bluuebunny/crossref_metadata_2025 huggingface dataset:
Beyond the hype: ‘acceptable futures’ for AI and robotic technologies in healthcare
Authors: De Togni Giulia , Erikainen S. , Chan S. , Cunningham-Burley S.
Published: April 2023

AI and robotic technologies attract much hype, including utopian and dystopian future visions of technologically driven provision in the health and care sectors. Based on 30 interviews with scientists, clinicians and other stakeholders in the UK, Europe, USA, Australia, and New Zealand, this paper interrogates how those engaged in developing and using AI and robotic applications in health and care characterize their future promise, potential and challenges. We explore the ways in which these professionals articulate and navigate a range of high and low expectations, and promissory and cautionary future visions, around AI and robotic technologies. We argue that, through these articulations and navigations, they construct their own perceptions of socially and ethically ‘acceptable futures’ framed by an ‘ethics of expectations.’ This imbues the envisioned futures with a normative character, articulated in relation to the present context. We build on existing work in the sociology of expectations, aiming to contribute towards better understanding of how technoscientific expectations are navigated and managed by professionals. This is particularly timely since the COVID-19 pandemic gave further momentum to these technologies.
Analytical investigation of the finite viscoelastic model proposed by Simo: critical review and a suggested modification
Authors: Yagimli Bülent , Lion Alexander , Abdelmoniem Mohamed A.
Published: April 2023

Rubber components such as engine or suspension bearings are loaded during operation with large deformations and high-frequency loads. In industrial applications, finite element analysis software is therefore needed to simulate and predict the behaviour of these components under different scenarios of loading conditions. The usage of such software requires the user to be aware of certain limitations and shortcomings in the implemented material models. In this paper, the stresses as well as the storage and loss modulus are calculated analytically for an example of cyclic simple shear deformations. The analysed material model was firstly proposed by Simo and is available in Abaqus version 2018 for viscoelastic materials under finite strains. The analytical solution is used to highlight the non-physical response of the model under certain loading conditions. A modification of the modelling approach is then proposed to avoid such limitations. The modified model is implemented in the Abaqus software using a user material subroutine (UMAT). The behaviour of the modified model and the original Abaqus model are compared using an example of tie rod under different loading conditions. It is shown that with the suggested modification, reasonable results are obtained and the non-physical responses are eliminated.
Peptide extract from spent yeast improves resistance of Saccharomyces cerevisiae to oxidative stress
Authors: Lopes Ana , Azevedo-Silva João , Carsanba Erdem , Pintado Manuela , Oliveira Ana Sofia , Ferreira Carlos , Pereira Joana Odila , Carvalho Ana P. , Oliveira Carla
Published: April 2023

Yeast cells face various stress factors during industrial fermentations, since they are exposed to harsh environmental conditions, which may impair biomolecules productivity and yield. In this work, the use of an antioxidant peptide extract obtained from industrial spent yeast was explored as supplement for Saccharomyces cerevisiae fermentation to prevent a common bottleneck: oxidative stress. For that, a recombinant yeast strain, producer of β-farnesene, was firstly incubated with 0.5 and 0.7 g/L peptide extract, in the presence and absence of hydrogen peroxide (an oxidative stress inducer), for 1–5 h, and then assayed for intracellular reactive oxygen species, and growth ability in agar spot assays. Results showed that under 2 mM H2O2, the peptide extract could improve cells growth and reduce reactive oxygen species production. Therefore, this antioxidant effect was further evaluated in shake-flasks and 2-L bioreactor batch fermentations. Peptide extract (0.7 g/L) was able to increase yeast resistance to the oxidative stress promoted by 2 mM H2O2, by reducing reactive oxygen species levels between 1.2- and 1.7-fold in bioreactor and between 1.2- and 3-fold in shake-flask fermentations. Moreover, improvements on yeast cell density of up to 1.5-fold and 2-fold, and on biomolecule concentration of up to 1.6-fold and 2.8-fold, in bioreactor and shake-flasks, respectively, were obtained. Thus, culture medium supplementation with antioxidant peptide extracted from industrial spent yeast is a promising strategy to improve fermentation performance while valuing biomass waste. This valorization can promote a sustainable and eco-friendly solution for the biotechnology industry by the implementation of a circular economy model.

Key points

• Peptide extract from spent yeast applied for the first time on yeast fermentation.

• Antioxidant peptide extract enhanced S. cerevisiae oxidative stress resistance.

• Fermentation performance under stress improved by peptide extract supplementation.
Fibroblast activation protein targeted radiotherapy induces an immunogenic tumor microenvironment and enhances the efficacy of PD-1 immune checkpoint inhibition
Authors: Zboralski Dirk , Osterkamp Frank , Christensen Esben , Bredenbeck Anne , Schumann Anne , Hoehne Aileen , Schneider Eberhard , Paschke Matthias , Ungewiss Jan , Haase Christian , Robillard Liliane , Simmons Andrew D. , Harding Thomas C. , Nguyen Minh
Published: April 2023

Purpose

FAP is a membrane-bound protease under investigation as a pan-cancer target, given its high levels in tumors but limited expression in normal tissues. FAP-2286 is a radiopharmaceutical in clinical development for solid tumors that consists of two functional elements: a FAP-targeting peptide and a chelator used to attach radioisotopes. Preclinically, we evaluated the immune modulation and anti-tumor efficacy of FAP-2287, a murine surrogate for FAP-2286, conjugated to the radionuclide lutetium-177 (177Lu) as a monotherapy and in combination with a PD-1 targeting antibody.

Methods

C57BL/6 mice bearing MCA205 mouse FAP-expressing tumors (MCA205-mFAP) were treated with 177Lu-FAP-2287, anti-PD-1, or both. Tumor uptake of 177Lu- FAP-2287 was assessed by SPECT/CT scanning, while therapeutic efficacy was measured by tumor volume and survival. Immune profiling of tumor infiltrates was evaluated through flow cytometry, RNA expression, and immunohistochemistry analyses.

Results

177Lu-FAP-2287 rapidly accumulated in MCA205-mFAP tumors leading to significant tumor growth inhibition (TGI) and longer survival time. Significant TGI was also observed from anti-PD-1 and the combination. In flow cytometry analysis of tumors, 177Lu-FAP-2287 increased CD8+ T cell infiltration which was maintained in the combination with anti-PD-1. The increase in CD8+ T cells was accompanied by an induction of STING-mediated type I interferon response and higher levels of co-stimulatory molecules such as CD86.

Conclusion

In a preclinical model, FAP-targeted radiotherapy enhanced anti-PD-1-mediated TGI by modulating the TME and increasing the recruitment of tumor-infiltrating CD8+ T cells. These findings provide a rationale for clinical studies of combined 177Lu-FAP-2286 radiotherapy and immune checkpoint inhibition in FAP-positive tumors.
Ground kinematically aligned total knee arthroplasty: new personalized technique which enables a stable knee with deep flexion
Authors: Matsumoto Tomoyuki , Nakano Naoki , Ishida Kazunari , Kuroda Yuichi , Hayashi Shinya , Muratsu Hirotsugu , Kuroda Ryosuke
Published: April 2023

Purpose

This study aimed to evaluate kinematically aligned total knee arthroplasty (KA-TKA) targeting the neutral ground mechanical axis (MA) (hip-to-calcaneus axis), the line from the hip centre to the bottom of the calcaneus, (ground KA-TKA) in terms of its comparison with tibia-restricted modified KA-TKA (modified KA-TKA).

Methods

This retrospective cohort study included 106 consecutive patients who underwent unilateral KA-TKA for varus osteoarthritis (OA) (60 modified KA-TKAs and 46 ground KA-TKAs). After 1:1 propensity score matching, 60 patients (30 pairs) were matched between the groups with comparable demographic data. The hip-knee-ankle (HKA) angle, coronal femoral component alignment (FCA), and coronal tibial component alignment (TCA) were compared between groups. Intraoperative soft tissue balance, including the joint component gap and varus/valgus balance, was also compared between the groups. One year postoperatively, the clinical outcomes, including the range of motion and 2011 Knee Society Score, were compared between groups.

Results

The HKA angle and FCA/TCA were not significantly different between groups. Whereas the varus/valgus balance showed no significant differences between groups, smaller joint component gaps were found throughout the range of motion in the ground KA-TKA group than in the modified KA-TKA group. Despite no difference in clinical scores between groups, a significantly deeper postoperative flexion angle was achieved in the ground KA-TKA group than in the modified KA-TKA group (p < 0.05).

Conclusion

Targeting neutral ground MA in KA-TKA for patients with varus OA has the potential to provide a better flexion angle with stable intraoperative soft tissue balance.
Simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF trial
Authors: Bavendiek Udo , Großhennig Anika , Schwab Johannes , Berliner Dominik , Liu Xiaofei , Maier Lars , Gaspar Thomas , Rieth Andreas , Philipp Sebastian , Hambrecht Rainer , Westenfeld Ralf , Münzel Thomas , Winkler Sebastian , Hülsmann Martin , Westermann Dirk , Zdravkovic Marja , Lichtinghagen Ralf , von der Leyen Heiko , Zimmermann Silke , Veltmann Christian , Böhm Michael , Störk Stefan , Koch Armin , Bauersachs Johann
Published: April 2023

Background

The present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing first data from the randomized, double-blinded DIGIT-HF trial.

Methods and results

In DIGIT-HF, digitoxin was started with a dose of 0.07 mg once daily (o.d.) in all patients. For score derivation, 317 patients were analyzed who had been randomized to digitoxin. In these patients, after scheduled determination of serum levels at study week 6, the digitoxin dose had remained unchanged or had been reduced to 0.05 mg o.d. (97% of patients) to achieve serum concentrations within a predefined range (10.5–23.6 nmol/l). In logistic regression analyses, sex, age, body mass index (BMI), and estimated glomerular filtration rate (eGFR) were associated with need for dose reduction and, therefore, selected for further developing the dosing score. Optimal cut-points were derived from ROC curve analyses. Finally, female sex, age ≥ 75 years, eGFR < 50 ml/min/1.73 m2, and BMI < 27 kg/m2 each were assigned one point for the digitoxin dosing score. A score of ≥ 1 indicated the need for dose reduction with sensitivity/specificity of 81.6%/49.7%, respectively. Accuracy was confirmed in a validation data set including 64 patients randomized to digitoxin yielding sensitivity/specificity of 87.5%/37.5%, respectively.

Conclusion

In patients with HFrEF, treatment with digitoxin should be started at 0.05 mg o.d. in subjects with either female sex, eGFR < 50 ml/min/1.73m2, BMI < 27 kg/m2, or age ≥ 75 years. In any other patient, digitoxin may be safely started at 0.07 mg o.d.

Graphical Abstract
Emotion dysregulation, impulsivity and anger rumination in borderline personality disorder: the role of amygdala and insula
Authors: Mitolo M. , D’Adda F. , Evangelisti S. , Pellegrini L. , Gramegna L. L. , Bianchini C. , Talozzi L. , Manners D. N. , Testa C. , Berardi D. , Lodi R. , Menchetti M. , Tonon C.
Published: April 2023

Borderline Personality Disorder (BPD) is a severe mental disorder, characterized by deficits in emotion regulation, interpersonal dysfunctions, dissociation and impulsivity. Brain abnormalities have been generally explored; however, the specific contribution of different limbic structures to BPD symptomatology is not described. The aim of this study is to cover this gap, exploring functional and structural alterations of amygdala and insula and to highlight their contribution to neuropsychiatric symptoms. Twenty-eight BPD patients (23.7 ± 3.42 years; 6 M/22F) and twenty-eight matched healthy controls underwent a brain MR protocol (1.5 T, including a 3D T1-weighted sequence and resting-state fMRI) and a complete neuropsychiatric assessment. Volumetry, cortical thickness and functional connectivity of amygdala and insula were evaluated, along with correlations with the neuropsychiatric scales. BPD patients showed a lower cortical thickness of the left insula (p = 0.027) that negatively correlated with the Anger Rumination Scale (p = 0.019; r = − 0.450). A focused analysis on female patients showed a significant reduction of right amygdala volumes in BPD (p = 0.037), that correlate with Difficulties in Emotion Regulation Scale (p = 0.031; r =  − 0.415), Beck Depression Inventory (p = 0.009; r =  − 0.50) and Ruminative Response Scale (p = 0.045; r =  − 0.389). Reduced functional connectivity was found in BPD between amygdala and frontal pole, precuneus and temporal pole. This functional connectivity alterations correlated with Anger Rumination Scale (p = .009; r = − 0.491) and Barratt Impulsiveness Scale (p = 0.020; r = − 0.447). Amygdala and insula are altered in BPD patients, and these two limbic structures are implicated in specific neuropsychiatric symptoms, such as difficulty in emotion regulation, depression, anger and depressive rumination.
NO-mediated dormancy release of Avena fatua caryopses is associated with decrease in abscisic acid sensitivity, content and ABA/GAs ratios
Authors: Kępczyński Jan , Wójcik Agata , Dziurka Michał
Published: April 2023

Main conclusion

NO releases caryopsis dormancy in Avena fatua, the effect being dependent on the level of dormancy. The NO effect involves also the reduction of caryopsis sensitivity to ABA and to a decrease in the ABA to GAs ratio due to a decrease in ABA levels and the lack of effect on GAs levels before germination is completed.

Nitric oxide (NO) from various donors (i.e. SNP, GSNO and acidified KNO2), applied to dry caryopses or during initial germination, released primary dormancy in caryopses. Dormancy in caryopses was gradually lost during dry storage (after-ripening) at 25 °C, enabling germination at 20 °C in the dark. The after-ripening effect is associated with a decrease in NO required for germination. In addition, NO decreased the sensitivity of dormant caryopses to exogenous abscisic acid (ABA) and decreased the embryos’ ABA content before germination was completed. However, NO did not affect the content of bioactive gibberellins (GAs) from non-13-hydroxylation (GA4, GA7) and 13-hydroxylation (GA1, GA3, GA6.) pathways. Paclobutrazol (PAC), commonly regarded as a GAs biosynthesis inhibitor, counteracted the dormancy-releasing effect of NO and did not affect the GAs level; however, it increased the ABA content in embryos before germination was completed. Ascorbic acid, sodium benzoate and tiron, scavengers of reactive oxygen species (ROS), reduced the stimulatory effect of NO on caryopsis germination. This work provides new insight on the participation of NO in releasing A. fatua caryopses dormancy and on the relationship of NO with endogenous ABA and GAs.
Characterization and digital spatial deconvolution of the immune microenvironment of intraductal oncocytic papillary neoplasms (IOPN) of the pancreas
Authors: Pea Antonio , Paolino Gaetano , Martelli Filippo , Bariani Elena , Piccoli Paola , Sereni Elisabetta , Salvia Roberto , Lawlor Rita T. , Cheng Liang , Chang David , Scarpa Aldo , Luchini Claudio
Published: April 2023

Intraductal oncocytic papillary neoplasm (IOPN) of the pancreas is a distinct entity from intraductal papillary mucinous neoplasms (IPMNs) and is considered one of the precursor lesions of pancreatic cancer. Through immunohistochemistry (IHC) and an artificial intelligence (AI)-based approach, this study aims at characterizing its immune microenvironment. Whole-slide IHC was performed on a cohort of 15 IOPNs, 2 of which harboring an associated adenocarcinoma. The following markers were tested: CD3, CD4, CD8, CD20, CD68, CD163, PD-1, PD-L1, MLH1, PMS2, MSH2, and MSH6. The main findings can be summarized as follows: (i) CD8+ T lymphocytes were the predominant immune cells (p < 0.01); (ii) the vast majority of macrophages were concurrently CD68+ and CD163+; (iii) all tumors showed an activated PD-1/PD-L1 axis, but none had mismatch repair deficiency; (iv) AI-based analysis revealed the presence of 2 distinct regions in each case, namely, Re1, localized at the center of the tumor, and Re2, located at tumor periphery; (v) the infiltrating component of the 2 invasive IOPNs showed a smaller extent of Re1 and a reduced rate of CD4+ cells, as well as a larger extent of Re2 and increased rate of CD8+ cells. IOPNs are lesions enriched in immune cells, with a predominance of CD8+ T lymphocytes and class 2 macrophages. Differently from IPMN-oncogenesis, the progression towards invasive carcinoma is accompanied by an increased rate of CD8+ lymphocytes. This finding may suggest the presence of an active self-immune surveillance in invasive IOPNs, potentially explaining, at least in part, the excellent survival rate of IOPN patients.
Hypofibrinolysis in pediatric patients with veno-occlusive disease in hematopoietic stem cell transplantation
Authors: Schneider Veronika , Cabanillas Stanchi Karin M. , Althaus Karina , Schober Sarah , Michaelis Sebastian , Seitz Christian , Lang Peter , Handgretinger Rupert , Bakchoul Tamam , Hammer Stefanie , Döring Michaela
Published: April 2023

Purpose

Veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplantation (HSCT) with a high incidence in pediatric patients. This study aimed to detect signs of hypofibrinolysis using thrombelastography.

Methods

In this prospective single-center study, thrombelastographic measurements (EX and TPA tests) were taken during HSCT to detect signs of impaired coagulation, clot formation, or hypofibrinolysis.

Results

Of 51 patients undergoing allogeneic and autologous HSCT, five (9.8%) developed VOD and received defibrotide treatment. Thrombelastography measurements were also obtained from 55 healthy children as a control group. The results show that clot lysis was prolonged in VOD patients compared to other HSCT patients and control group (lysis time, TPA test: day + 14 to + 21: VOD: 330 ± 67 s vs. HSCT: 246 ± 53 s; p = 0.0106; control: 234 ± 50 s; control vs. VOD: p = 0.0299). The maximum lysis was reduced in HSCT patients compared to controls (EX test: control: 8.3 ± 3.2%; HSCT: day 0 to + 6: 5.3 ± 2.6%, p < 0.0001; day + 7 to + 13: 3.9 ± 2.1%, p < 0.0001; day + 14 to d + 21: 4.1 ± 2.3%, p < 0.0001).

Conclusion

These results suggest that HSCT patients exhibit reduced fibrinolytic capacities and patients diagnosed with VOD show signs of hypofibrinolysis. This prospective study shows that fibrinolysis can be assessed in a rapid and accessible way via thrombelastography. Thrombelastography might be a parameter to support the diagnosis of a VOD and to serve as a follow-up parameter after the diagnosis of a VOD.
The exocyst complex in neurological disorders
Authors: Halim Dilara O. , Munson Mary , Gao Fen-Biao
Published: April 2023

Exocytosis is the process by which secretory vesicles fuse with the plasma membrane to deliver materials to the cell surface or to release cargoes to the extracellular space. The exocyst—an evolutionarily conserved octameric protein complex—mediates spatiotemporal control of SNARE complex assembly for vesicle fusion and tethering the secretory vesicles to the plasma membrane. The exocyst participates in diverse cellular functions, including protein trafficking to the plasma membrane, membrane extension, cell polarity, neurite outgrowth, ciliogenesis, cytokinesis, cell migration, autophagy, host defense, and tumorigenesis. Exocyst subunits are essential for cell viability; and mutations or variants in several exocyst subunits have been implicated in human diseases, mostly neurodevelopmental disorders and ciliopathies. These conditions often share common features such as developmental delay, intellectual disability, and brain abnormalities. In this review, we summarize the mutations and variants in exocyst subunits that have been linked to disease and discuss the implications of exocyst dysfunction in other disorders.
Assessing variants of uncertain significance implicated in hearing loss using a comprehensive deafness proteome
Authors: Tollefson Mallory R. , Gogal Rose A. , Weaver A. Monique , Schaefer Amanda M. , Marini Robert J. , Azaiez Hela , Kolbe Diana L. , Wang Donghong , Weaver Amy E. , Casavant Thomas L. , Braun Terry A. , Smith Richard J. H. , Schnieders Michael J.
Published: April 2023

Hearing loss is the leading sensory deficit, affecting ~ 5% of the population. It exhibits remarkable heterogeneity across 223 genes with 6328 pathogenic missense variants, making deafness-specific expertise a prerequisite for ascribing phenotypic consequences to genetic variants. Deafness-implicated variants are curated in the Deafness Variation Database (DVD) after classification by a genetic hearing loss expert panel and thorough informatics pipeline. However, seventy percent of the 128,167 missense variants in the DVD are “variants of uncertain significance” (VUS) due to insufficient evidence for classification. Here, we use the deep learning protein prediction algorithm, AlphaFold2, to curate structures for all DVD genes. We refine these structures with global optimization and the AMOEBA force field and use DDGun3D to predict folding free energy differences (∆∆GFold) for all DVD missense variants. We find that 5772 VUSs have a large, destabilizing ∆∆GFold that is consistent with pathogenic variants. When also filtered for CADD scores (> 25.7), we determine 3456 VUSs are likely pathogenic at a probability of 99.0%. Of the 224 genes in the DVD, 166 genes (74%) exhibit one or more missense variants predicted to cause a pathogenic change in protein folding stability. The VUSs prioritized here affect 119 patients (~ 3% of cases) sequenced by the OtoSCOPE targeted panel. Approximately half of these patients previously received an inconclusive report, and reclassification of these VUSs as pathogenic provides a new genetic diagnosis for six patients.
AI apology: interactive multi-objective reinforcement learning for human-aligned AI
Authors: Harland Hadassah , Dazeley Richard , Nakisa Bahareh , Cruz Francisco , Vamplew Peter
Published: April 2023

For an Artificially Intelligent (AI) system to maintain alignment between human desires and its behaviour, it is important that the AI account for human preferences. This paper proposes and empirically evaluates the first approach to aligning agent behaviour to human preference via an apologetic framework. In practice, an apology may consist of an acknowledgement, an explanation and an intention for the improvement of future behaviour. We propose that such an apology, provided in response to recognition of undesirable behaviour, is one way in which an AI agent may both be transparent and trustworthy to a human user. Furthermore, that behavioural adaptation as part of apology is a viable approach to correct against undesirable behaviours. The Act-Assess-Apologise framework potentially could address both the practical and social needs of a human user, to recognise and make reparations against prior undesirable behaviour and adjust for the future. Applied to a dual-auxiliary impact minimisation problem, the apologetic agent had a near perfect determination and apology provision accuracy in several non-trivial configurations. The agent subsequently demonstrated behaviour alignment with success that included up to complete avoidance of the impacts described by these objectives in some scenarios.
Impact of material combinations and removal and insertion cycles on the retention force of telescopic systems
Authors: Micovic Soldatovic Danka , Bitter Maximiliane , Meinen John , Huth Karin Christine , Liebermann Anja , Stawarczyk Bogna
Published: April 2023

Objectives

A variety of dental materials are available for the fabrication of telescopic crowns. The aim was to investigate the impact of material combinations and removal and insertion cycles on their retention forces.

Materials and methods

CAD/CAM-fabricated cobalt–chromium–molybdenum (CoCr) and zirconia (ZrO2) primary crowns were combined with polyetheretherketone (PEEK), polyetherketoneketone (PEKK), CoCr, and ZrO2 secondary crowns (four combinations included PEEK/PEKK secondary crowns in a thickness of 0.5 mm bonded to the CoCr tertiary construction), resulting in 12 different material combinations: CoCr–PEEK; CoCr–PEKK; CoCr–ZrO2; CoCr–CoCr; CoCr–PEEK 0.5; CoCr–PEKK 0.5; ZrO2–PEEK; ZrO2–PEKK; ZrO2–ZrO2, ZrO2–CoCr; ZrO2–PEEK 0.5; and ZrO2–PEKK 0.5 (n = 15 pairings per material combination). Pull-off tests were performed with a universal testing machine initially and after 500, 5000, and 10,000 removal and insertion cycles in a mastication simulator. Descriptive statistics with the Kolmogorov–Smirnov, Kruskal–Wallis, and Mann–Whitney U tests were computed (α = 0.05).

Results

The tested parameters, material combination, and removal and insertion cycles had significant impact on the retention force values (p < 0.001). An increase in removal and insertion cycles was associated with a decrease in retention forces within CoCr and ZrO2 secondary crowns, regardless of the primary crown material. In contrast, PEEK and PEKK secondary crowns presented higher retention load values after 10,000 cycles than initially.

Conclusion

Different material combinations behaved differently after simulated removal and insertion regimens. This difference should be considered during treatment planning.

Clinical relevance

Telescopic crown systems should be made of materials with predictable retention forces that do not deteriorate with time. The implementation of new materials and technologies facilitates reproducibility and time-saving fabrication.
Lynch syndrome-associated chordoma with high tumor mutational burden and significant response to immune checkpoint inhibitors
Authors: Shinojima Naoki , Ozono Kazutaka , Yamamoto Haruaki , Abe Sakiko , Sasaki Rumi , Tomita Yusuke , Kai Azusa , Mori Ryosuke , Yamamoto Takahiro , Uekawa Ken , Matsui Hirotaka , Nosaka Kisato , Matsuzaki Hiroaki , Komohara Yoshihiro , Mikami Yoshiki , Mukasa Akitake
Published: April 2023

Chordoma is a rare malignant bone tumor arising from notochordal tissue. Conventional treatments, such as radical resection and high-dose irradiation, frequently fail to control the tumor, resulting in recurrence and re-growth. In this study, genetic analysis of the tumor in a 72-year-old male patient with refractory conventional chordoma of the skull base revealed a high tumor mutational burden (TMB) and mutations in the MSH6 and MLH1 genes, which are found in Lynch syndrome. The patient and his family had a dense cancer history, and subsequent germline genetic testing revealed Lynch syndrome. This is the first report of a chordoma that has been genetically proven to be Lynch syndrome. Chordomas usually have low TMB; however, this is an unusual case, because the TMB was high, and immune checkpoint inhibitors effectively controlled the tumor. This case provides a basis for determining the indications for immunotherapy of chordoma based on the genetic analysis. Therefore, further extensive genetic analysis in the future will help to stratify the treatment of chordoma.
Rockfall susceptibility along Pasang Lhamu and Galchhi-Rasuwagadhi highways, Rasuwa, Central Nepal
Authors: Pokharel Badal , Lim Samsung , Bhattarai Tara Nidhi , Alvioli Massimiliano
Published: April 2023

The road network in Central Nepal suffered blockades and damage from numerous landslides and rockfalls due to the earthquake sequence in Gorkha, Nepal, in 2015. Additionally, frequent rainstorms in the area contributed to the recurrence of rockfalls and other types of landslides, hindering road infrastructure development and environmental management. Despite the several existing regional and local studies on landslide susceptibility in the area, rockfall-specific analysis is still lacking. In this paper, we assessed rockfall susceptibility in the sections of the Pasang Lhamu highway and the Galchhi-Rasuwagadhi highway in the Rasuwa district using a physically based model. We generated three-dimensional rockfall trajectories along the roads and used them to infer the rockfall susceptibility of the area. We selected potential locations for the initiation of rockfalls based on the optimization of the gridded slope angle, relief, and terrain ruggedness, validated the source map using statistical parameters, and compared them with a field-mapped rockfall source inventory. As a result, we identified which road sections in Ramche, Dandagaun, and Syaprubesi are highly susceptible to rockfalls. We published the field-based inventory of rockfall sources and segment-wise rockfall susceptibility of highways, where a rockfall susceptibility index of 5 indicated very high susceptibility and 1 very low susceptibility. Such findings and maps are helpful for researchers, land planners, developers, government bodies working on disaster risk reduction, and policymakers to design a preliminary framework for rockfall mitigation and sustainable roads.
Behavioral scales variability in patients with prolonged disorders of consciousness
Authors: Cortese Maria Daniela , Vatrano Martina , Arcuri Francesco , Raso Maria Girolama , Tonin Paolo , Calabrò Rocco Salvatore , Riganello Francesco
Published: April 2023

Background

The principal conditions differentiating disorders of consciousness (DOC) patients are the unresponsive wakefulness syndrome/vegetative state (UWS/VS) and the minimally conscious state (MCS). Many individuals who suffer from sudden-onset severe brain injury move through stages of UWS/VS and MCS before regaining full awareness. In some patients, the DOC condition is protracted for years (PDOC). In this study, we observed PDOC patients for 6 months to assess possible changes in their level of consciousness.

Methods

We enrolled 40 PDOC patients, 23 UWS/VS and 17 MCS hosted in a dedicated unit for long-term brain injury care. The time from injury was 472 ± 533 days for UWS/VS and 1090 ± 1079 days for MCS. The Wessex Head Injury Matrix (WHIM), Coma Recovery Scale-R (CRS-R), and Nociception Coma Scale were administered monthly for 6 months.

Results

During the period of assessment, the percentage of UWS/VS shifted from 58 to 45%, while for the MCS, from 42 to 55%. A positive correlation was found for the UWS/VS patients between the months of observation with the CRS-R total score and WHIM total numbers of behaviors (TNB). In the UWS/VS group, the CRS-R auditive and visual subscales correlated positively with the observation time. During the whole period of observation, 8 patients had constant CRS-R total scores while the WHIM TNB changed in 7 of them.

Conclusion

Our findings demonstrated that the monthly assessment of PDOC by means of the CRS-R and WHIM was able to detect also subtle changes in consciousness level.
Transcriptomic analysis of lung development in wildtype and CFTR−/− sheep suggests an early inflammatory signature in the CF distal lung
Authors: Kerschner Jenny L. , Paranjapye Alekh , Schacht Makayla , Meckler Frederick , Huang Felix , Bebek Gurkan , Van Wettere Arnaud J. , Regouski Misha , Perisse Iuri Viotti , White Kenneth L. , Polejaeva Irina A. , Leir Shih-Hsing , Harris Ann
Published: April 2023

The precise molecular events initiating human lung disease are often poorly characterized. Investigating prenatal events that may underlie lung disease in later life is challenging in man, but insights from the well-characterized sheep model of lung development are valuable. Here, we determine the transcriptomic signature of lung development in wild-type sheep (WT) and use a sheep model of cystic fibrosis (CF) to characterize disease associated changes in gene expression through the pseudoglandular, canalicular, saccular, and alveolar stages of lung growth and differentiation. Using gene ontology process enrichment analysis of differentially expressed genes at each developmental time point, we define changes in biological processes (BP) in proximal and distal lung from WT or CF animals. We also compare divergent BP in WT and CF animals at each time point. Next, we establish the developmental profile of key genes encoding components of ion transport and innate immunity that are pivotal in CF lung disease and validate transcriptomic data by RT-qPCR. Consistent with the known pro-inflammatory phenotype of the CF lung after birth, we observe upregulation of inflammatory response processes in the CF sheep distal lung during the saccular stage of prenatal development. These data suggest early commencement of therapeutic regimens may be beneficial.
Proctitis in patients with monkeypox infection: a single-center analysis of 42 consecutive cases from a multidisciplinary observational study on monkeypox proctitis
Authors: Guevara-Martínez J. , La-Noire F. Prieto , Arteaga-Asensio P. , Pascual-Miguelañez I. , Moraes Souza R. , Quiles M. , Montes M. , Fondevila C. , Álvarez-Gallego M. ,   Monkeypox multidisciplinary collaboration group, Sendagorta Elena , Gonzalez-Alcolea Natalia , Zapata-Syro Camilo , Maldonado Alfredo , González Claudia Sanz , Marijuan J. L.
Published: April 2023

Background

The current monkeypox (MP) virus outbreak was declared an international emergency in July 2022. The aim of this report is to describe our initial experience with patients with MP, focusing on proctitis.

Methods

We conducted an observational study between 20 May and 31 July 2022, on patients with MP at a reference tertiary center in Madrid, Spain. A descriptive analysis on MP was performed, focusing on its characteristics, symptoms, diagnosis, and outcomes.

Results

A total of 143 positive MP cases were diagnosed in our center; 42 of them [all male, median age 39 years (range: 22–57 years)] had proctitis (29.37%), and 3 patients (2.09%/MP total cases and 7.14%/MP proctitis) required surgical drainage of a perianal abscess.

Conclusions

General and digestive surgeons must be aware of the presence of proctological impairment and complications due to MP virus.
Clinical implications of myeloid malignancy‑related somatic mutations in aplastic anemia
Authors: Liu Lingling , Zhang Danfeng , Fu Qiuhao , Wang Jingdi , Yu Jifeng , Chen Dandan , Wang Fang , Guo Rong , Xie Xinsheng , Jiang Zhongxing , Li Yingmei
Published: April 2023

Aplastic anemia (AA) is a potentially fatal bone marrow failure syndrome characterized by a paucity of hematopoietic stem cells and progenitor cells with varying degrees of cytopenia and fatty infiltration of the bone marrow space. Recent advances in genomics have uncovered a link between somatic mutations and myeloid cancer in AA patients. At present, the impact of these mutations on AA patients remains uncertain. We retrospectively investigated 279 AA patients and 174 patients with myelodysplastic syndromes (MDS) and performed targeted sequencing of 22 genes on their bone marrow cells using next-generation sequencing (NGS). Associations of somatic mutations with prognostic relevance and response to treatment were analyzed. Of 279 AA patients, 25 (9.0%) patients had somatic mutations, and 20 (7.2%) patients had one mutation. The most frequently mutated genes were ASXL1(3.2% of the patients), DNMT3A (1.8%) and TET2 (1.8%). In the MDS group, somatic mutations were detected in 120 of 174 (69.0%) patients, and 81 patients (46.6%) had more than one mutation. The most frequently mutated genes were U2AF1 (24.7% of the patients), ASXL1 (18.4%) and TP53 (13.2%). Compared with MDS patients, AA patients had a significantly lower frequency of somatic mutations and mostly one mutation. Similarly, the median variant allele frequency was lower in AA patients than in MDS patients (6.9% vs. 28.4%). The overall response of 3 and 6 months in the somatic mutation (SM) group was 37.5% and 66.7%, respectively. Moreover, there was no significant difference compared with the no somatic mutation (N-SM) group. During the 2-years follow-up period, four (20%) deaths occurred in the SM group and 40 (18.1%) in the N-SM group, with no significant difference in overall survival and event-free survival between the two groups. Our data indicated that myeloid tumor-associated somatic mutations in AA patients were detected in only a minority of patients by NGS. AA and MDS patients had different gene mutation patterns. The somatic mutations in patients with AA were characterized by lower mutation frequency, mostly one mutation, and lower median allelic burden of mutations than MDS. Somatic mutations were a common finding in the elderly, and the frequency of mutations increases with age. The platelet count affected the treatment response at 3 months, and ferritin level affected the outcome at 6 months, while somatic mutations were not associated with treatment response or long-term survival. However, our cohort of patients with the mutation was small; this result needs to be further confirmed with large patient sample.
Resin tapping influence on maritime pine growth depends on tree age and stand characteristics
Authors: Moura Mikael , Campelo Filipe , Nabais Cristina , Garcia-Forner Núria
Published: April 2023

Resin is a renewable forest resource that can increase the economic value of some forests in rural areas. Resin production is associated with climatic conditions. However, its impact on trees’ growth remains unclear. Here, we studied radial growth in six Portuguese Pinus pinaster forests that had been resin tapped for 5–7 years along a latitudinal and climatic gradient to understand whether resin tapping affects tree growth, and how it is affected by climate, stand and tree traits. Tree-ring width (TRW) on tapped and untapped trunk sides was compared before and during the tapping period. Tree-ring width decreased in the three youngest populations (< 30 years), with no changes in older populations (> 40 years), while TRW increased after resin harvesting began in the oldest stand (> 55 years). Annual resin-tapping impact (RTI), calculated as the ratio between TRW during tapping years and the 5-year average TRW before tapping, was below and above 1 in the younger and older stands, respectively. Among stand characteristics and across sites, RTI was negatively correlated with tree competition and positively correlated with TRW, cambial age, and tree height. Climatic conditions had a minor role on tree growth response to resin tapping. Our main conclusion is that the effect of resin extraction on growth is age-dependent. Our results encourage the co-production of resin and wood on maritime pine stands over 40 years old where resin extraction impact on growth is negligible.
Models of Cochlea Used in Cochlear Implant Research: A Review
Authors: Hrncirik Filip , Roberts Iwan , Sevgili Ilkem , Swords Chloe , Bance Manohar
Published: April 2023

As the first clinically translated machine-neural interface, cochlear implants (CI) have demonstrated much success in providing hearing to those with severe to profound hearing loss. Despite their clinical effectiveness, key drawbacks such as hearing damage, partly from insertion forces that arise during implantation, and current spread, which limits focussing ability, prevent wider CI eligibility. In this review, we provide an overview of the anatomical and physical properties of the cochlea as a resource to aid the development of accurate models to improve future CI treatments. We highlight the advancements in the development of various physical, animal, tissue engineering, and computational models of the cochlea and the need for such models, challenges in their use, and a perspective on their future directions.
QCBA: improving rule classifiers learned from quantitative data by recovering information lost by discretisation
Authors: Kliegr Tomáš , Izquierdo Ebroul
Published: April 2023

A prediscretisation of numerical attributes which is required by some rule learning algorithms is a source of inefficiencies. This paper describes new rule tuning steps that aim to recover lost information in the discretisation and new pruning techniques that may further reduce the size of rule models and improve their accuracy. The proposed QCBA method was initially developed to postprocess quantitative attributes in models generated by Classification based on associations (CBA) algorithm, but it can also be applied to the results of other rule learning approaches. We demonstrate the effectiveness on the postprocessing of models generated by five association rule classification algorithms (CBA, CMAR, CPAR, IDS, SBRL) and two first-order logic rule learners (FOIL2 and PRM). Benchmarks on 22 datasets from the UCI repository show smaller size and the overall best predictive performance for FOIL2+QCBA compared to all seven baselines. Postoptimised CBA models have a better predictive performance compared to the state-of-the-art rule learner CORELS in this benchmark. The article contains an ablation study for the individual postprocessing steps and a scalability analysis on the KDD’99 Anomaly detection dataset.
Analyzing Human Search Behavior When Subjective Returns are Unobservable
Authors: Nakazato Shinji , Yang Bojian , Shimokawa Tetsuya
Published: April 2023

The exploration versus exploitation dilemma is a critical issue in human information acquisition and sequential belief formation, and the multi-armed bandit problem has been widely used to address it. Because of its high descriptive accuracy, the SGU model, which combines SoftMax type probabilistic selection, Gaussian process regression type belief updating, and upper confidence interval type evaluation, has attracted much attention. However, this model assumes that the analyst has access to the returns from people’s choices, but in many realistic tasks, this assumption cannot be made because only choices are observable. Moreover, many of the returns are subjective. The authors introduce a new model-fitting method that overcomes this barrier and evaluates its performance using data sets derived from agent-based simulations and real consumer data. This approach has the potential to significantly broaden the range of issues to which the SGU model can be applied.
Empagliflozin attenuates intestinal inflammation through suppression of nitric oxide synthesis and myeloperoxidase activity in in vitro and in vivo models of colitis
Authors: Makaro Adam , Świerczyński Mikołaj , Pokora Kacper , Sarniak Barbara , Kordek Radzisław , Fichna Jakub , Salaga Maciej
Published: April 2023

Inflammatory bowel diseases (IBD) are characterized by chronic and relapsing inflammation affecting the gastrointestinal (GI) tract. The incidence and prevalence of IBD are relatively high and still increasing. Additionally, current therapeutic strategies for IBD are not optimal. These facts urge todays’ medicine to find a novel way to treat IBD. Here, we focused on the group of anti-diabetic drugs called gliflozins, which inhibit sodium glucose co-transporter type 2 (SGLT-2). Numerous studies demonstrated that gliflozins exhibit pleiotropic effect, including anti-inflammatory properties. In this study, we tested the effect of three gliflozins; empagliflozin (EMPA), dapagliflozin (DAPA), and canagliflozin (CANA) in in vitro and in vivo models of intestinal inflammation. Our in vitro experiments revealed that EMPA and DAPA suppress the production of nitric oxide in LPS-treated murine RAW264.7 macrophages. In in vivo part of our study, we showed that EMPA alleviates acute DSS-induced colitis in mice. Treatment with EMPA reduced macro- and microscopic colonic damage, as well as partially prevented from decrease in tight junction gene expression. Moreover, EMPA attenuated biochemical inflammatory parameters including reduced activity of myeloperoxidase. We showed that SGLT-2 inhibitors act as anti-inflammatory agents independently from their hypoglycemic effects. Our observations suggest that gliflozins alleviate inflammation through their potent effects on innate immune cells.
Finetuning Analytics Information Systems for a Better Understanding of Users: Evidence of Personification Bias on Multiple Digital Channels
Authors: Jansen Bernard J. , Jung Soon-gyo , Salminen Joni
Published: April 2023

Although the effect of hyperparameters on algorithmic outputs is well known in machine learning, the effects of hyperparameters on information systems that produce user or customer segments are relatively unexplored. This research investigates the effect of varying the number of user segments on the personification of user engagement data in a real analytics information system, employing the concept of persona. We increment the number of personas from 5 to 15 for a total of 330 personas and 33 persona generations. We then examine the effect of changing the hyperparameter on the gender, age, nationality, and combined gender-age-nationality representation of the user population. The results show that despite using the same data and algorithm, varying the number of personas strongly biases the information system’s personification of the user population. The hyperparameter selection for the 990 total personas results in an average deviation of 54.5% for gender, 42.9% for age, 28.9% for nationality, and 40.5% for gender-age-nationality. A repeated analysis of two other organizations shows similar results for all attributes. The deviation occurred for all organizations on all platforms for all attributes, as high as 90.9% in some cases. The results imply that decision makers using analytics information systems should be aware of the effect of hyperparameters on the set of user or customer segments they are exposed to. Organizations looking to effectively use persona analytics systems must be wary that altering the number of personas could substantially change the results, leading to drastically different interpretations about the actual user base.
Processing Speed is Related to the General Psychopathology Factor in Youth
Authors: Kramer Eliza , Willcutt Erik G. , Peterson Robin L. , Pennington Bruce F. , McGrath Lauren M.
Published: April 2023

The relationship between the p factor and cognition in youth has largely focused on general cognition (IQ) and executive functions (EF). Another cognitive construct, processing speed (PS), is dissociable from IQ and EF, but has received less research attention despite being related to many different mental health symptoms. The present sample included 795 youth, ages 11–16 from the Colorado Learning Disabilities Research Center (CLDRC) sample. Confirmatory factor analyses tested multiple p factor models, with the primary model being a second-order, multi-reporter p factor. We then tested the correlation between the p factor and a latent PS factor. There was a significant, negative correlation between the p factor and PS (r(87) = -0.42, p < .001), indicating that slower processing speed is associated with higher general mental health symptoms. This association is stronger than previously reported associations with IQ or EF. This finding was robust across models that used different raters (youth and caregiver) and modeling approaches (second-order vs. bifactor). Our findings indicate that PS is related to general psychopathology symptoms. This research points to processing speed as an important transdiagnostic construct that warrants further exploration across development.