxicity.
Structural and Evolutionary Relationships of Melanin Cascade Proteins in Cnidarian Innate Immunity
Authors: Van Buren Emily W , Ponce Ivan E , Beavers Kelsey M , Stokes Alexia , Cornelio Mariah N , Emery Madison , Mydlarz Laura D
Published: July 2024

Synopsis

Melanin is an essential product that plays an important role in innate immunity in a variety of organisms across the animal kingdom. Melanin synthesis is performed by many organisms using the tyrosine metabolism pathway, a general pathway that utilizes a type-three copper oxidase protein, called PO-candidates (phenoloxidase candidates). While melanin synthesis is well-characterized in organisms like arthropods and humans, it is not as well-understood in non-model organisms such as cnidarians. With the rising anthropomorphic climate change influence on marine ecosystems, cnidarians, specifically corals, are under an increased threat of bleaching and disease. Understanding innate immune pathways, such as melanin synthesis, is vital for gaining insights into how corals may be able to fight these threats. In this study, we use comparative bioinformatic approaches to provide a comprehensive analysis of genes involved in tyrosine-mediated melanin synthesis in cnidarians. Eighteen PO-candidates representing five phyla were studied to identify their evolutionary relationship. Cnidarian species were most similar to chordates due to domain presents in the amino acid sequences. From there, functionally conserved domains in coral proteins were identified in a coral disease dataset. Five stony corals exposed to stony coral tissue loss disease were leveraged to identify 18 putative tyrosine metabolism genes, genes with functionally conserved domains to their Homo sapiens counterpart. To put this pathway in the context of coral health, putative genes were correlated to melanin concentration from tissues of stony coral species in the disease exposure dataset. In this study, tyrosinase was identified in stony corals as correlated to melanin concentrations and likely plays a key role in immunity as a resistance trait. In addition, stony coral genes were assigned to all modules within the tyrosine metabolism pathway, indicating an evolutionary conservation of this pathway across phyla. Overall, this study provides a comprehensive analysis of the genes involved in tyrosine-mediated melanin synthesis in cnidarians.
Challenges to heart failure medication prescribing post-hospitalization
Authors: Li Jiaqi , Sanyu Visopiano , Coia Elise , Fernando Romaniya , Asghari-Jafarabadi Mohammad , Better Nathan , Wojnar Robert
Published: July 2024

Objectives

To determine the prevalence of heart failure (HF) medication prescribing on discharge post-HF-related admission.

Methods

A retrospective audit was conducted for 216 HF admissions over a period of 6 months; medication data from electronic records were collected for analysis.

Key findings

The prevalence of HF medication prescribing on discharge was: 32.9% (95% confidence interval: 26.6–39.6) renin–angiotensin–aldosterone system inhibitors, 10.6% (6.9–15.6) angiotensin receptor-neprilysin inhibitors, 31.5% (25.4–38.1) HF-specific beta-blockers, 42.6% (35.9–49.5) aldosterone receptor antagonists, and 11.6% (7.6–16.6) sodium-glucose cotransporter-2 inhibitors.

Conclusion

HF medication prescribing remains relatively low despite the known benefits and recommendations listed in the guidelines.
Cultivating global antimicrobial stewardship: linguistic and cultural validation of the Australian National Antimicrobial Prescribing Survey appropriateness assessment definitions for Portugal
Authors: Palos C , Ierano C , Santos M J D , Leitão I , Nogueira P , James R , Paiva J A , Thursky K , Sousa P
Published: July 2024

Background

Antimicrobial resistance is driven by inappropriate antimicrobial prescribing. The National Antimicrobial Prescribing Survey (NAPS) is an Australian-developed auditing platform to assist in the assessments of antimicrobial quality by antimicrobial stewardship programmes using consensus-based definitions. The NAPS has demonstrated to be transferable to other countries. Its adaptation to Portugal could improve knowledge about the quality of antimicrobial prescribing in the country.

Objectives

To translate, culturally adapt, and validate the Australian Hospital NAPS appropriateness assessment definitions of antimicrobial prescribing for Portugal.

Methods

International recommendations on translation and adaptation of instruments were followed. Two panels of experts participated in the process, using Zoom® for discussions and interviews, and Google Forms® for assessing vignettes. A native English-speaking person proficient in Portuguese conducted the back-translation. SPSS v.28 and Excel® were used for validity calculation.

Results

The Portuguese version was well accepted, its implementation being perceived as desirable and feasible by the experts. Validation process showed a Fleiss’ κ score of 0.483 (95% CI, 0.415–0.551, P < 0.005) for appropriateness, and an average agreement with the Australian NAPS team of 0.8 and 0.9, respectively, for appropriateness and reasons for inappropriateness.

Conclusions

The Portuguese version of the Australian Hospital NAPS appropriateness assessment definitions of antimicrobial prescribing, the first to be translated from English, was deemed non-inferior to the original, was well accepted, considered to be desirable and feasible, and could inspire other countries, particularly other Portuguese-speaking countries, to adapt and validate them in their own contexts, reinforcing the possibility of transferring NAPS use beyond Australia.
Development of antibacterial drug + bacteriophage combination assays
Authors: Attwood Marie , Griffins Pippa , Noel Alan , Josephs Theo , Adler Karen , Clokie Martha , MacGowan Alasdair
Published: July 2024

Background

The best methods to study the interactions between phages and antibacterials are unclear. As laboratory methodologies used to assess conventional antibacterials are established, we assessed their ability to evaluate phage plus antibacterial.

Methods

The efficacy of three characterized Escherichia coli phages (UP17, JK08, 113) were tested on a 100 MDR E coli. strains. The phages were assessed individually and in a 1:1:1 cocktail. In a phage microbial inhibitory concentration (PmIC) assay, a range of phage concentrations from 101 to 108 were inoculated with 5 × 105 bacteria/well in 96-well microtitre plates. The first fully lysed well was taken as the PmIC. Amikacin and meropenem MICs were determined by ISO 2776-1:2019 methods alone and in combination with a fixed phage concentration of 105/per well. Time–kill curves (TKCs) were conducted at fosfomycin concentrations of 133, 50 and 5 mg/L, with and without phage.

Results

The PmIC50/90 values, in plaque-forming units (pfu)/mL, for individual phage titre were >108/>108 for UP17, 107/>108 for JK08, 107/>108 for 113 and 106/>108 for the 1:1:1 phage cocktail, all with a standard deviation (SD) of <0.05. Amikacin and meropenem MIC50/90 (SD) values were 2/8 mg/L (<0.05–9.2) and 0.12/8 mg/L (<0.05–8.7), respectively. The addition of UP17 to amikacin increased amikacin MICs >2-fold in 78 strains, with equivalent trends in 39 strains with JK08, 54 strains with 113 and 45 strains with phage cocktail. Meropenem MICs in the presence of phage were reduced >2-fold in 24 strains with UP17. Equivalent decreases were seen with 34 strains with JK08, 26 strains with 113 and 29 strains with the cocktail. In TKCs, the addition of phage suppressed regrowth.

Conclusions

Microbroth methodologies based on ISO 2776-1:2019 lend themselves to be viable options for phage assessment, alone or in combination with antibiotics. The reproducibility of PmIC and familiarity of the methodology described allows for laboratory validation for phage and antibiotic combinations.
Comparing algorithms to approximate accuracies for single-step genomic best linear unbiased predictor
Authors: Ramos Pedro , Garcia Andre , Retallik Kelli , Bermann Matias , Tsuruta Shogo , Misztal Ignacy , Veroneze Renata , Lourenco Daniela
Published: July 2024

The exact accuracy of estimated breeding values can be calculated based on the prediction error variances obtained from the diagonal of the inverse of the left-hand side (LHS) of the mixed model equations (MME). However, inverting the LHS is not computationally feasible for large datasets, especially if genomic information is available. Thus, different algorithms have been proposed to approximate accuracies. This study aimed to: 1) compare the approximated accuracies from 2 algorithms implemented in the BLUPF90 suite of programs, 2) compare the approximated accuracies from the 2 algorithms against the exact accuracy based on the inversion of the LHS of MME, and 3) evaluate the impact of adding genotyped animals with and without phenotypes on the exact and approximated accuracies. Algorithm 1 approximates accuracies based on the diagonal of the genomic relationship matrix (G). In turn, algorithm 2 combines accuracies with and without genomic information through effective record contributions. The data were provided by the American Angus Association and included 3 datasets of growth, carcass, and marbling traits. The genotype file contained 1,235,930 animals, and the pedigree file contained 12,492,581 animals. For the genomic evaluation, a multi-trait model was applied to the datasets. To ensure the feasibility of inverting the LHS of the MME, a subset of data under single-trait models was used to compare approximated and exact accuracies. The correlations between exact and approximated accuracies from algorithms 1 and 2 of genotyped animals ranged from 0.87 to 0.90 and 0.98 to 0.99, respectively. The intercept and slope of the regression of exact on approximated accuracies from algorithm 2 ranged from 0.00 to 0.01 and 0.82 to 0.87, respectively. However, the intercept and the slope for algorithm 1 ranged from −0.10 to 0.05 and 0.98 to 1.10, respectively. In more than 80% of the traits, algorithm 2 exhibited a smaller mean square error than algorithm 1. The correlation between the approximated accuracies obtained from algorithms 1 and 2 ranged from 0.56 to 0.74, 0.38 to 0.71, and 0.71 to 0.97 in the groups of genotyped animals, genotyped animals without phenotype, and proven genotyped sires, respectively. The approximated accuracy from algorithm 2 showed a closer behavior to the exact accuracy when including genotyped animals in the analysis. According to the results, algorithm 2 is recommended for genetic evaluations since it proved more precise.
Setrusumab for the treatment of osteogenesis imperfecta: 12-month results from the phase 2b asteroid study
Authors: Glorieux Francis H , Langdahl Bente , Chapurlat Roland , De Beur Suzanne Jan , Sutton Vernon Reid , Poole Kenneth E S , Dahir Kathryn M , Orwoll Eric S , Willie Bettina M , Mikolajewicz Nicholas , Zimmermann Elizabeth , Hosseinitabatabaei Seyedmahdi , Ominsky Michael S , Saville Chris , Clancy James , MacKinnon Alastair , Mistry Arun , Javaid Muhammad K
Published: July 2024

Osteogenesis imperfecta (OI) is a rare genetic disorder commonly caused by variants of the type I collagen genes COL1A1 and COL1A2. OI is associated with increased bone fragility, bone deformities, bone pain, and reduced growth. Setrusumab, a neutralizing antibody to sclerostin, increased areal bone mineral density (aBMD) in a 21-week phase 2a dose escalation study. The phase 2b Asteroid (NCT03118570) study evaluated the efficacy and safety of setrusumab in adults. Adults with a clinical diagnosis of OI type I, III, or IV, a pathogenic variant in COL1A1/A2, and a recent fragility fracture were randomized 1:1:1:1 to receive 2, 8, or 20 mg/kg setrusumab doses or placebo by monthly intravenous infusion during a 12-mo treatment period. Participants initially randomized to the placebo group were subsequently reassigned to receive setrusumab 20 mg/kg open label. Therefore, only results from the 2, 8, and 20 mg/kg double-blind groups are presented herein. The primary endpoint of Asteroid was change in distal radial trabecular volumetric bone mineral density (vBMD) from baseline at month 12, supported by changes in high-resolution peripheral quantitative computed tomography micro-finite element (microFE)-derived bone strength. A total of 110 adults were enrolled with similar baseline characteristics across treatment groups. At 12 mo, there was a significant increase in mean (SE) failure load in the 20 mg/kg group (3.17% [1.26%]) and stiffness in the 8 (3.06% [1.70%]) and 20 mg/kg (3.19% [1.29%]) groups from baseline. There were no changes in radial trabecula vBMD (p>05). Gains in failure load and stiffness were similar across OI types. There were no significant differences in annualized fracture rates between doses. Two adults in the 20 mg/kg group experienced related serious adverse reactions. Asteroid demonstrated a beneficial effect of setrusumab on estimates of bone strength across the different types of OI and provides the basis for additional phase 3 evaluation.
A three-dimensional immersed boundary method for accurate simulation of acoustic wavefields with complex surface topography
Authors: Li Xiang , Hu Ziduo , Zou Zhen , Niu Fenglin , Tian Yancan , Liu Wei , Yao Gang
Published: July 2024

Irregular topography of the free surface significantly affects seismic wavefield modelling, especially when employing finite-difference methods on rectangular grids. These methods represent the free surface as discrete points, resulting in a boundary that resembles a ‘staircase’. This approximation inaccurately represents surface topography, introducing errors in surface reflection traveltimes and generating artificial diffractions in wavefield simulation. We introduce a stable three-dimensional immersed boundary method (3DIBM) employing Cartesian coordinates to address these challenges. The 3DIBM enables the simulation of acoustic waves in media with complex topography through standard finite difference, extending the two-dimensional immersed boundary approach to compute spatial coordinates for ghost and mirror points in a three-dimensional space. Wavefield values at these points are obtained by three-dimensional spatial iterative symmetric interpolation, specifically through the Kaiser-windowed sinc method. By implicitly implementing the free surface boundary condition in three dimensions, this method effectively reduces artificial diffractions and enhances the accuracy of reflection traveltime. The effectiveness and accuracy of 3DIBM are validated through numerical tests and pre-stack depth migration imaging with simulated data, demonstrating its superiority as a modelling engine for migration imaging and waveform inversion in three-dimensional land seismic analysis.
Venous thromboembolism in patients undergoing surgery for lung cancer: a post hoc analysis of the Cancer-VTE Registry
Authors: Kawachi Riken , Okano Tetsuya , Awano Nobuyasu , Matsumoto Masaru , Hosokawa Jun , Takita Atsushi , Oba Mari S , Kunitoh Hideo
Published: July 2024

The relationship between lung cancer surgery and venous thromboembolism (VTE) in Japan has not been elucidated. This was a post hoc analysis of the Cancer-VTE Registry. The 1057 patients who underwent surgery for lung cancer were divided into the surgery alone (SA) group (n = 598) and the surgery plus chemotherapy (SC) group (n = 459), and the 1-year incidences of VTE and cerebral ischemia were analyzed. In the SA and SC groups, composite VTE was observed in one (0.2%) and 15 (3.3%) patients, respectively, and cerebral ischemia was observed in eight (1.3%) and four (0.9%) patients, respectively. Lymph node metastasis was more common in patients with D-dimer >1.2 μg/ml (odds ratio: 1.781, P = .004). SA had a low risk of VTE but a high risk of cerebral ischemia. Chemotherapy increases the risk of VTE. The D-dimer level was related to VTE and advanced cancer.
Bacterial efflux pump OMPs as vaccine candidates against multidrug-resistant Gram-negative bacteria
Authors: Silva Thaynara O , Bulla Ana Carolina S , Teixeira Bárbara A , Gomes Vinnicius Machado Schelk , Raposo Thiago , Barbosa Luiza S , da Silva Manuela Leal , Moreira Lilian O , Olsen Priscilla C
Published: July 2024

The emergence and propagation of bacteria resistant to antimicrobial drugs is a serious public health threat worldwide. The current antibacterial arsenal is becoming obsolete, and the pace of drug development is decreasing, highlighting the importance of investment in alternative approaches to treat or prevent infections caused by antimicrobial-resistant bacteria. A significant mechanism of antimicrobial resistance employed by Gram-negative bacteria is the overexpression of efflux pumps that can extrude several compounds from the bacteria, including antimicrobials. The overexpression of efflux pump proteins has been detected in several multidrug-resistant Gram-negative bacteria, drawing attention to these proteins as potential targets against these pathogens. This review will focus on the role of outer membrane proteins from efflux pumps as potential vaccine candidates against clinically relevant multidrug-resistant Gram-negative bacteria, discussing advantages and pitfalls. Additionally, we will explore the relevance of efflux pump outer membrane protein diversity and the possible impact of vaccination on microbiota.
Combination of microparticles vaccine with MSI-1436 exerts a strong immune response for hepatocellular carcinoma
Authors: Zhan Zhao , Cheng Jiaqing , Liu Fang , Tao Shili , Wang Ling , Lin Xiandong , Ye Yunbin
Published: July 2024

Although tumor cell-derived microparticles (MPs) vaccines have reportedly induced antitumor immune reactions for various cancers, the mechanism by which MPs derived from Hepa1-6 cells are taken up by dendritic cells (DCs) and provide the MPs antigens message to CD8+ T cells to exert their anti-hepatocellular carcinoma (HCC) effects remain unclear. Furthermore, the role of MPs in combination with the small-molecule drug MSI-1436, an inhibitor of protein tyrosine phosphatase 1B (PTP1B), in HCC has not yet been reported. In this study, protein mass spectrometry combined with cytology revealed that MPs are mainly taken up by DCs via the clathrin-mediated endocytosis and phagocytosis pathway and localized mainly in lysosomes. High concentration of tumor necrosis factor-α and interferon-γ was detected in CD8+ T cells stimulated with MPs-loaded DCs. Moreover, MPs combined with MSI-1436 further suppressed the proliferation of HCC cells in C57BL/6 tumor-bearing mice, which was closely correlated with CD4+/CD8+ T cells counts in peripheral blood, spleen, and the tumor microenvironment. Mechanistically, the combination of MPs and MSI-1436 exerts a more powerful anti-HCC effect, which may be related to the further inhibition of the expression of PTP1B. Overall, MPs combined with MSI-1436 exerted stronger antitumor effects than MPs or MSI-1436 alone. Therefore, the combination of MPs and MSI-1436 may be a promising means of treating HCC.
Pharmacological investigation of genistein for its therapeutic potential against nitroglycerin-induced migraine headache
Authors: Sajjad Qirrat , Khan Arif-ullah , Khan Aslam
Published: July 2024

Objectives

Migraine, typically occurs on one side of the head, lasts for hours to days. Trigemino-vascular system (TVS) plays a vital role in pain generation, with neurogenic inflammation and oxidative stress playing key roles in its pathophysiology.

Methods

This study aimed to investigate genistein’s potential as anti-inflammatory and anti-oxidant agent in mitigating migraine pain. Genistein (20 and 50 mg/kg) was administered intraperitoneally (IP) to nitroglycerin (NTG; 10 mg/kg)-induced migraine model in rats. Behavioral analysis, antioxidant assay, immunohistochemistry (IHC), histopathological examination, ELISA, and RT-PCR were conducted to evaluate the antimigraine potential of genistein.

key findings

In-silico analysis showed genestien’s ACE values of −4.8 to −9.2 Kcal/mol against selected protein targets. Genistein significantly reversed mechanical and thermal nociception, light phobicity, and head scratching; increased the intensities of GST, GSH, catalase; and down regulated lipid peroxidase (LPO) in cortex and trigeminal nucleus caudalis (TNC). It also reduced Nrf2, NF-kB, and IL6 expression, analyzed through IHC, improved histopathological features, and increased COX-2 and decreased PPAR-γ expressions, while RT-PCR analysis revealed increased PPAR-γ expressions in genistein-treated rats.

Conclusion

Genistein exhibited potent antioxidant and anti-inflammatory properties in migraine treatment, acting through multifactorial mechanisms by modulating the expression of numerous proteins in the region cortex and TNC.
The therapeutic potential of curculigoside in poststroke depression: a focus on hippocampal neurogenesis and mitochondrial function
Authors: Zeng Ning-Xi , Chen Xin , Yang Xiao-Yan , Chen De-sheng , Shen Mei
Published: July 2024

Objectives

To investigate the effects and mechanism of curculigoside against poststroke depression (PSD).

Methods

In vivo, a PSD rat model was created by combining bilateral common carotid artery occlusion and chronic unpredictable mild stress stimulations. After 4-week modeling and intragastrically administration of curculigoside, the effects of curculigoside on behavior, hippocampal neurogenesis, and hippocampal mitochondrial oxidative phosphorylation (OxPhos) were investigated. In vitro, PSD-like primary neural stem cells (NSCs) model was established by oxygen-glucose deprivation/recovery (OGD/R) combing high-corticosterone (CORT) concentration, followed by treatment with curculigoside. The investigation subsequently examined the impact of curculigoside on mitochondrial OxPhos, proliferation, and differentiation of NSCs under OGD/R + CORT conditions.

Key findings

In vivo, PSD rats showed significantly depressive behaviors, dysfunctional neurogenesis in hippocampus, as well as decreased hippocampus adenosine triphosphate (ATP) levels, reduced electron transport chain complexes activity, and downregulates mitochondrial transcription factor A (TFAM) and PPAR-gamma coactivator 1 alpha (PGC-1α) expression in hippocampus. In vitro, OGD/R +CORT significantly injured the proliferation and differentiation, as well as impaired the mitochondrial OxPhos in NSCs. Curculigoside treatment was effective in improving these abnormal changes.

Conclusion

Curculigoside may repair hippocampal neurogenesis in PSD rats by enhancing hippocampal mitochondrial OxPhos, and has shown a great potential for anti-PSD.
A prediction method for the individual serum concentration and therapeutic effect for optimizing adalimumab therapy in inflammatory bowel disease
Authors: Kimura Koji , Yoshida Atsushi
Published: July 2024

Objectives

Adalimumab (ADM) therapy is effective for inflammatory bowel disease (IBD), but a significant number of IBD patients lose response to ADM. Thus, it is crucial to devise methods to enhance ADM’s effectiveness. This study introduces a strategy to predict individual serum concentrations and therapeutic effects to optimize ADM therapy for IBD during the induction phase.

Methods

We predicted the individual serum concentration and therapeutic effect of ADM during the induction phase based on pharmacokinetic and pharmacodynamic (PK/PD) parameters calculated using the empirical Bayesian method. We then examined whether the predicted therapeutic effect, defined as clinical remission or treatment failure, matched the observed effect.

Results

Data were obtained from 11 IBD patients. The therapeutic effect during maintenance therapy was successfully predicted at 40 of 47 time points. Moreover, the predicted effects at each patient’s final time point matched the observed effects in 9 of the 11 patients.

Conclusion

This is the inaugural report predicting the individual serum concentration and therapeutic effect of ADM using the Bayesian method and PK/PD modelling during the induction phase. This strategy may aid in optimizing ADM therapy for IBD.
Estimating spatially varying health effects of wildland fire smoke using mobile health data
Authors: Wu Lili , Gao Chenyin , Yang Shu , Reich Brian J , Rappold Ana G
Published: July 2024

Wildland fire smoke exposures are an increasing threat to public health, highlighting the need for studying the effects of protective behaviours on reducing health outcomes. Emerging smartphone applications provide unprecedented opportunities to deliver health risk communication messages to a large number of individuals in real-time and subsequently study the effectiveness, but also pose methodological challenges. Smoke Sense, a citizen science project, provides an interactive smartphone app platform for participants to engage with information about air quality, and ways to record their own health symptoms and actions taken to reduce smoke exposure. We propose a doubly robust estimator of the structural nested mean model that accounts for spatially and time-varying effects via a local estimating equation approach with geographical kernel weighting. Moreover, our analytical framework also handles informative missingness by inverse probability weighting of estimating functions. We evaluate the method using extensive simulation studies and apply it to Smoke Sense data to increase the knowledge base about the relationship between health preventive measures and health-related outcomes. Our results show that the protective behaviours’ effects vary over space and time and find that protective behaviours have more significant effects on reducing health symptoms in the Southwest than the Northwest region of the U.S.
Thermodynamics of Alfvénic slow solar wind produced by Alfvénic turbulence
Authors: Lee Hwanhee , Seough Jungjoon , Li Bo , Kim Yeon-Han , Cho Kyung-Suk
Published: July 2024

Alfvén-wave turbulence is known as a plasma heating mechanism associated with the acceleration of fast solar wind, found emanating from open magnetic fields adjacent to coronal holes. In this study, we expand the scope of this mechanism to investigate the thermodynamics of Alfvénic slow solar wind, a phenomenon originating from open fields near a streamer, as observed in recent inner heliospheric missions. We demonstrate a one-dimensional two-fluid model that incorporates three components: (1) low-frequency Alfvén-wave turbulence, serving as the primary dissipation mechanism, (2) a curved magnetic field that reproduces the streamer’s boundary, and (3) the kinetic instabilities to address proton temperature anisotropy. Our findings suggest that this dissipation mechanism can be applied in common to both fast and Alfvénic slow solar winds. We identify the proton-cyclotron instability near the Sun and the oblique and parallel firehose instabilities occurring close to 1 au as crucial factors governing temperature anisotropy. This study contributes to our understanding of the complex thermodynamics of solar winds and provides valuable insights for future space missions.