Laypeople, usually the first on scene at a mass casualty event, still have no input into early operational tactics. A new and easy to learn algorithm done by laypeople might gain additional information for operational tactics, especially reinforcement. A validated mass casualty data set was used to generate sets of 20 patients. The triage gold standard was compared to severity scores of different already established algorithms as well as the new invented allocation algorithm LACA. For algorithm quality Cronbach's Kappa, specificity, sensitivity, over- and underassessment was examined. Kullback-Leibler-Divergence was used to show information loss. The LACA algorithm showed a moderate severity correlation (Cohen's Kappa = 0.469), lower than mSTaRT or PRIOR. PRIOR showed the already well known and intentional overassessment. LACA showed highest underassessment of all three evaluated algorithms. After adjustment the information loss could be reduced to DKL = 0,0002 bits. The "LACA" represents a practical and layperson-friendly addition to pre-hospital response strategies in mass casualty incidents. It can provide a reliable initial assessment that supports early operational decision-making. Additionally, this new approach enables emergency dispatch centers to perform a more tailored mobilization of rescue resources in the first place, based on the structured information provided by laypeople or lay responders. To maximize individual survival LACA must be followed by established triage algorithms like mSTaRT or PRIOR applied by trained emergency personnel.
At the frontiers of X-ray and high-power laser optics, Professor Zhanshan Wang has made outstanding contributions from fundamental mechanism to fabrication technologies and high performance applications over the last 25 years. As a Professor at Tongji University, he leads the Innovative Research Group of the National Natural Science Foundation of China, pioneered a novel theoretical framework for the synergistic tailoring of spectral response, electric field distribution, irradiation damage and optical loss in thin films optics. He developed high-precision characterization methods for resolving atomic-scale defects in coatings, invented a full-process and quantitative fabrication technology for thin film optics. By establishing premier research platforms and cultivating a highly skilled scientific team, his sustained efforts have greatly improved the performance of X-ray and optical thin-film devices which have been widely applied in synchrotron radiation, high power laser facilities, and space telescope. In this interview, he reflects on the scientific concepts guiding his research on X-ray and laser optics, the philosophy behind cultivating a world-class research team, and his vision for the future of optical science and technology.
Flexible antenna design is described in this study, prototyping of a flexible graphene-based antenna for data transmission from wearable arm and abdomen imaging equipment over a 5G network. The antenna uses an 18-μm-thick graphene thin sheet for the conductive and ground radiating patch. The proposed design operates in the from 25.2-40.2 GHz frequency band and it based on the radiation patch fractal structure which allowed for adequate antenna flexibility. The invention is appropriate for wearable applications because the patch was constructed on a flexible polyamide substrate that was 1.575 mm thick. In terms of the radiation pattern, gain, and antenna reflection coefficient, the proposed design is studied and analyzed. Additionally, a time-domain signal analysis between two antennas as transmitter and receiver was carried out to mimic wearable device real-time communication. A 3D modeling and analysis of a flexible 5G antenna for communication in the arm to assess its basic electromagnetic properties is introduced. Also the design was used with abdomen in order to replicate actual biological settings, detect and track tumor growth and dissemination throughout the body. The simulation results showed that the antenna shows simulated sensitivity to tumor-induced dielectric changes, particularly in its advanced stages.
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The invention in this patent application relates to 2-amino-7-aza-quinoline derivatives represented herein by formula 1. These compounds are inhibitors of the enhancer of zeste homologue 2 (EZH2), and may potentially provide useful treatment for a disease or condition mediated by EZH2 and PRC2-EZH2 complex such as breast cancer, prostate cancer, hepatocellular carcinoma and possibly other cancers.
Building on prior development work, the objective of this study of health care utilization of all Weill Cornell Medicine health insurance beneficiaries over a six-year period was to demonstrate the validity of the Charlson Comorbidity Health Analytics (CCHA), a summed weighted measure of 38 chronic conditions in adults and children, that prospectively predict longitudinal risk of hospital admissions, repeated admissions and resultant high cost in populations. The objective of the Charlson Comorbidity Health Analytics (CCHA) is to provide a new foundational framework for population management strategies by identifying the highest risk patients who can then be the focus for interventions designed to reduce unplanned hospitalizations and resultant high costs. All 27,190 Weill Cornell Medicine beneficiaries in the years 2016-2021, that is, employees and their dependents, including spouses/partners and their children, were linked across the years in a de-identified way, and CCHA was calculated from claims data. In addition to basic demographics, data included all outpatient and inpatient claims, including payments for each service over each year, excluding pharmacy. While two pharmaceuticals are part of the CCHA (anticoagulants and anti-psychotics), no data about pharmaceuticals was available for this analysis. First, CCHA from each year 2016-2021 was evaluated cross-sectionally as a predictor of that year's hospitalizations and costs. Second, the CCHA from 2016 beneficiaries who were followed for five years were used to predict longitudinal risk of hospitalizations, repeated hospitalizations, and costs in each of the next five years. Then the CCHA was compared to the CMS Chronic Conditions Warehouse 30 (CCW30) measure. Finally, the CCHA from any given year (2016-2021) was analyzed for its predictive ability over the remaining one to five years of follow-up to predict hospitalizations, repeated hospitalizations, and costs. Of the total 27,190 beneficiaries over the six years, 55.8% were employees (66.2% women with an average age of 40.9 years), and 25.7% children (average age of 6.1 years). The Charlson Comorbidity Health Analytics (CCHA) score from an index year longitudinally predicts the risk of hospitalizations--including repeated hospitalizations--which drive healthcare costsover six years (p < .01), providing the foundation for interventions in the highest risk patients. Moreover, the 2016 CCHA was a more significant predictor of readmission in 2017-2021 than a 2016 admission. In addition, comorbidity from any index year can be used to predict subsequent admissions and costs; therefore, it works in dynamic populations, like employers and unions that have changes in beneficiaries over time. The Charlson Comorbidity Health Analytics is a method for prospectively identifying the small percent of patients who are at high longitudinal risk for unplanned hospitalizations and high costs. Intervention efforts can then be focused on high-comorbidity patients at high risk [1], with the goal of preventing health deterioration leading to health crises. Comorbidity Health Analytics provides a new foundational framework for population management strategies and specifically for interventions designed to reduce unplanned hospitalizations and thereby reduce costs.
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In embryos, intrinsic and extrinsic signals cooperatively shape cellular decisions to form tissues and organs. Developmental engineering seeks to harness insights into the molecular mechanisms governing embryonic development and leverage pluripotent stem cells to enable the synthetic reconstitution of organ-like multicellular systems in vitro, including organoids. These cellular systems can partially emulate the complexity of in vivo organs in terms of structure and function, facilitating disease modeling and regenerative medicine applications. Nonetheless, the field faces challenges, such as ensuring reproducibility and achieving adult-level maturation. In this Review, we discuss liver development in the human embryo and current models that are routinely used for generating liver organoids in vitro as well as their limitations. Next, we discuss how synthetic biology and computational analyses can be integrated to enhance organoids, particularly liver organoids, by promoting vascularization, establishing zonation, refining fate specification and enabling responsiveness to external cues. Together, these approaches pave the way for next-generation multicellular human stem cell-derived systems.
The ternary complex, composed of eIF2, GTP and initiator methionyl-tRNA, delivers the first amino acid to the ribosome to initiate protein synthesis. Eukaryotic initiation factor 2B (eIF2B) catalyzes GDP to GTP exchange on eIF2, thereby setting the ternary complex level. Stress-induced phosphorylation converts eIF2 from the substrate of eIF2B into an inhibitor (eIF2-P). This conversion reduces ternary complex levels and induces the integrated stress response (ISR). Here we chart an allosteric axis running through eIF2B, revealing the importance of an α-helix in its β-subunit, the 'latch-helix', that hooks onto the α-subunit to induce eIF2B activity. eIF2-P binding promotes latch-helix unhooking, opening eIF2B, which inhibits its activity. Convergently evolved viral proteins stabilize this latch-helix-binding active state of eIF2B. Using these insights, we generated ISR-activating compounds that stabilize eIF2B in its inhibited, unlatched state. Our study thus highlights how long-range eIF2B allostery can be pharmacologically manipulated to sustain or attenuate the ISR.
Nanoprecipitation is a widely used and highly effective method for synthesizing polymer nanoparticles, especially in pharmaceutical and biomedical applications, due to its reproducibility and ease of use. However, controlling the nanoparticle yield, size, size distribution, and surface charge remains a significant challenge. To overcome these challenges and optimize the nanoprecipitation method, it is critical to understand the effects of process parameters on the yield and physicochemical properties of nanoparticles. To address these challenges, we systematically investigated five critical process parameters: surfactant (Pluronic F-127) concentration, stirring speed, solvent evaporation duration, organic-phase flow rate, and ultrasonication time. These parameters were optimized to enhance the yield of poly-(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles while maintaining controlled physicochemical properties. Twenty different process conditions were evaluated for the yield, hydrodynamic size, polydispersity index (PDI), and ζ-potentials. Further, empirical modeling using a nonlinear polynomial fit was performed to fit the reaction yield and physicochemical properties. Empirical second- and third-order polynomial models described (R 2 > 0.90 for most parameters) the process parameter response relationships with the reaction yield, size, PDI, and ζ-potential sufficiently well. Finally, we identified that process condition PC10 (7.5 h solvent evaporation, 1500 rpm stirring speed, 0.01 g/mL Pluronic F-127 (PF-127), 0.3 mL/min organic-phase flow rate, no ultrasonication) achieved a yield of 90.35%, a 9-fold improvement over the conventional method (10.06 ± 0.67%). This work provides a quantitative framework for rational PLGA nanoparticle production, enabling high-yield, monodisperse, and stable formulations, and supporting future translational pipelines.
The landscape of in vitro models has evolved from simple two dimensional (2D) cultures to three-dimensional (3D) organoids and multi-organ microphysiological systems. Early monolayer cultures enabled directed differentiation but provided limited physiological relevance. The development of organoid technology is a significant invention, which allows the cells to self-organize into complex 3D structures to recapitulate the cell diversity, architecture and functions of natural tissues. This has enabled more effective modelling of patient-specific diseases and processes. The latest development of the multi-organ microphysiological systems, integrates organoids or engineered tissues with microfluidic channels through which nutrients are perfused, and blood flow as well as mechanical stimuli are mimicked. This technology provides precise control over the tissue microenvironment to facilitate dynamic cell interactions and communication among different tissue types. These platforms more precisely mimic human biological processes, thereby improving disease modelling, drug screening, and the development of tissue grafts for regenerative therapies. This review discusses the evolution from 2D monolayer cell cultures, through the formation of organoids, to the engineering of organ-on-a-chip systems. It underlines how these technologies have advanced regenerative therapies by enhancing the ability to repair or replace damaged tissues and precision medicine through the creation of patient-specific disease models and personalized treatment strategies. Importantly, this review provides a comparative critical assessment of the functional capabilities, limitations, and translational readiness of each platform, identifying the specific contexts in which each system excels or falls short of its alternatives.
The invention in this patent application relates to 1H-indazole derivatives represented herein by formula 1. These compounds are inhibitors of hyperpolarization activated cyclic-nucleotide (HCN) modulated ion channel activity, with a selectivity for the inhibition of HCN1/HCN2 isoforms over the HCN4 isoform. The compounds may provide methods for treating, inhibiting, or ameliorating inflammatory and/or neuropathic pain, CNS disorders, psychiatric disorders, mood disorders, and tinnitus.
Shifts reflect the maturation of institutions surrounding science.
The acute hepatic venous pressure gradient (HVPG)-response to i.v. propranolol predicts outcomes in patients with advanced chronic liver disease (ACLD) and clinically significant portal hypertension (CSPH). While non-invasive tests (NIT) to monitor non-selective beta-blocker (NSBB)-induced HVPG changes are lacking, spleen stiffness measurement (SSM) has shown promising results as a surrogate for HVPG. This study aimed to assess the correlation between changes in SSM at 100 Hz and HVPG upon acute i.v. propranolol. ACLD patients with CSPH undergoing paired HVPG and SSM-100 Hz assessments pre- and post-i.v. propranolol (0.15 mg/kg) at three expert centres between 2019 and 2024 were included. HVPG-response was defined as a ≥ 10% decrease in HVPG. Ninety-four patients (63.8% males, median age 57.5 [Q1-Q3: 50.0-65.0] years, BMI 26.6 [22.8-31.1] kg/m2) were included. Most had alcohol-related liver disease (ALD)/metabolic-associated liver disease (59.6%) or metabolic-associated steatotic liver disease (11.7%). The median HVPG decreased from 17 (Q1-Q3: 15-20) mmHg to 16 (Q1-Q3: 12-19) mmHg post-NSBB (p < 0.001), with 45.7% achieving an acute HVPG-response. SSM decreased by -8.7 ([Q1-Q3: -19.2; -0.2] kPa, p < 0.001). HVPG-responders had a significant SSM decrease (-12.4 [Q1-Q3: -26.3; -5.6] kPa, p < 0.001), while non-responders showed no change. A moderate correlation between relative changes in SSM and HVPG was observed (Spearman's ρ: 0.387; p < 0.001). Relative change in SSM achieved an area under the receiver operating characteristic curve (AUROC) of 0.717 (95% CI: 0.614-0.820, p < 0.001) for diagnosing HVPG-response. SSM-100 Hz dynamics are associated with HVPG changes upon i.v. propranolol administration. Although the discriminative ability of changes in SSM was insufficient for clinical use, they may serve as a surrogate of efficacy in clinical trials investigating medical therapies for portal hypertension. In advanced chronic liver disease, the hepatic venous pressure gradient (HVPG) response is a key determinant of treatment efficacy, but its assessment currently requires an invasive procedure. Spleen stiffness measurement is a promising non‐invasive alternative and was shown in this study to be associated with changes in portal pressure and treatment response. However, its accuracy is insufficient to replace HVPG measurement in routine clinical practice, although it may still be useful in clinical trials or under standardised conditions.
Cervical cancer screening using cervical Papanicolaou (Pap) smears has been well established since the mid-20th century. Specimen adequacy is considered the most relevant quality assurance component since the invention of the Bethesda system for reporting cervical cytology. Cervical smears that are reported as unsatisfactory (US) can significantly delay diagnosis and increase the risk of cancer in follow-up tests. They also lead to unnecessary use of resources. The cases signed out as US for one and half year duration in the cytology laboratory were retrieved, and demographic details were collected. Among the 4,139 Pap tests accepted and reported for the period, 240 (5.8%) were signed out as US. The ratio of conventional to ThinPrep smears was 2.4:1. 70% cases were conventional Pap smears. 66% (159/ 240) cases of the patients were in the fourth and fifth decade age group. Low squamous cellularity was the most common cause (80%) of US smears, obscured by inflammation (12%); other causes were obscuration by blood (0.8%) and mucus (0.4%), drying artifacts (1.6%) and cytolysis (0.4%). US smears largely depend on various factors, that is, the expertise of the person taking a sample, the date of collection in the menstrual cycle, the method of sampling, sampling devices and staining procedures. The variability in sample collection, including occasional collection by personnel with inadequate training, may also have contributed to the US smears. The result of our study is expected to have a significant impact on proper sampling and the use of adequate quality control measures. In addition, through our follow-up data, we could emphasize the importance of follow-up and human papilloma virus co-testing in patients with US smears.
Spinocerebellar ataxia type 27B is a recently described autosomal dominant, late-onset cerebellar ataxia caused by an intronic GAA repeat expansion in the fibroblast growth factor 14 (FGF14) gene. Despite being recognized as a frequent adult-onset ataxia, its full clinical spectrum remains incompletely understood. To characterize the neurological, cognitive, and paraclinical phenotype of patients with heterozygous FGF14 repeat expansions (>200) and expand the currently known motor and non-motor features, as well as to assess the co-occurrence of other repeat expansions. In this cross-sectional single-center study, patients with heterozygous FGF14 repeat expansions underwent standardized neurological examination and cognitive screening. Paraclinical data were reviewed when available. 18 patients were included in the study (mean age at onset: 64 [37-79], at examination: 76 [61-94]). They all presented with gait ataxia, most commonly a lateral veering gait with corrective sidesteps. In addition to the core known cerebellar phenotype, we identified other movement-disorder manifestations, including myokymia, myoclonus, dystonia, and parkinsonism, with nigrostriatal degeneration confirmed in one patient. Cognitive impairment was common, with two-thirds of patients fulfilling criteria for cerebellar cognitive-affective syndrome (mean MoCA: 25 [21-29], CCAS: 86.9/120 [62-108]). Worse CCAS and MoCA performance was associated with increasing ataxia severity. FGF14 repeat expansions ranged from 210 to 520, and co-occurrence with heterozygous expansions in RFC1 or ATXN8/ATXN8OS were identified in three patients. Earlier diagnostic misclassification as transient ischemic attack was reported in 33%. These findings expand the known phenotype of spinocerebellar ataxia type 27B, emphasizing it as a multisystem movement disorder.
The invention in this patent application relates to thieno-and thiazolo-pyrimidinone derivatives. These compounds possess activities as inhibitors of NADPH-oxidase 4 (NOX4), and may potentially be useful for the treatment of diseases associated with the modulation of NOX4 such as idiopathic pulmonary disease, fibrotic diseases, allergic and inflammatory diseases, as well as cancer.
Since the invention of the polymerase chain reaction (PCR) in 1985, the technology has evolved from qualitative PCR to real-time fluorescent quantitative PCR (qPCR) and ultimately to digital PCR (dPCR). Notably, dPCR based on wettable substrates has attracted considerable attention and application owing to its advantages, which include automated droplet manipulation, low reagent consumption, minimal cross-contamination, and the capability for absolute nucleic acid quantification. In this review, we trace the history of PCR, with a focus on digital nucleic acid detection technologies. Subsequently, we discuss the three strategic approaches for engineering wettable substrates: surface roughening, surface modification, and surface patterning. Additionally, the application of this technology in biomedicine is introduced. Finally, we summarize the challenges facing this technology and outline future directions in materials innovation, artificial intelligence (AI)-assisted analysis, and the development of portable point-of-care testing (POCT) platforms.
This article examines the effects of recognising the rights of the Mar Menor by questioning the traditional concept of efficacy. Having become the first European natural entity to be recognised as a legal entity in&#160;2022, the Spanish lagoon of Mar Menor would seem to be an ideal case study for empirically assessing the efficacy of Rights of Nature in Europe. However, field research suggests that the rights of the Mar Menor have effects that go beyond legal efficacy. Drawing on the concept of creolisation theorised by &#201;douard Glissant, I propose to describe the rights of the Mar Menor as a European creolisation of the rights of nature. I then develop the concept of fecundity to describe the political inventiveness of a law that invites the creation of new institutions for political deliberation on the future of the living community. Cet article &#233;tudie les effets de la reconnaissance des droits de la Mar Menor en questionnant le concept traditionnel d&#8217;efficacit&#233;. Devenue en&#160;2022&#160;la premi&#232;re entit&#233; naturelle europ&#233;enne reconnue comme sujet de droit, la lagune espagnole de la Mar Menor pourrait sembler un terrain id&#233;al afin d&#8217;&#233;valuer empiriquement l&#8217;efficacit&#233;, en Europe, des droits de la nature. Les enqu&#234;tes men&#233;es sur le terrain sugg&#232;rent toutefois que les droits de la Mar Menor ont des effets qui d&#233;passent le cadre de l&#8217;efficacit&#233; juridique. &#192; partir du concept de cr&#233;olisation th&#233;oris&#233; par &#201;douard Glissant, je propose de d&#233;crire les droits de la Mar Menor comme une cr&#233;olisation europ&#233;enne des droits de la nature. Je d&#233;veloppe ensuite le concept de f&#233;condit&#233; pour d&#233;crire l&#8217;inventivit&#233; politique d&#8217;une loi qui invite &#224; cr&#233;er de nouvelles institutions pour d&#233;lib&#233;rer politiquement de l&#8217;avenir du milieu de vie.
Succinate dehydrogenase inhibitors (SDHIs) are widely used worldwide for their broad-spectrum antifungal activity. Structural optimization of natural products offers a viable route to novel SDHI skeletons. Herein, a series of coumarin hydrazone derivatives were designed and synthesized by a scaffold splicing strategy. Compound 3p showed 100% antifungal activity against Rhizoctonia solani at 50 μg/mL, with an EC50 of 1.16 μg/mL. On rice leaves, 3p achieved 98.4% preventive efficacy against R. solani, outperforming Boscalid (69.6%) at the same concentration. Furthermore, it caused hyphal distortion and mitochondrial damage, similar to boscalid. Enzymatic assays confirmed 3p as an SDHI with an IC50 of 8.69 μM, and molecular docking indicated stable binding within the SDH active site. ATP analysis revealed intracellular levels were reduced to 72% in 3p-treated mycelia compared to controls. Therefore, compound 3p is a promising leader for developing novel SDH inhibitors.