The clinical proteomics field has seen enormous growth in the past 20 years, with over 40000 scientific manuscripts published. At the same time, actual clinical application of the reported findings is obviously scarce. In this manuscript we discuss the key issues that may be responsible for this apparent lack of success, which cannot be measured by the numbers of publications, but by the impact on patient management and treatment. We proceed with suggestions for potential solutions, which include keeping a strict focus on potential patient benefit. We hope this manuscript can help shaping the field, so it can in fact deliver on its realistic promise, to bring significant improvement in management and care to patients.

The norovirus GII.13 [P16] genotype, which is rarely detected and has unclear transmission routes, caused outbreaks in four Korean regions with no known infection source. By analyzing variations in the hypervariable P2 domain, identical sequences among patients were identified in this study, suggesting a common contamination source across the regions.

Smart mobile devices have gained popularity worldwide and facilitated interactions among people around the world. The demand for reliable and efficient system-on-chip (SoC) architectures has increased in response to the increased use of these devices. The southbridge subsystem is an important module that plays a major role in coordinating the essential activities of SoCs. It monitors and regulates input/output (IO) activities in low-bandwidth systems. Additionally, it provides access to non-volatile basic input/output system (BIOS) memory. The storage of essential data related to the system settings requires this memory. In this paper, we present the architecture of a trusted platform module (TPM) using an embedded processor for the SoC southbridge subsystem.

Environmental stochasticity impacts population dynamics and their viability. As such, understanding how organisms cope with this variability is crucial. Here, we investigate demographic buffering, the ability of populations to maintain stable growth despite environmental fluctuations. We integrate well-established stochastic and deterministic approaches to investigate characteristics of demographic buffering, analysing stochastic elasticities and self-second derivatives of deterministic population growth rate. We test the hypothesis that buffered species exhibit low stochastic elasticity to temporal variability and signs of concave selection (i.e. negative second derivatives of population growth rate with respect to demographic processes), reducing variance in key demographic processes. Analysing 43 natural populations of 37 mammal species, we find limited support for this hypothesis. Indeed, while primates often show low stochastic elasticity, concave selection is less prevalent than expected. Our findings highlight the complex and dynamic relationship between demographic processes, environmental variability, and selection pressures in determining population persistence.

Terabytes of data are recorded per flight by modern aircraft, providing a goldmine for predictive maintenance modelling, however, the required domain knowledge to build machine learning tools limits the number developed by airline manufacturers each year. Automated machine learning (AutoML) libraries can simplify model development, providing features such as automated preprocessing, model selection and hyperparameter tuning to improve the efficiency and accessibility of the development workflow. This research presents an experimental analysis comparing industry-selected machine-learning models and a hand-picked selection of automated machine-learning tools. The selected models were evaluated against real and synthetic time series datasets for different Airbus landing gear components across six datasets. The traditional and automated models obtained comparable MAE and F1 scores on regression and classification problems accordingly, demonstrating the effectiveness of their use in this field. Based on these findings, a robust framework is proposed to utilise automated machine learning to optimise predictive maintenance tool development. This research is a stepping stone towards greater use of automation for predictive maintenance and presents insights into the field and AutoML. By integrating greater automation, AutoML can exploit more of the available data, and deskill the development process to enable non-data scientists to produce health monitoring models for a more diverse pool of aircraft components.

Ciprofol (HSK3486), a novel short-acting intravenous anesthetic, is a positive allosteric regulator and direct agonist of γ-aminobutyric acid type A (GABAA) receptor. It is synthetized by introducing a cyclopropyl group in the isopropyl side chain of propofol. The incorporation of cyclopropyl not only increases the steric effect, but also the new chiral molecules formed introduce stereoselective effects, thereby increasing the affinity for GABA receptors. Ciprofol activates GABAARs, producing sedative or anesthetic effects. Ciprofol is expected to become the new choice for intravenous anesthetics due to its characteristics of high potency, rapid onset, rapid recovery, and fewer adverse reactions. It is suitable for sedation and general anesthesia in the endoscopy center, operating room, and intensive care unit. This review summarizes the pharmacological characteristics and clinical research progress of ciprofol.

Introduction: Pulsed Field Cryoablation (PFCA) is a dual-energy cardiac ablation modality consisting of short-duration ultra-low temperature cryoablation (ULTC) followed immediately by pulsed field ablation (PFA) delivered from the same catheter. It is hypothesized that PFCA may improve contact stability during PFA, while maintaining lesion depth and effectiveness of ULTC. Methods: PARALELL is a first-in-human multicenter study evaluating safety and effectiveness of a novel PFCA catheter and system in patients with persistent atrial fibrillation (PsAF) using the combination of pulmonary vein (PVI) and posterior wall (PWI) isolation. Results: 66 patients were ablated at six sites. Groin hematoma in one patient was the only serious procedure- or device-related adverse event recorded in the study. Per protocol, acute effectiveness was evaluated in 46 patients, including 31 patients with post-hoc analysis of cryogenic energy per lesion. After an average of 21.1 ± 9.3 lesions per patient the rates of PVI and PWI were 95.7% (176/184) and 97.7% (42/43), respectively. The average cryogenic energy per patient was highly predictive of acute isolation success with ROC AUC = 0.944 and 100% rates of both PVI and PWI in 24 patients in the optimal energy cohort. Grade I microbubbles and faint muscle contractions were detected in 1.1% and 0.5% of ablations, respectively. Conclusion: This initial multi-center experience suggests that PFCA can be efficiently performed for PVI and PWI using a single versatile catheter system, with high acute success and good early safety profile. The evaluation of the chronic 12-month effectiveness of PFCA is ongoing.

Background: The development or progression of tricuspid regurgitation (TR) following the implantation of cardiovascular implantable electronic devices (CIED) represents a significant concern. Although the link between transvalvular lead placement and TR is well established, further research is required to elucidate the underlying factors that predispose patients to develop patient-related and lead-induced TR. The impact of the number of leads passing through the tricuspid valve and the lead diameter on the severity of tricuspid regurgitation remains unclear. This study investigated the effect of adding a pacing/ sensing lead (PSL) or an add-on ICD lead implantation on tricuspid valve function. Methods: In this retrospective, single-center, case-control study, all ICD implantation patients, in cases performed by one of these authors, presenting with lead failure were screened. Echocardiographic reports of patients who underwent additional PSL or ICD lead implantation were reviewed. Results: A total of 52 patients were included in the study. An additional pacing/sensing lead was implanted in 28 patients and an add-on ICD lead was implanted in 24 patients. The mean echocardiographic follow-up time (months) after intervention was similar in both groups (19.7 ± 17.7 vs. 18.2 ± 16.5 p:0.94). There was no significant difference between groups regarding age, gender, etiology of heart disease, and types of ICD. The addition of PSL did not result in a statistically significant increase in the degree of tricuspid regurgitation. (p:0,705). We did not find a significant increase in the degree of tricuspid regurgitation in patients in whom ICD leads were added (p: 0.059). There was no significant difference between the two groups in terms of the change in TR grade (p: 0.130). Conclusion: Although the relationship between CIED-mediated TV dysfunction and tricuspid valve dysfunction is clear, the effect of lead-related factors, such as the increased number and diameter of leads, on tricuspid valve dysfunction is unknown. This is the first study to investigate the effect of new shock lead insertion versus new PSL insertion strategies on lead-related tricuspid regurgitation in patients with lead failure. The findings indicate that adding a PSL or ICD lead in patients requiring lead addition due to lead failure did not increase tricuspid valve dysfunction.

Aim: To inform healthcare professionals and patients about the discussion held by regulatory authorities on a potential risk that links the use of semaglutide and thyroid neoplasms. Methods: Review of all information available about this association using the Spanish pharmacovigilance database (FEDRA), the WHO’s pharmacovigilance database (VigiBase) and literature. Results: We found a large discrepancy regarding the development of thyroid neoplasms with semaglutide among the information provided by different regulatory agencies. However, the epidemiological analyses of the cases retrieved from FEDRA and VigBase shows qualitative and statistical significance and the literature provides a plausibility mechanism to explain the development of these neoplasms. The Summary of Product Characteristics also includes this risk, referring to preclinical studies, without ruling out its relevance in humans. Conclusion: We believe that the existence of this discussion should be known by healthcare professionals and European users, just as the FDA has done with Americans as a risk minimization strategy.

not-yet-known not-yet-known not-yet-known unknown Background and purpose: Anaphylatoxin (C5a) plays a critical role in the pathogenesis of virus-induced acute respiratory distress syndrome (v-ARDS). However, evidence for the effect of innovative C5a inhibitor on the mortality of ARDS has been lacking. STSA1002 is a human anti-C5a antibody currently in a phase II trial for treating ARDS disease. To support its clinical development in humans, in vitro assays and in vivo studies were conducted to determine the pharmacology, preclinical characteristics and safety of this monoclonal antibody. Experimental approach: The vitro pharmacology, pharmacokinetics (PK), pharmacodynamics and toxicology of STSA1002 were firstly evaluated in cynomolgus monkeys, mouse models and health adults. Key results: In vitro experiments, we showed that STSA1002 can specifically bind to recombinant human and rhesus monkeys C5a with comparable blocking effects. Furthermore, STSA1002 remarkably blocked C5a-primed neutrophil degranulation response, dose-dependently prevented C5a-stimulated chemotaxis, continuously inhibited C5a induced up-regulation of human neutrophil CD11b and effectively decreased the levels of NETs specific biomarkers (myeloperoxidase, neutrophil elastase and proteinase 3). In vivo experiments, single intravenous administration of STSA1002 (1, 3 and 10 mg/kg) significantly improved the mortality of LPS-induced ARDS in C5a-e (hC5)1 humanized mice. In addition, PK study revealed a linear PK profile within the dose range of 5-50 mg/kg following single intravenous administration in cynomolgus monkeys. 4-week repeat-dose toxicity study in rhesus monkeys was performed to prove well safety of STSA1002. Conclusions and implications: We demonstrated, for the first time, a comprehensive preclinical characterization of STSA1002 that supports its clinical development in an immunomodulatory therapy.

Background: Betulinic acid, a natural pentacyclic triterpenoid, has been studied for its anti-inflammatory and anti-tumoural properties in various species. Recent in vitro and in vivo work has shown promise for treatment of equine skin tumours’ in horses. Objective: The objective of this study is to evaluate the safety and efficacy of a compounded 1% betulinic acid cream for the treatment of equine cutaneous melanoma and sarcoid in clinical cases. Study Design: Prospective randomized, blinded, placebo-controlled clinical trial. Methods: In select cases, biopsies were performed to confirm the diagnosis prior to enrolment. Photographs and measurements were obtained before and after the trial period. A compounded 1% betulinic acid or placebo cream was applied twice daily for 7 days, then once daily for 21 days. Owners completed a daily questionnaire to evaluate adverse reactions. Tumour volume was calculated based on width and length measurements using an established model. Mann-Whitney U tests were used to evaluate the change in tumour volume between groups. Results: A total of 37 horses completed the clinical trial, 16 horses with melanoma and 21 horses with sarcoid tumours. There were no significant differences in the change in tumour volume between treatment and placebo groups for either tumour type. The compounded cream was well tolerated. Main Limitations: This study was limited by owner subjectivity in application and questionnaires. Follow-up tumour measurements were not always performed by the same veterinarian. Conclusions: Based on this data, application of a compounded 1% betulinic acid cream was safe but did not result in a statically significant reduction in tumour volume for equine melanoma or sarcoid during a 30-day application period compared to a placebo. In general, tumour volume decreased in all groups and clinical trials evaluating the compound at twice daily application for an extended application period would be valuable.

The lack of approved age-appropriate formulations in health systems undermines treatment efficacy in Paediatric populations and increases the risk of adverse drug reactions. This study assessed the availability of age-appropriate formulations for children in three selected hospitals in Kabul: the Indira Gandhi Institute of Child Health, Ataturk Hospital, and FMIC. A comprehensive review of hospital formularies was conducted to evaluate medications based on their approval status across Paediatric subgroups using drug labelling information in the UK and USA. Additionally, the suitability of oral formulations was assessed following WHO recommendations, including oral liquids, chewable tablets, rapidly disintegrating tablets, and granules. Semi-structured interviews with hospital pharmacists explored how the lack of Paediatric formulations is managed. Findings revealed that unlicensed medications were most prevalent in neonates (61.9%), with a marked decline in adolescents (17.8%). For children under six years, 40.1% of medications had suitable Paediatric formulations, while only 26.8% were both suitable and licensed. Respiratory and antibiotic medications had the highest availability of suitable and licensed formulations, whereas cardiovascular and haematological medicines had the lowest. Notably, FMIC was the only hospital providing compounded medication services for both inpatients and outpatients.

The paper investigates a non-zero-sum differential investment and reinsurance problem between two alpha-robust, risk-averse competitive insurers under a time-consistent mean-variance criterion inspired by Li et al. (2016). The claim arrival processes for both insurers follow the classical Cramér-Lundberg model, and the reinsurance premium is calculated using the variance premium principle. Each insurer can invest their surplus in one risk-free asset, one risky asset, and a defaultable corporate bond. The paper also considers the effect of bounded memory, which is characterized by the wealth process with delay. Using the dynamic programming approach, we solve for the non-zero-sum alpha-robust optimal strategy and the corresponding value function by solving the Hamilton-Jacobi-Bellman (HJB) equation. In the numerical simulation section, we observe a phenomenon where the optimal strategy for investing in defaultable bonds decreases as the competitor’s risk aversion coefficient increases, provided that one’s own risk aversion coefficient remains constant. However, when there is a change in one’s own risk aversion coefficient, even if the competitor’s risk aversion changes in the opposite direction, the optimal investment strategy in defaultable bonds still decreases as one’s own risk aversion coefficient increases.

not-yet-known not-yet-known not-yet-known unknown Traumatic Brain Injury (TBI) is a severe neurological disorder with an incomplete understanding of its underlying mechanisms, primarily due to the lack of effective strategy for in situ spatiotemporal analysis. Biomarkers associated with TBI, such as glial fibrillary acidic protein (GFAP), are typically detected in vitro rather than in situ, with a notable absence of spatiotemporal dynamics analysis. Herein, we developed a resveratrol-functionalized silver nanowires-doped MXene-based field-effect transistor biopatch (Res-Ag-MFETs) for in-situ spatiotemporal GFAP analysis, aiming to elucidate the TBI’s biomolecular mechanisms. We employed silver nanowires (AgNWs)-doped two-dimensional MXene as the FETs semiconductor and validated the favorable capability of MXene@AgNWs via morphological, elemental characterization, and DFT simulations. Res-Ag-MFETs demonstrated a favourable capability to suppress neuronal damage and inflammation, as evidenced by histological staining and bioactivity tests. Additionally, Res-Ag-MFETs demonstrated remarkable reproducibility (RSD=2.12%), stability, and sensitivity for GFAP quantification, achieving a detection limit as low as 0.47 pg/mL. Ultimately, Res-Ag-MFETs enabled efficient in-situ spatiotemporal analysis of GFAP in a Sprague Dawley (SD) rat with TBI, revealing a progressive diffusion of GFAP from the centre to the periphery over time. This advancement provides a novel platform for spatiotemporal dynamics analysis of biochemical markers in brain disorders, potentially laying the groundwork for further exploration of underlying pathogenic mechanisms.

Background and Purpose Proteolytic balance is dysregulated in many diseases, with proteases playing critical roles in pathological pathways. A high level of Trypsin-3 expression has been implicated as a significant mediator of tumour progression and metastasis and this protease is associated with poor prognosis for patient in various cancers. Therefore, Trypsin-3 inhibition has emerged as a promising therapeutic target. However, no physiological or pharmacological inhibitor has yet been described that specifically target Trypsin-3. A major challenge in developing druggable inhibitor for this protease lies in achieving enough selectivity, as proteases belong to a large enzymatic family with close homologues that share similarities in their three-dimensional folding of their active conformation. Experimental Approach An advanced screening strategy of a large library of synthetic humanized nanobodies was employed to isolate highly selective recombinant antibodies targeting the active conformation of Trypsin-3. Among five hits, we combined two domains with distinct paratopes and inhibitory mechanisms to generate a macrodrug candidate capable to efficiently block the Trypsin-3 activity. Key Results This bispecific nanobody demonstrated exceptionally high selectivity and affinity towards Trypsin-3 in vitro, as well as a strong ability to inhibit cancer cell migration ex vivo on PC-3 cancer cell line. Conclusion and Implications. This study underscores the versatility and potential of synthetic nanobody engineering in the development of very selective protease inhibitors, paving the way for their consideration as drug candidates for clinical development.

A document by Jiang Zhou. Click on the document to view its contents.

not-yet-known not-yet-known not-yet-known unknown Leaf nutrient resorption efficiency (NuRE) serves as a metric for delineating plant strategies that range from ‘slow-fast’ performance to conservative-acquisitive resource management. However, the relationships between the interspecific variations in NuRE and the economic traits of both leaves and roots remain unclear. In this study, we gathered both green and senesced leaves to explore mass-based nitrogen (N) and phosphorus (P) concentrations, as well as leaf structural investment and root economic traits, across 10 tree and shrub species within mangrove ecosystems in Hainan, China. This study challenges the initial hypothesis by revealing that species with low leaf structural investment, indicated by low leaf mass per area and leaf dry matter content, exhibit high N and P resorption efficiency. These findings suggest that plants with less investment in the leaf structure are more efficient at resorbing nutrients. Contrary to expectations, root economic traits such as specific root length, root nitrogen content, root diameter, and root tissue density did not significantly influence NuRE. These findings indicate that above-ground nutrient conservation mechanisms may function independently of root foraging traits. This study highlights mangroves’ key role in nutrient recycling, enhancing our grasp of plant dynamics and their impact on global cycles, especially in coastal areas.

A document by Ranee Thakar. Click on the document to view its contents.

The oil industry exerts substantial environmental pressure on drylands, posing a major threat to these fragile ecosystems. Specifically, the construction of drilling facilities disturbs approximately 0.6–1 ha around each borehole, where vegetation is removed, and the topsoil is replaced with a compacted layer of gravel and fine-textured materials. This process increases soil bulk density, disrupts soil aggregates, reduces porosity, aeration, and infiltration, and ultimately intensifies soil strength, runoff, and degradation. Scarification is commonly employed in Monte Austral (Argentina) to promote soil and vegetation recovery by enhancing water infiltration and root penetration, thereby improving soil structure and expediting ecosystem rehabilitation. To evaluate the effectiveness of scarification as a decompaction technique and its influence on rehabilitation, we assessed penetrometer resistance and unsaturated hydraulic conductivity under two conditions: (1) in natural, undisturbed areas, and (2) in scarified areas, categorized by the time elapsed since scarification: 8–13 years, 4–8 years, and less than 4 years. Our findings show that scarification reduces compaction within the 0–10 cm soil depth in the short term, but re-compaction and a hardened surface crust develop within eight years post-treatment. The results indicate that scarification alone is insufficient to trigger pedogenetic processes in compacted Technosols or to rehabilitate the ecosystem’s structural attributes.

not-yet-known not-yet-known not-yet-known unknown Aims: Patients with liver disease, particularly cirrhosis, are often excluded from clinical trials on anticoagulant therapy, therefore, the optimal choice of anticoagulants for this population is still unclear. Methods: We searched the databases of PubMed, the Cochrane Library, Medline, and Embase for relevant studies. Results: In this meta-analysis, we included 19 studies with 51,728 participants. In patients with liver disease, compared with that in the traditional group, the DOAC group showed a significantly lower risk for major bleeding, intracranial bleeding (ICH), gastrointestinal bleeding and composite outcome. We did not observe statistically significant differences between the groups with respect to ischemic stroke/thromboembolism (IS/TE), all-cause mortality. In patients with liver cirrhosis, the DOAC group performed better than the traditional group in terms of major bleeding, gastrointestinal bleeding, ICH, IS/TE + major bleeding and composite outcome. The efficacy and safety of regular-dose and low-dose DOACs showed no difference (P>0.05), whereas the efficacy and safety of apixaban were superior to those of rivaroxaban (P<0.05). Conclusion: The effectiveness of DOACs for anticoagulation treatment in patients with liver disease was not inferior to that of traditional anticoagulation regimens, and the safety of DOACs was better. The results were also applicable to patients with cirrhosis. When selecting among DOACs, apixaban demonstrated superior efficacy and safety compared to rivaroxaban. Furthermore, the clinical benefits observed between regular-dose and low-dose DOACs showed no significant difference.

Transparent objects are difficult to perceive due to their unique optical properties, and the dynamic interaction between the hand and object further complicates pose estimation. To address this problem, we propose HTPE-Net, a monocular instance-level 6D pose estimation method for hand-held transparent objects, addressing the significant challenges posed by the texture-less, non-Lambertian surfaces, and hand-object occlusions. HTPE-Net integrates hand and object features through a dual-stream feature extraction backbone and a hand-to-object feature enhancement module, generating geometric features and hand attention maps to improve robustness to background changes and occlusions. The network is trained on a modified version of the TransHand-14K dataset and demonstrates superior performance compared to state-of-the-art methods. Additionally, a sim-to-real experiment validates the practical applicability of HTPE-Net in real-world robot perception tasks. The proposed approach significantly advances the accuracy and robustness of 6D pose estimation for hand-held transparent objects, with potential applications in robotics, human-machine interaction, and augmented reality.

Transparent liquid volume estimation is crucial for robot manipulation tasks, such as pouring. However, estimating the volume of transparent liquids is a challenging problem. Most existing methods primarily focus on data collection in the real world, and the sensors are fixed to the robot body for liquid volume estimation. These approaches limit both the timeliness of the research process and the flexibility of perception. In this paper, we present SimLiquid20k, a high-fidelity synthetic dataset for liquid volume estimation, and propose a YOLO-based multi-modal network trained on fully synthetic data for estimating the volume of transparent liquids. Extensive experiments demonstrate that our method can effectively transfer from simulation to the real world. In scenarios involving changes in background, viewpoint, and container variations, our approach achieves an average error of 5% in real-world volume estimation. In addition, our work conducts two application experiments integrate with ChatGPT, showcasing the potential of our method in service robotics. The accompanying video and supplementary materials are available at https://simliquid.github.io/.

not-yet-known not-yet-known not-yet-known unknown in this paper an improved A* algorithm which combines a priority-based node selecting strategy and a novel termination condition for bidirectional search was proposed. Through numerical experiments on grid maps of various sizes and complexity, it is found that this improved A* algorithm searches much less nodes and thus take substantially less time in pathfinding compared to the traditional bidirectional A* algorithm. The superiority of the improved A* algorithm become more pronounced as map size grows.

not-yet-known not-yet-known not-yet-known unknown This article digs into the current significance of Low Earth Orbit (LEO) Satellite Networks in both academia and industry, starting with an examination of the various uses envisioned for Low Earth Orbit Satellites (LEOS) and its clear advantages over 5G technology, LEOS offer global internet access, low latency, and scalability, surpassing 5G’s coverage. The applications of LEO satellites include global connectivity, remote sensing, and aerospace advancements, revolutionizing communication and space exploration. Notably, These networks, which include SpaceX, OneWeb, LeoSat, Telesat, and Amazon Kuiper, have been in development since 2018. The satellites operate as routing nodes connected via ISLs, and terminals connect dynamically to one or more satellites in these networks, which also have onboard processing capabilities. The dynamic changes in the network architecture present particular challenges for service planning and traffic routing. To determine an optimal path for transmitting data from a single source terminal to a single destination terminal within the dynamic and complex network architecture of LEO satellites is known as unicast routing. We are interested in unicast routing because it addresses the specific needs of individual communication, optimizing network efficiency, minimizing latency, and enhancing security, all of which are critical factors in the success of these networks. There are changes in routing information that might be frequent and have a latency of 100 ms due to the continual movement of satellites and the Earth. Routing traffic from a source terminal to a destination terminal connected to several satellites is a challenge. In this paper, we will present different approaches from literature to model the satellite constellation and solve the routing problem (with or without inter-satellite links and w/wo dynamic routing). This paper also introduces the simulators to model satellite constellation such as Starlink constellation.