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Glioblastoma multiforme (GBM) progression is associated with changes in matrix stiffness, and different regions of the tumor niche exhibit distinct stiffnesses. Using elastic hydrogels, previous work has demonstrated that matrix stiffness modulates GBM behavior and drug responses. However, brain tissue is viscoelastic, and how stiffness impacts the GBM invasive phenotype and response to therapy within a viscoelastic niche remains largely unclear. Here, we report a three-dimensional (3D) viscoelastic GBM hydrogel system that models the stiffness heterogeneity present within the tumor niche. We find that GBM cells exhibit enhanced migratory ability, proliferation, and resistance to radiation in soft matrices, mimicking the tumor core and perifocal margins. Conversely, GBM cells remain confined and demonstrate increased resistance to chemotherapy in stiff matrices mimicking edematous tumor regions. We identify that stiffness-induced changes in the GBM phenotype are regulated by nuclear mechanosensing and chromatin condensation. Pharmacologically decondensing the chromatin significantly impedes GBM migration and overcomes stiffness-induced chemoresistance and radioresistance. Our findings highlight that stiffness regulates aggressive GBM behavior in viscoelastic matrices through mechanotransduction processes. Finally, we reveal the critical role of chromatin condensation in mediating GBM migration and therapy resistance, offering a potential new therapeutic target to improve GBM treatment outcomes.

The quantum Cramér-Rao bound (QCRB) stands as a cornerstone of quantum metrology. Yet, akin to its classical counterpart, it provides only local information and overlooks higher-order details. We leverage the theory of higher-order asymptotics to circumvent these issues, providing corrections to the performance of estimators beyond the QCRB. While the QCRB often yields a whole family of optimal states and several optimal measurements, our approach allows us to identify optimal states and measurements within the family that are otherwise equivalent according to the QCRB alone; these are requisite for optimal metrology before reaching the asymptotic limit. These results are especially pertinent when dealing with unitary processes.

Introduction: Cervical dysplasia is a precursor lesion of cervical cancer, one of the leading causes of morbidity and mortality in women, especially in developing countries. This study aimed to identify the risk factors associated with the development of cervical dysplasia in women treated at the Santa María del Socorro Hospital in Ica, Peru, between 2017 and 2019., Methods: An observational case-control study was conducted with 92 cases of women with confirmed high-grade intraepithelial lesion and 184 controls with consecutive negative results in Pap smears. Sociodemographic, behavioral, and clinical data were collected. Bivariate and multivariate logistic regression analyses were performed to identify factors associated with precancerous cervical lesions., Results: The factors significantly associated with cervical dysplasia were age under 35 years (odds ratio: 1.2; 95% confidence interval: 0.1 to 0.7), having a partner (7.4; 2.3 to 23.5), body mass index ≥ 25 (12.9; 3.9 to 42.0), more than three sexual partners (71.4; 16.4 to 310.9), bacterial vaginosis (101.2; 12.2 to 838.2), grand multiparity (39.0; 7.1 to 225.4), rural origin (0.2; 0.1 to 0.8), use of injectables (0.2; 0.1 to 0.6), and intrauterine devide (0.04; 0.01 to 0.2)., Conclusions: Identifying these risk factors is crucial for cervical cancer prevention. It is recommended to implement early detection programs targeted at women with risk factors, especially those under 35 years and with multiple sexual partners., Competing Interests: All authors declare no competing interests., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

The literature on health care disparities among U.S. minority men remains limited, and post-pandemic changes in the health care delivery system may uniquely affect this population. We assessed the factors influencing California-based minority men's compliance with routine health checkup. An IRB-approved survey was conducted electronically by convenience sampling between October 2022 and July 2023. Data was collected on demographics, socioeconomic status, health insurance, and routine checkup attendance. Health insurance literacy was assessed by self-reported ability to locate insurance-covered clinics and health care information. The data was analyzed using random forest modeling with both feature importance and SHAP values for interpretability, and logistic regression analysis. A total of 266 male respondents participated. Of these, 60.5% were under 30 years old, and 66.9% identified as Latino/Hispanic.The majority were employed (82.7%), insured (84.9%), and earned less than $50,000 annually (64.5%). While 71.8% were connected to a clinic or hospital, only 50.8% attended routine health checkup, and 6.8% had visited a doctor in the past year. Key factors influencing compliance included zip code, connection to a clinic and the ability to locate a clinic covered by insurance. These findings highlight that half of insured minority men in California under 60 years of age are not attending routine checkups, suggesting significant barriers related to accessibility and health insurance literacy. Addressing these disparities could improve health care utilization and outcomes in this population., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Quantum entanglement describes superposition states in multi-dimensional systems-at least two partite-which cannot be factorized and are thus non-separable. Non-separable states also exist in classical theories involving vector spaces. In both cases, it is possible to violate a Bell-like inequality. This has led to controversial discussions, which we resolve by identifying an operational distinction between the classical and quantum cases.This article is part of the theme issue 'The quantum theory of light'.

Background and Purpose: Ultra-high dose-rate radiotherapy (FLASH) has been shown to mitigate normal tissue toxicities associated with conventional dose rate radiotherapy (CONV) without compromising tumor killing in preclinical models. A prominent challenge in preclinical radiation research, including FLASH, is validating both the physical dosimetry and the biological effects across multiple institutions., Materials and Methods: We previously demonstrated dosimetric reproducibility of two different electron FLASH devices at separate institutions using standardized phantoms and dosimeters. In this study, tumor-free adult female mice were given 10 Gy whole brain FLASH and CONV irradiation at both institutions and evaluated for the reproducibility and temporal evolution of multiple neurobiological endpoints., Results: FLASH sparing of behavioral performance on novel object recognition (4 months post-irradiation) and of electrophysiologic long-term potentiation (LTP, 5 months post-irradiation) was reproduced between institutions. Differences between FLASH and CONV on the endpoints of hippocampal neurogenesis (Sox2, doublecortin), neuroinflammation (microglial activation), and electrophysiology (LTP) were not observed at early times (48 h to 2 weeks), but recovery of immature neurons by 3 weeks was greater with FLASH., Conclusion: In summary, we demonstrated reproducible FLASH sparing effects on the brain between two different beams at two different institutions with validated dosimetry. FLASH sparing effects on the endpoints evaluated manifested at later but not the earliest time points., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Halobacterium sp. strain NMX12-1, an extremely halophilic Archaeon, was isolated from 250 million-year-old Salado Formation salt crystal in Carlsbad, New Mexico. Single-molecule real-time sequencing revealed a 3.2-Mbp genome with a 2.6-Mbp chromosome and five plasmids (234, 211, 119, 21, and 1.6-kbp). The GC-rich genome encodes an acidic proteome, characteristic of Haloarchaea., Competing Interests: R.J.R. and T.V. work at, and B.P.A. formerly worked for, New England Biolabs, a company that sells research reagents, including restriction enzymes and DNA methyltransferases, to the scientific community. None of the other authors declare any conflict of interest.

We use the recently developed wave model of geometric phase to track the continuous evolution of geometric phase as a wave propagates through optical elements and throughout an optical system. By working directly with the wave properties, we encounter a natural explanation of why the conventional Poincaré sphere solid angle method must use geodesic paths rather than the physical paths of the polarization state-the "geodesic rule"-and show that the existing rules for the solid angle algorithm are incomplete. Finally, we use the physical model to clarify the differences between the Pancharatnam connection and the geometric phase of a wave.

In this document we present two important topics in childhood, one completely new, the promotion of reading in the first years of life, and the other is an update that continues to generate doubts and questions from Parents, caregivers and health professionals: Is it necessary to screen for iron deficiency in children under 5 years of age?, (Copyright © 2024 The Authors. Publicado por Elsevier España S.L.U. All rights reserved.)

This study explores the development of biocompatible scaffolds for bone regeneration, utilizing polylactic acid (PLA) combined with calcium phosphate as a pH buffer and diatomaceous earth as a biocompatibilizer. These materials were extruded and 3D-printed to enhance cell adhesion and biodegradability after enough cell growth. The biocompatibility of the resulting composites, with different proportions of the components and sterilization methods, was tested according to the ISO 10993 protocol. The optimal performance, with nearly zero cytotoxicity, was observed with 20 PLA/1 CP/1 DE mass ratios and gamma sterilization. Tension analysis and scanning electron microscopy (SEM) were applied to the 3D-printed composites, which were also analyzed by differential scanning calorimetry (DSC) to understand the origin of the tension properties better, which were comparable to those of cancellous bone. Degradation tests under physiological conditions for 13 weeks showed no significant mass loss. Furthermore, it was observed that cell adhesion, viability, proliferation, and osteoconduction are possible in the scaffolds studied, opening opportunities for future studies to substantiate the use of 3D-printed silica-filled composites as an alternative to homologous implants for various bone regeneration applications.

Purpose: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with the absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies, which are often adapted from SCLC and non-small cell lung cancer approaches., Experimental Design: To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed IHC and single-cell RNA sequencing of core needle biopsies from patients with LCNEC and preclinical models., Results: In this study, we demonstrate that the presence or absence of YAP1 distinguishes two subsets of LCNEC. The YAP1-high subset is mesenchymal and inflamed and is characterized, alongside TP53 mutations, by co-occurring alterations in CDKN2A/B and SMARCA4. Therapeutically, the YAP1-high subset demonstrates vulnerability to MEK- and AXL-targeting strategies, including a novel preclinical AXL chimeric antigen receptor-expressing T cell. Meanwhile, the YAP1-low subset is epithelial and immune-cold and more commonly features TP53 and RB1 co-mutations, similar to those observed in pure SCLC. Notably, the YAP1-low subset is also characterized by the expression of SCLC subtype-defining transcription factors, especially ASCL1 and NEUROD1, and as expected, given its transcriptional similarities to SCLC, exhibits putative vulnerabilities reminiscent of SCLC, including delta-like ligand 3 and CD56 targeting, as is with novel preclinical delta-like ligand 3 and CD56 chimeric antigen receptor-expressing T cells, and DNA damage repair inhibition., Conclusions: YAP1 defines distinct subsets of LCNEC with unique biology. These findings highlight the potential for YAP1 to guide personalized treatment strategies for LCNEC., (©2024 American Association for Cancer Research.)

Purpose: The National Institute of Health Toolbox Cognition Battery (NIHTB-CB) is increasingly used in Alzheimer disease (AD) research. We examined the relation of AD biomarkers with performance in the NIHTB-CB in late middle age., Methods: This is a cross-sectional analysis of 334 Hispanic participants aged 64.22±3.35 years from a study of AD biomarkers. White matter hyperintensities (WMH), infarcts, and cortical thickness in AD regions (CT) were assessed with 3T magnetic resonance imaging. Amyloid and tau were assessed with 18F-Florbetaben and 18F-MK6240 positron emission tomography, respectively., Results: Lower CT and infarcts were associated with worse Oral Reading Recognition and Cognition Crystallized Composite scores. Lower CT and higher WMH were associated with worse Pattern Comparison Processing Speed. Amyloid and tau were not associated with any test., Discussion: Amyloid and tau, the culprits of AD, are not related to the NIHTB-CB in late middle age. Continued follow-up will reveal if AD impacts performance on the NIHTB-CB., Competing Interests: J.A.L. receives a stipend from Wolters Kluwer. N.V. is Editor in Chief of the journal Alzheimer Disease and Associated Disorders and has served as a paid consultant to vTv Therapeutics Inc. and Recruitment Partners. K.W. has a consulting agreement with Cerveau Technologies. Cerveau Technologies provided a standard and precursor for 18F-MK-6240; however, Cerveau was not involved in the design or interpretation of study results. A.M.B. received consulting/advisory fees from Cognition Therapeutics, Cognito Therapeutics, and CogState. He is a Section Editor of Alzheimer & Dementia. The remaining authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In psychotherapy, physical exercise has gained recognition and extensive research attention, displaying promise in various mental health conditions. Practices such as yoga, tai chi, and the Feldenkrais Method® (FM) have also emerged as effective mental health interventions., Objectives: This systematic literature review (SLR) explores the applicability of FM, a somatic practice, in psychiatric care and emotional regulation, as it emphasizes the interplay between bodily sensations, action patterns, and cognitive processes., Methods: Following PRISMA guidelines, a systematic search was conducted across selected databases from 2000 to 2022, identifying 14 articles, including randomized controlled trials, cohort studies, narrative papers, and SLRs. Thematic analysis was conducted., Results: The findings indicate global FM adoption, primarily in studies related to pain conditions, musculoskeletal disorders, and neurological disorders. Various measures were used, covering quality of life, psychological dimensions, self-image, self-efficacy, mindfulness, and interoception. However, direct application of FM in psychiatric care remains limited, with few studies addressing psychological issues. This review calls for more comprehensive investigations of FM's potential in psychiatric contexts, advocating precise measures and a dimensional approach to assessing psychological outcomes., Conclusion: Further research is needed to explore the application of FM in psychiatric care. While existing research suggests potential benefits, especially in enhancing body awareness and emotional regulation, robust studies are necessary to establish its effectiveness in treating specific mental health conditions. This review serves as the foundation for future research into the potential role of FM in enhancing psychiatric care and emotional well-being., Competing Interests: Declaration of Competing Interest Authors declare none., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In this research, we aimed to determine the antioxidant activity of an atomized extract of Cnidoscolus diacanthus (Pax & K. Hoffm.) J.F. Macbr., known in Peru as "huanarpo hembra", and its effect on sex hormone levels. Its phytochemical profile was determined using liquid chromatography-mass spectrometry (LC-MS), while its total phenol content (TPC) and total flavonoids (TFs) were determined using the Folin-Ciocalteu method and the aluminum chloride method. Its antioxidant activity was determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH), the radical 2,2-azino-bis-3-ethylbenzthiazolin-6 sulfonic acid (ABTS), and ferric-reducing antioxidant power (FRAP). The biological activity of C. diacanthus and its effect on sexual hormones were determined in Holtzman rats of both sexes. Phytochemical analysis revealed the presence of flavonoids and phenolic compounds in its leaves and stems, mainly rutin, quercetin, chlorogenic acid, and genistein. However, the stem extract contained higher total phenol (464.38 ± 4.40 GAE/g) and flavonoid (369.17 ± 3.16 mg QE/g of extract) contents than the leaf extract (212.38 ± 3.19 mg GAE/g and 121.49 ± 2.69 mg QE/g). For DPPH, ABTS, and FRAP, the Trolox-equivalent antioxidant capacity (TEAC) was 597.20 ± 5.40 µmol/g, 452.67 ± 5.76 µmol/g, and 535.91 ± 1.56 µmol/g, respectively, for the stems, while for the leaves, it was 462.39 ± 3.99 µmol/g, 202.32 ± 5.20 µmol/g, and 198.13 ± 1.44 µmol/g, respectively. In terms of the values for hormonal levels, at a dose of 100 mg/kg of the extract, testosterone levels of 1.430 ng/mL (with the leaf extract) and 1.433 ng/mL (with the stem extract), respectively, were found in the male rats. Regarding estradiol levels, in the female rats, these were 10.425 ng/mL (leaf extract) and 8.775 ng/mL (stem extract), while their levels of luteinizing hormone were 0.320 mIU/mL (leaf extract) and 0.273 mIU/mL (stem extract). For the follicle-stimulating hormone, levels of 0.858 mIU/mL (leaf extract) and 0.840 mIU/mL (stem extract) were found in the female rats, and levels of 0.220 mIU/mL (leaf extract) and 0.200 mIU/mL (stem extract) were found in the male rats. It is concluded that the C. diacanthus stem extract had a greater antioxidant capacity than the leaf extract, while both extracts had a superior effect on the sex hormone levels in the female rats compared to the male rats.

This paper examines the construct validity of the spiritual leadership model proposed by (Fry et al. 2005). The analysis focused on examining the relationships proposed by the model through CFA and structural equation modeling (SEM). A confirmatory factor analysis indicated the SL scale provides acceptable reliability and convergent validity indexes; however, it did not achieve discriminant validity. Model convergence was obtained using MLR (Robust Maximum Likelihood) methods. However, when the robustness indices were analyzed, it was found that some obtained acceptable results and others were deficient, so that an acceptable model fit was not achieved. Regarding the relationship between the hypotheses, it was found that they were significant in all cases except for the reciprocal relationship between vision and altruistic love. In light of this finding, alternative models were developed that also failed to yield significant results. The theoretical and methodological discussion focuses on the relationships of Fry's model and addresses the need to review its causal nature, considering recursive and non-recursive aspects., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Martinez-Soto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Resource islands are vegetative formations in arid and semi-arid ecosystems that harbor microorganisms facing extreme conditions. However, there is a limitation in the knowledge of the agricultural biotechnological potential of microorganisms present in these islands. This study aimed to determine the capacity of Bacillus velezensis C3-3 and Cytobacillus sp. T106 isolates from resource islands to promote plant growth and control the phytopathogen Rhizoctonia solani. The bacteria were sequenced, and both grew at 50 °C, resisted 5% NaCl, withstood UV exposure, and grew in extreme pH conditions. Sixty-six genes in C3-3 and 71 in T106 were identified associated with plant growth promotion, and C3-3 was shown to promote leaf growth in lettuce plants. This promotional effect was associated with the production of indole-3-acetic acid (IAA), phosphorus solubilization, and the presence of genes related to the assimilation of rhizosphere exudates. Both strains inhibited R. solani through the production of volatile compounds and antagonism. Forty-five and 40 of these genes in C3-3 and T106, respectively, were associated with the production of proteases, lipases, siderophores, antimicrobial compounds, degradation enzymes, and secretion systems. Notably, Cytobacillus sp. has not been previously reported as a biocontrol agent. This work contributes to the evidence of the biotechnological potential of semi-arid region bacteria, offering prospects for improving agricultural production in areas with limiting conditions., (© 2024. The Author(s).)

Plasma focus devices represent a class of hot and dense plasma sources that serve a dual role in fundamental plasma research and practical applications. These devices allow the observation of various phenomena, including the z-pinch effect, nuclear fusion reactions, plasma filaments, bursts, shocks, jets, X-rays, neutron pulses, ions, and electron beams. In recent years, considerable efforts have been directed toward miniaturizing plasma focus devices, driven by the pursuit of both basic studies and technological advancements. In this paper, we present the design and construction of a compact, portable pulsed plasma source based on plasma focus technology, operating at the ~2-4 Joule energy range for versatile applications (PF-2J: 120 nF capacitance, 6-9 kV charging voltage, 40 nH inductance, 2.16-4.86 J stored energy, and 10-15 kA maximum current at short circuit). The components of the device, including capacitors, spark gaps, discharge chambers, and power supplies, are transportable within hand luggage. The electrical characteristics of the discharge were thoroughly characterized using voltage and current derivative monitoring techniques. A peak current of 15 kiloamperes was achieved within 110 nanoseconds in a short-circuit configuration at a 9 kV charging voltage. Plasma dynamics were captured through optical refractive diagnostics employing a pulsed Nd-YAG laser with a 170-picosecond pulse duration. Clear evidence of the z-pinch effect was observed during discharges in a deuterium atmosphere at 4 millibars and 6 kilovolts. The measured pinch length and radius were approximately 0.8 mm and less than 100 μm, respectively. Additionally, we explore the potential applications of this compact pulsed plasma source. These include its use as a plasma shock irradiation device for analyzing materials intended for the first wall of nuclear fusion reactors, its capability in material film deposition, and its utility as an educational tool in experimental plasma physics. We also show its potential as a pulsed plasma thruster for nanosatellites, showcasing the advantages of miniaturized plasma focus technology.

Purpose: We conducted a multi-institutional dosimetric audit between FLASH and conventional dose rate (CONV) electron irradiations by using an anatomically realistic 3-dimensional (3D) printed mouse phantom., Methods and Materials: A computed tomography (CT) scan of a live mouse was used to create a 3D model of bony anatomy, lungs, and soft tissue. A dual-nozzle 3D printer was used to print the mouse phantom using acrylonitrile butadiene styrene (∼1.02 g/cm 3 ) and polylactic acid (∼1.24 g/cm 3 ) simultaneously to simulate soft tissue and bone densities, respectively. The lungs were printed separately using lightweight polylactic acid (∼0.64 g/cm 3 ). Hounsfield units (HU), densities, and print-to-print stability of the phantoms were assessed. Three institutions were each provided a phantom and each institution performed 2 replicates of irradiations at selected anatomic regions. The average dose difference between FLASH and CONV dose distributions and deviation from the prescribed dose were measured with radiochromic film., Results: Compared with the reference CT scan, CT scans of the phantom demonstrated mass density differences of 0.10 g/cm 3 for bone, 0.12 g/cm 3 for lung, and 0.03 g/cm 3 for soft tissue regions. Differences in HU between phantoms were <10 HU for soft tissue and bone, with lung showing the most variation (54 HU), but with minimal effect on dose distribution (<0.5%). Mean differences between FLASH and CONV decreased from the first to the second replicate (4.3%-1.2%), and differences from the prescribed dose decreased for both CONV (3.6%-2.5%) and FLASH (6.4%-2.7%). Total dose accuracy suggests consistent pulse dose and pulse number, although these were not specifically assessed. Positioning variability was observed, likely due to the absence of robust positioning aids or image guidance., Conclusions: This study marks the first dosimetric audit for FLASH using a nonhomogeneous phantom, challenging conventional calibration practices reliant on homogeneous phantoms. The comparison protocol offers a framework for credentialing multi-institutional studies in FLASH preclinical research to enhance reproducibility of biologic findings., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is a prototypical autoimmune disease of the central nervous system (CNS). In addition to CD4 + T cells, memory B cells are now recognized as a critical cell type in the disease. This is underlined by the fact that the best-characterized environmental risk factor for MS is the Epstein-Barr virus (EBV), which can infect and persist in memory B cells throughout life. Several studies have identified changes in anti-EBV immunity in patients with MS. Examples include elevated titers of anti-EBV nuclear antigen 1 (EBNA1) antibodies, interactions of these with the MS-associated HLA-DR15 haplotype, and molecular mimicry with MS autoantigens like myelin basic protein (MBP), anoctamin-2 (ANO2), glial cell adhesion molecule (GlialCAM), and alpha-crystallin B (CRYAB). In this study, we employ a simple in vitro assay to examine the memory B cell antibody repertoire in MS patients and healthy controls. We replicate previous serological data from MS patients demonstrating an increased secretion of anti-EBNA1 380-641 IgG in cell culture supernatants, as well as a positive correlation of these levels with autoantibodies against GlialCAM 262-416 and ANO2 1-275 . For EBNA1 380-641 and ANO2 1-275 , we provide additional evidence suggesting antibody cross-reactivity between the two targets. Further, we show that two efficacious MS treatments - natalizumab (NAT) and autologous hematopoietic stem cell transplantation (aHSCT) - are associated with distinct changes in the EBNA1-directed B cell response and that these alterations can be attributed to the unique mechanisms of action of these therapies. Using an in vitro system, our study confirms MS-associated changes in the anti-EBNA1 memory B cell response, EBNA1 380-641 antibody cross-reactivity with ANO2 1-275, and reveals treatment-associated changes in the immunoglobulin repertoire in MS., Competing Interests: Authors ZM and RM were employed by company Cellerys. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Marti, Ruder, Thomas, Bronge, De La Parra Soto, Grönlund, Olsson and Martin.)

Purpose: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed., Experimental Design: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI)., Results: Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%-123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%-80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib., Conclusions: Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Microbes found in soil can have a significant impact on the taste and quality of wine, also referred to as wine terroir. To date, wine terroir has been thought to be associated with the physical and chemical characteristics of the soil. However, there is a fragmented understanding of the contribution of vineyard soil microbes to wine terroir. Additionally, vineyards can play an important role in carbon sequestration since the promotion of healthy soil and microbial communities directly impacts greenhouse gas emissions in the atmosphere. We review 24 studies that explore the role of soil microbial communities in vineyards and their influence on grapevine health, grape composition, and wine quality. Studies spanning 2015 to 2018 laid a foundation by exploring soil microbial biogeography in vineyards, vineyard management effects, and the reservoir function of soil microbes for grape-associated microbiota. On the other hand, studies spanning 2019 to 2023 appear to have a more specific and targeted approach, delving into the relationships between soil microbes and grape metabolites, the microbial distribution at different soil depths, and microbial influences on wine flavor and composition. Next, we identify research gaps and make recommendations for future work. Specifically, most of the studies utilize targeted sequencing (16S, 26S, ITS), which only reveals community composition. Utilizing high-throughput omics approaches such as shotgun sequencing (to infer function) and transcriptomics (for actual function) is vital to determining the specific mechanisms by which soil microbes influence grape chemistry. Going forward, understanding the long-term effects of vineyard management practices and climate change on soil microbiology, grapevine trunk diseases, and the role of bacteriophages in vineyard soil and wine-making would be a fruitful investigation. Overall, the studies presented shed light on the importance of soil microbiomes and their interactions with grapevines in shaping wine production. However, there are still many aspects of this complex ecosystem that require further exploration and understanding to support sustainable viticulture and enhance wine quality.

Identifying a reasonably small Hilbert space that completely describes an unknown quantum state is crucial for efficient quantum information processing. We introduce a general dimension-certification protocol for both discrete and continuous variables that is fully evidence based, relying solely on the experimental data collected and no other unjustified assumptions whatsoever. Using the Bayesian concept of relative belief, we take the effective dimension of the state as the smallest one such that the posterior probability is larger than the prior, as dictated by the data. The posterior probabilities associated with the relative-belief ratios measure the strength of the evidence provide by these ratios so that we can assess whether there is weak or strong evidence in favor or against a particular dimension. Using experimental data from spectral-temporal and polarimetry measurements, we demonstrate how to correctly assign Bayesian plausible error bars for the obtained effective dimensions. This makes relative belief a conservative and easy-to-use model-selection method for any experiment.

Background: The creation of highly muscled and strong fighters is a recurring theme in human performance enhancement concepts. Physical readiness standards, intended to prevent obesity in the military, produce contradictory objectives, hounding large individuals to lose weight because of confusion between body size and body composition. Through selection, specialised training and policy exceptions the US Marine Corps has successfully developed a unique group of large (body mass index (BMI) >30 kg/m 2 ) and strong individuals, the body bearers (BB) who carry coffins of Marines to their final resting place., Methods: We examined the relationship between adiposity and body size from nine male BB (age 25.0±2.1, height: 1.84±0.04 (1.80-1.92) m, BMI: 33.0±2.1 (30-37) kg/m 2 ). Body composition was assessed by dual-energy X-ray absorptiometry (DXA), bioelectrical impedance (BIA) and tape measured abdominal circumference (AC)-based equations and from three-dimensional scanning (3DS)., Results: Measures were made of fat-free mass (FFM): 90.5±7.0 (82.0-106.7) kg, where FFM included total body water: 62.8±5.0 (55.8-71.8) L, representing 69±2 (67-73) % of FFM, along with calculated FFM index: 26.8±2.4 (24.4-32.9) kg/m 2 ). DXA measures were made for bone mineral content 4.1±0.4 (3.5-4.9) kg, bone mineral density (BMD) 1.56±0.10 (1.37-1.76) g/cm 2 and %BF 19.5±6.6 (9.0-27.8). Additional measures of percent body fat (%BF) were made by AC: 20.3±2.9 (15.2-24.6), BIA: 23.7±6.4 (9.8-29.2) and 3DS: 25.5±4.7 (18.9-32.2). AC %BF reasonably matched DXA %BF, with expected overprediction and underprediction at low and high DXA %BF. BIA %BF was affected by deviations from assumed FFM hydration (72%-73%)., Conclusion: These men are classified as obese by BMI but carried massive amounts of muscle and bone on their large frames, while presenting a range of %BF irrelevant to strength performance. BMI did not predict obesity and adiposity had no association with muscle mass and strength performance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Major antibiotic groups are losing effectiveness due to the uncontrollable spread of antimicrobial resistance (AMR) genes. Among these, β-lactam resistance genes -encoding β-lactamases- stand as the most common resistance mechanism in Enterobacterales due to their frequent association with mobile genetic elements. In this context, novel approaches that counter mobile AMR are urgently needed. Collateral sensitivity (CS) occurs when the acquisition of resistance to one antibiotic increases susceptibility to another antibiotic and can be exploited to eliminate AMR selectively. However, most CS networks described so far emerge as a consequence of chromosomal mutations and cannot be leveraged to tackle mobile AMR. Here, we dissect the CS response elicited by the acquisition of a prevalent antibiotic resistance plasmid to reveal that the expression of the β-lactamase gene bla OXA-48 induces CS to colistin and azithromycin. We next show that other clinically relevant mobile β-lactamases produce similar CS responses in multiple, phylogenetically unrelated E. coli strains. Finally, by combining experiments with surveillance data comprising thousands of antibiotic susceptibility tests, we show that β-lactamase-induced CS is pervasive within Enterobacterales. These results highlight that the physiological side-effects of β-lactamases can be leveraged therapeutically, paving the way for the rational design of specific therapies to block mobile AMR or at least counteract their effects., (© 2024. The Author(s).)

Oyster reefs are invaluable ecosystems that provide a wide array of critical ecosystem services, including water filtration, coastal protection, and habitat provision for various marine species. However, these essential habitats face escalating threats from climate change and anthropogenic stressors. To combat these challenges, numerous oyster restoration initiatives have been undertaken, representing a global effort to preserve and restore these vital ecosystems. A significant, yet poorly understood, component of oyster reefs is the microbial communities. These communities account for a substantial proportion of marine reefs and are pivotal in driving key biogeochemical processes. Particularly, the environmental microbiome plays a crucial role in supporting the health and resilience of oyster populations. In our study, we sought to shed light on the microbiome within oyster reef ecosystems by characterizing the abundance, and diversity of microorganisms in the soil, biofilm, and oysters in 4 sites using a combinatorial approach to identify differentially abundant microbes by sample type and by sampling location. Our investigation revealed distinct microbial taxa in oysters, sediment and biofilm. The maximum Shannon Index indicated a slightly increased diversity in Heron's Head (5.47), followed by Brickyard park (5.35), Dunphy Park (5.17) and Point Pinole (4.85). This is likely to be driven by significantly higher oyster mortality observed at Point Pinole during routine monitoring and restoration efforts. Interestingly Ruminococcus, Streptococcus, Staphylococcus, Prevotella, Porphyromonas, Parvimonas, Neisseria, Lactococcus, Haemophilus, Fusobacterium, Dorea, Clostridium, Campylobacter, Bacteroides, and Akkermansia were positively associated with the biofilm. Yet we have limited understanding of their beneficial and/or detrimental implications to oyster growth and survival. By unraveling the intricate relationships in microbial composition across an oyster reef, our study contributes to advancing the knowledge needed to support effective oyster reef conservation and restoration efforts., Competing Interests: Conflict of interest: The authors declare no conflict of interest.

Key Clinical Message: An interesting case that shows an infrequent cause of cardiorespiratory arrest such as coronary vasospasm due to intravenous amiodarone induced Kounis syndrome. It highlights the usefulness of circulatory support with ECMO in the scenario of CPR., Abstract: A patient with atrial fibrillation was admitted for an elective electrical cardioversion. He was given an amiodarone bolus that triggered Kounis syndrome with cardiac arrest due to vasospasm requiring emergency coronary angiography with infusion of nitroglycerin. Due to following refractory shock and severe refractory hypoxemia required mechanical circulatory support with ECMO and inhaled nitric oxide with favorable evolution. Allergy to amiodarone was later confirmed., Competing Interests: No relationship with industry., (© 2024 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Antimicrobial resistance (AMR) is one of the biggest threats in modern times. It was estimated that in 2019, 1.27 million deaths occurred around the globe due to AMR. Methicillin-resistant Staphylococcus aureus (MRSA) strains, a pathogen considered of high priority by the World Health Organization, have proven to be resistant to most of the actual antimicrobial treatments. Therefore, new treatments are required to be able to manage this increasing threat. Under this perspective, an important metabolic pathway for MRSA survival, and absent in mammals, is the shikimate pathway, which is involved in the biosynthesis of chorismate, an intermediate for the synthesis of aromatic amino acids, folates, and ubiquinone. Therefore, the enzymes of this route have been considered good targets to design novel antibiotics. The fifth step of the route is performed by shikimate kinase (SK). In this study, an in-house chemical library of 170 benzimidazole derivatives was screened against MRSA shikimate kinase (SaSK). This effort led to the identification of the first SaSK inhibitors, and the two inhibitors with the greatest inhibition activity ( C1 and C2 ) were characterized. Kinetic studies showed that both compounds were competitive inhibitors with respect to ATP and non-competitive for shikimate. Structural analysis through molecular docking and molecular dynamics simulations indicated that both inhibitors interacted with ARG113, an important residue involved in ATP binding, and formed stable complexes during the simulation period. Biological activity evaluation showed that both compounds were able to inhibit the growth of a MRSA strain. Mitochondrial assays showed that both compounds modify the activity of electron transport chain complexes. Finally, ADMETox predictions suggested that, in general, C1 and C2 can be considered as potential drug candidates. Therefore, the benzimidazole derivatives reported here are the first SaSK inhibitors, representing a promising scaffold and a guide to design new drugs against MRSA.

Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive and fatal pediatric brain cancer. One pre-requisite for tumor cells to infiltrate is adhesion to extracellular matrix (ECM) components. However, it remains largely unknown which ECM proteins are critical in enabling DIPG adhesion and migration and which integrin receptors mediate these processes. Here, we identify laminin as a key ECM protein that supports robust DIPG cell adhesion and migration. To study DIPG infiltration, we developed a DIPG-neural assembloid model, which is composed of a DIPG spheroid fused to a human induced pluripotent stem cell-derived neural organoid. Using this assembloid model, we demonstrate that knockdown of laminin-associated integrins significantly impedes DIPG infiltration. Moreover, laminin-associated integrin knockdown improves DIPG response to radiation and HDAC inhibitor treatment within the DIPG-neural assembloids. These findings reveal the critical role of laminin-associated integrins in mediating DIPG progression and drug response. The results also provide evidence that disrupting integrin receptors may offer a novel therapeutic strategy to enhance DIPG treatment outcomes. Finally, these results establish DIPG-neural assembloid models as a powerful tool to study DIPG disease progression and enable drug discovery., (© 2024. The Author(s).)

The management of proteinuria in patients with lupus nephritis represents a challenge for the specialist. Recently, Calcineurin Inhibitors have been positioned as an effective alternative in these patients, but their use is not widespread in our country. We report the experience of three centers in this regard., Methods: a review of lupus nephritis patients treated with Tacrolimus from 3 centers in southern Chile., Results: Data from 10 patients with Lupus nephritis were obtained. All of them had significant proteinuria after the traditional induction scheme. In most of them, there was a significant decrease in proteinuria without deterioration of creatinine at 12 months after treatment with Tacrolimus alone or in combination with Mycophenolate., Conclusions: Tacrolimus alone or in combination with Mycophenolate is a safe and effective alternative in the management of Lupus nephritis-associated proteinuria.

Abdominal pain has been rarely reported in individuals infected with Toxoplasma gondii (T. gondii). The aim of this study was to determine the association between T. gondii infection and abdominal pain. Two hundred and ninety-nine patients with abdominal pain (cases) and 299 age- and gender-matched people without abdominal pain (controls) were tested for anti-T. gondii IgG and IgM antibodies. Twenty-four (8.0%) of the 299 cases and 12 (4.0%) of the 299 controls were positive for anti-T. gondii IgG antibodies (OR: 2.08; 95% CI: 1.02-4.25; P = 0.03). The seroprevalence of T. gondii infection was significantly higher in women with frequent abdominal pain than in women without this clinical feature (OR: 2.30; 95% CI: 1.06-4.96; P = 0.02). Twelve (4.0%) of the 299 cases and 7 (2.3%) of the 299 controls had high (>150 IU mL-1) anti-T. gondii IgG antibody levels (OR: 1.74; 95% CI: 0.67-4.49; P = 0.24). Seven (29.2%) of the 24 cases with anti-T. gondii IgG antibodies and 3 (25.0%) of the 12 controls with anti-T. gondii IgG antibodies were positive to anti-T. gondii IgM antibodies (OR: 1.23; 95% CI: 0.25-5.97; P = 1.00). Results suggest an association between T. gondii infection and frequent abdominal pain. Further research to confirm this association should be conducted.

Two metagenome-assembled genomes (MAGs) were recovered from the ammonia-oxidizing enrichment culture BO1 obtained from the sediment of the freshwater reservoir Lake Burr Oak, Ohio, USA. High quality MAGs were assembled for the archaeal ammonia oxidizer Nitrosarchaeum sp. BO1 and the canonical nitrite oxidizer Nitrospira sp. BO1., Competing Interests: The authors declare no conflict of interest.

The identification of VHL-binding proteolysis targeting chimeras (PROTACs) that potently degrade the BRM protein (also known as SMARCA2) in SW1573 cell-based experiments is described. These molecules exhibit between 10- and 100-fold degradation selectivity for BRM over the closely related paralog protein BRG1 (SMARCA4). They also selectively impair the proliferation of the H1944 "BRG1-mutant" NSCLC cell line, which lacks functional BRG1 protein and is thus highly dependent on BRM for growth, relative to the wild-type Calu6 line. In vivo experiments performed with a subset of compounds identified PROTACs that potently and selectively degraded BRM in the Calu6 and/or the HCC2302 BRG1 mutant NSCLC xenograft models and also afforded antitumor efficacy in the latter system. Subsequent PK/PD analysis established a need to achieve strong BRM degradation (>95%) in order to trigger meaningful antitumor activity in vivo . Intratumor quantitation of mRNA associated with two genes whose transcription was controlled by BRM ( PLAU and KRT80 ) also supported this conclusion.

We show white light interferometer experiments that clearly demonstrate the basic differences between geometric and propagation phases. These experimental results also suggest a way to answer the "boundedness problem" in geometric phase-whether geometric phase is unbounded (i.e., can take on any values without limit) or bounded (i.e., limited to values between - π and + π ). We show why the answer to this question is not as easy as it seems, from both a theoretical and an experimental perspective, and explain how the answer depends on one's choice of phase convention. We also hope that the videos provided will be pedagogically useful for explaining geometric phase.

Background: Scleroderma is a systemic inflammatory disorder that can compromise the gastrointestinal tract in up to 90% of patients., Aim: The purpose of this work is to characterize esophageal, gastric, and intestinal compromise in patients with scleroderma by means of minimally invasive methods and its association with symptoms and severity of their rheumatological condition., Methods: Patients with systemic sclerosis were recruited according to the criteria of the American College of Rheumatology. The study of digestive involvement was carried out on four consecutive days: esophageal manometry was performed on the first day, intestinal manometry on the second day, surface electrogastrography on the third, and hydrogen breath test on the fourth. The Mann-Whitney test was used for quantitative variables and the chi-squared test for categorical variables (p < 0.05)., Results: A total of 30 patients were included, with an average age of 52.7 years and 93% women. Average disease evolution duration was 6.5 years, 70% with limited variety. Rodnan averaged 12 points, being higher in the diffuse variety. The main symptom was heartburn, followed by abdominal distension, with no differences between subtypes except for diffuse nausea; 80% had intestinal manometric compromise, 76% esophageal manometric compromise, and 30% electrogastrographic compromise. Bacterial overgrowth was evidenced in two-thirds (66%) of the patients, and 23% of the patients had simultaneous esophageal, gastric, and intestinal involvement, which correlated with greater skin involvement but not with gastrointestinal symptoms., Conclusions: Gastrointestinal involvement in patients with scleroderma is frequent and is observed regardless of the symptoms and clinical characteristics of the latter, except for skin involvement., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Enhancing the ability to resolve axial details is crucial in three-dimensional optical imaging. We provide experimental evidence showcasing the ultimate precision achievable in axial localization using vortex beams. For Laguerre-Gauss (LG) beams, this remarkable limit can be attained with just a single intensity scan. This proof-of-principle demonstrates that microscopy techniques based on LG vortex beams can potentially benefit from the introduced quantum-inspired superresolution protocol.

Kappa-distributed velocities in plasmas are common in a wide variety of settings, from low-density to high-density plasmas. To date, they have been found mainly in space plasmas, but are recently being considered also in the modeling of laboratory plasmas. Despite being routinely employed, the origin of the kappa distribution remains, to this day, unclear. For instance, deviations from the Maxwell-Boltzmann distribution are sometimes regarded as a signature of the nonadditivity of the thermodynamic entropy, although there are alternative frameworks such as superstatistics where such an assumption is not needed. In this work we recover the kappa distribution for particle velocities from the formalism of nonequilibrium steady-states, assuming only a single requirement on the dependence between the kinetic energy of a test particle and that of its immediate environment. Our results go beyond the standard derivation based on superstatistics, as we do not require any assumption about the existence of temperature or its statistical distribution, instead obtaining them from the requirement on kinetic energies. All of this suggests that this family of distributions may be more common than usually assumed, widening its domain of application in particular to the description of plasmas from fusion experiments. Furthermore, we show that a description of kappa-distributed plasma is simpler in terms of features of the superstatistical inverse temperature distribution rather than the traditional parameters κ and the thermal velocity v&#95;{th}.

Background: Older adults with cognitive impairment (CI) have higher multimorbidity and frailty prevalence, lower functional status and an increased likelihood to develop dementia, non-cognitive deficits, and adverse health-related events. +AGIL, a real-world program for frail older adults in a primary care area of Barcelona, is a pragmatic, multi-component and integrated intervention implemented since 2016. It includes physical activity, nutrition, sleep hygiene, revision and adequacy of pharmacological treatment, detection of undesired loneliness and screening for CI; to improve physical function in community-dwelling older adults. We aimed to assess the + AGIL longitudinal impact on physical function among community-dwelling frail older persons with CI., Methods: An interventional cohort study included data from all the + AGIL consecutive participants from July 2016 until March 2020. Based on the comprehensive geriatric assessment, participants were offered a tailored multi-component community intervention, including a 10-week physical activity program led by an expert physical therapist. Physical performance was measured at baseline, three and six months follow-up. The pre-post impact on physical function was assessed by paired sample t-test for repeated samples. Linear mixed models were applied to analyze the + AGIL longitudinal impact. P-values < 0.05 were considered statistically significant., Results: 194 participants were included (82 with CI, based on previous diagnosis or the Mini-COG screening tool), 68% women, mean age 81.6 (SD = 5.8) yo. Participants were mostly independent in Activities of Daily Living (mean Barthel = 92.4, SD = 11.1). The physical activity program showed high adherence (87.6% attended ≥ 75% sessions). At three months, there was a clinically and statistically significant improvement in the Short Physical Performance Battery (SPPB) and its subcomponents in the whole sample and after stratification for CI [CI group improvements: SPPB = 1.1 (SD = 1.8) points, gait speed (GS) = 0.05 (SD = 0.13) m/s, Chair stand test (CST)=-2.6 (SD = 11.4) s. Non-CI group improvements: SPPB = 1.6 (SD = 1.8) points, GS = 0.08 (SD = 0.13) m/s, CST=-6.4 (SD = 12.1) seg]. SPPB and gait speed remained stable at six months in the study sample and subgroups. CI had no significant impact on SPPB or GS improvements., Conclusion: Our results suggest that older adults with CI can benefit from a multidisciplinary integrated and comprehensive geriatric intervention to improve physical function, a component of frailty., (© 2023. The Author(s).)

We conducted a multi-institutional audit of dosimetric variability between FLASH and conventional dose rate (CONV) electron irradiations by using an anatomically realistic 3D-printed mouse phantom. A CT scan of a live mouse was used to create a 3D model of bony anatomy, lungs, and soft tissue. A dual-nozzle 3D printer was used to print the mouse phantom using acrylonitrile butadiene styrene ($~1.02 g/cm^3$) and polylactic acid ($~1.24 g/cm^3$) simultaneously to simulate soft tissue and bone densities, respectively. The lungs were printed separately using lightweight polylactic acid ($~0.64 g/cm^3$). Hounsfield units (HU) and densities were compared with the reference CT scan of the live mouse. Print-to-print reproducibility of the phantom was assessed. Three institutions were each provided a phantom, and each institution performed two replicates of irradiations at selected mouse anatomic regions. The average dose difference between FLASH and CONV dose distributions and deviation from the prescribed dose were measured with radiochromic film. Compared to the reference CT scan, CT scans of the phantom demonstrated mass density differences of $0.10 g/cm^3$ for bone, $0.12 g/cm^3$ for lung, and $0.03 g/cm^3$ for soft tissue regions. Between phantoms, the difference in HU for soft tissue and bone was <10 HU from print to print. Lung exhibited the most variation (54 HU) but minimally affected dose distribution (<0.5% dose differences between phantoms). The mean difference between FLASH and CONV from the first replicate to the second decreased from 4.3% to 1.2%, and the mean difference from the prescribed dose decreased from 3.6% to 2.5% for CONV and 6.4% to 2.7% for FLASH. The framework presented here is promising for credentialing of multi-institutional studies of FLASH preclinical research to maximize the reproducibility of biological findings.

Background: Trunk inclination from semirecumbent head-upright to supine-flat positioning reduces driving pressure and increases respiratory system compliance in patients with acute respiratory distress syndrome (ARDS). These effects are associated with an improved ventilatory ratio and reduction in the partial pressure of carbon dioxide (PaCO 2 ). However, these physiological effects have not been completely studied, and their mechanisms have not yet been elucidated. Therefore, this study aimed to evaluate the effects of a change in trunk inclination from semirecumbent (45°) to supine-flat (10°) on physiological dead space and ventilation distribution in different lung regions., Results: Twenty-two ARDS patients on pressure-controlled ventilation underwent three 60-min steps in which trunk inclination was changed from 45° (baseline) to 10° (intervention) and back to 45° (control) in the last step. Tunk inclination from a semirecumbent (45°) to a supine-flat (10°) position resulted in a higher tidal volume [371 (± 76) vs. 433 (± 84) mL (P < 0.001)] and respiratory system compliance [34 (± 10) to 41 (± 12) mL/cmH 2 O (P < 0.001)]. The CO 2 exhaled per minute improved from 191 mL/min (± 34) to 227 mL/min (± 38) (P < 0.001). Accordingly, Bohr's dead space ratio decreased from 0.49 (± 0.07) to 0.41 (± 0.06) (p < 0.001), and PaCO 2 decreased from 43 (± 5) to 36 (± 4) mmHg (p < 0.001). In addition, the impedance ratio, which divides the ventilation activity of the ventral region by the dorsal region ventilation activity in tidal images, dropped from 1.27 (0.83-1.78) to 0.86 (0.51-1.33) (p < 0.001). These results, calculated from functional EIT images, indicated further ventilation activity in the dorsal lung regions. These effects rapidly reversed once the patient was repositioned at 45°., Conclusions: A change in trunk inclination from a semirecumbent (45 degrees) to a supine-flat position (10 degrees) improved Bohr's dead space ratio and reduced PaCO 2 in patients with ARDS. This effect is associated with an increase in tidal volume and respiratory system compliance, along with further favourable impedance ventilation distribution toward the dorsal lung regions. This study highlights the importance of considering trunk inclination as a modifiable determinant of physiological parameters. The angle of trunk inclination is essential information that must be reported in ARDS patients., (© 2023. European Society of Intensive Care Medicine and Springer Nature Switzerland AG.)

Introduction: Latin American Initiative for Lifestyle Intervention to Prevent Cognitive Decline (LatAm-FINGERS) is the first non-pharmacological multicenter randomized clinical trial (RCT) to prevent cognitive impairment in Latin America (LA). Our aim is to present the study design and discuss the strategies used for multicultural harmonization., Methods: This 1-year RCT (working on a 1-year extension) investigates the feasibility of a multi-domain lifestyle intervention in LA and the efficacy of the intervention, primarily on cognitive function. An external harmonization process was carried out to follow the FINGER model, and an internal harmonization was performed to ensure this study was feasible and comparable across the 12 participating LA countries., Results: Currently, 1549 participants have been screened, and 815 randomized. Participants are ethnically diverse (56% are Nestizo) and have high cardiovascular risk (39% have metabolic syndrome)., Discussion: LatAm-FINGERS overcame a significant challenge to combine the region's diversity into a multi-domain risk reduction intervention feasible across LA while preserving the original FINGER design., (© 2023 the Alzheimer's Association.)

The relationship between growth hormone (GH) excess and cancer is a controversial matter. Until 2016, most studies in patients with acromegaly found links with colon and thyroid neoplasms. However, recent studies found increased risks in gastric, breast, and urinary tract cancer also. Concordantly, clinical situations where GH and insulin-like growth facto-I deficits exist are indeed associated with diminished malignancy incidence. In line with these observations, gain-of-function mutations of various enzymes belonging to the GH and IGF-I signaling pathways have been associated with increased carcinogenesis; similarly, loss-of-function mutations of other enzymes that usually work as tumor repressors are also associated with augmented cancer risk. In a study performed in Ecuador, it was demonstrated that subjects in the Ecuadorian cohort with Laron syndrome (ELS), who have a mutant GH receptor and greatly diminished GH and IGF-I signaling, display diminished incidence of cancer. Along with absent action of GH and IGF-I, ELS individuals also have low serum insulin levels and decreased insulin resistance. Furthermore, hyperglycemia and hyperinsulinemia are indispensable for fast cell mitosis, including that of those cells present in the benign and malignant neoplasms. Notably, and despite their obesity, subjects with the ELS display normoglycemia and hypo-insulinemia, along with diminished incidence of malignancies. We believe that the dual low-IGF-I/low insulin serum levels are responsible for the cancer protection, especially considering that the insulin/INSR signaling is a central site for energy generation in the form of ATP and GDP, which are indispensable for all and every GH/IGF-I physiologic as well as pathologic events.

Bacteria resistance to antibiotics is a concerning global health problem; in this context, methicillin-resistant Staphylococcus aureus (MRSA) is considered as a high priority by the World Health Organization. Furthermore, patients with a positive result for COVID-19 received early antibiotic treatment, a fact that potentially encourages the increase in antibiotic resistance. Therefore, there is an urgency to develop new drugs with molecular mechanisms different from those of the actual treatments. In this context, enzymes from the shikimate pathway, a route absent in humans, such as dehydroquinate dehydratase (DHQD), are considered good targets. In this work, a computer-aided drug design strategy, which involved exhaustive virtual screening and molecular dynamics simulations with MM-PBSA analysis, as well as an in silico ADMETox characterization, was performed to find potential noncovalent inhibitors of DHQD from MRSA (SaDHQD). After filtering the 997 million compounds from the ZINC database, 6700 compounds were submitted to an exhaustive virtual screening protocol. From these data, four molecules were selected and characterized ( ZINC000005753647 ( 1 ), ZINC000001720488 ( 2 ), ZINC000082049768 ( 3 ), and ZINC000644149506 ( 4 )). The results indicate that the four potential inhibitors interacted with residues important for substrate binding and catalysis, with an estimated binding free energy like that of the enzyme's substrate. Their ADMETox-predicted properties suggest that all of them support the structural characteristics to be considered good candidates. Therefore, the four compounds reported here are excellent option to be considered for future in vitro studies to design new SaDHQD noncovalent inhibitors and contribute to the search for new drugs against MRSA.

Background and Objective: Comorbidities can influence asthma control and promote asthma exacerbations (AEs). However, the impact of multimorbidity in AEs, assessed based on long-term follow-up of patients with asthma of different degrees of severity, has received little attention in real-life conditions. To describe the epidemiological and clinical characteristics and predictors of AEs in patients who had presented at least 1 AE in the previous year in the MEchanism of Genesis and Evolution of Asthma (MEGA) cohort., Methods: The work-up included a detailed clinical examination, pulmonary function testing, fractional exhaled nitric oxide (FeNO), blood counts, induced sputum, skin prick-tests, asthma questionnaires, and assessment of multimorbidity. The number of moderate-severe AEs in the preceding year was registered for each patient., Results: The study population comprised 486 patients with asthma (23.7% mild, 35% moderate, 41.3% severe). Disease remained uncontrolled in 41.9%, and 47.3% presented ≥1 moderate-severe AE, with a mean (SD) annual exacerbation rate of 0.47 (0.91) vs 2.11 (2.82) in mild and severe asthma, respectively. Comorbidity was detected in 56.4% (66.6% among those with severe asthma). Bronchiectasis, chronic rhinosinusitis with nasal polyps, atopy, psychiatric illnesses, hyperlipidemia, and hypertension were significantly associated with AEs. No associations were found for FeNO, blood eosinophils, or total serum IgE. Sputum eosinophilia and a high-T2 inflammatory pattern were significantly associated with AEs. Multivariable regression analysis showed a significant association with asthma severity, uncontrolled disease, and low prebronchodilator FEV1/FVC., Conclusion: Our study revealed a high frequency of AE in the MEGA cohort. This was strongly associated with multimorbidity, asthma severity, poor asthma control, airflow obstruction, higher sputum eosinophils, and a very high-T2 inflammatory pattern.

Thallium poisoning is usually accidental. We present a case of a 51-year-old woman who was evaluated in June 2018 for myalgia, vertigo, asthenia, and abdominal pain. Physical examination revealed temporal-spatial disorientation, jaundice, and asterixis. The laboratory reported the following: bilirubin, 10.3 mg/dL; aspartate transaminase, 78 U/L; alanine transaminase, 194 U/L; albumin, 2.3 g/dL; prothrombin time, 40%; and platelet count, 60,000/mm3. Serology performed for hepatitis A, B, and C; Epstein-Barr virus; cytomegalovirus; and human immunodeficiency virus was negative, and a collagenogram was negative. Physical reevaluation revealed alopecia on the scalp, armpits, and eyebrows; macules on the face; plantar hyperkeratosis; and ulcers on the lower limbs. Tests for lead, arsenic, copper, and mercury were carried out, which were normal; however, elevated urinary thallium (540 µg/g; range, 0.4-10 µg/g) was observed. The patient was treated with ᴅ-penicillamine 1,000 mg/day and recovered her urinary thallium levels were within normal range at annual follow-up. Thallium poisoning is extremely rare and can be fatal in small doses. An adequate clinical approach can facilitate early diagnosis.

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis., Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms., Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options., Registration: NCT05172024., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Helen Chu reported consulting for Merck, GSK, Pfizer, Ellume, Janssen, Vindico CME, and the Bill and Melinda Gates Foundation, and receiving research support from Gates Ventures, Ellume, and Sanofi Pasteur. She also serves as a co-investigator on studies funded by Pfizer, Novavax, and GSK. Maged Costantine reported receiving grant support for work not related to RECOVER work/publications from Baxter International and Siemens Healthcare and personal consulting fees not related to this paper from Progenity, Quidel Ortho, and Siemens Healthcare. Kristine Erlandson reported research funding from Gilead Sciences and consulting payments from Gilead Sciences, Merck, and ViiV Pharmaceuticals, all paid to the University of Colorado. Emily Gallagher reported consulting for Novartis, Flare Therapeutics and Seagen. Edward Gardner reported research support (clinical trials) from Gilead Sciences, ViiV Healthcare, and Cepheid. Jason Goldman reported research support from Gilead, Eli Lilly and Regeneron; grants from Gilead, Merck (BARDA); personal fees for consulting from Gilead, Eli Lilly; and non-financial support from Adaptive Biotechnologies and Labcorp/Monogram Biosciences outside the submitted work. Timothy Heinrich reported grant support from Merck Inc. and consulting fees from Roche. Rachel Hess reported serving as Data Safety Monitoring Board member for Astellas Pharmaceuticals unrelated to the current work. Leora Horwitz reported being a member of the National Academy of Medicine Committee on the Long-Term Health Effects Stemming from COVID-19 and Implications for the Social Security Administration. Priscilla Hsue reported receiving honoraria from Gilead and Merck unrelated to study topic, receiving study drug from Regeneron unrelated to study topic, and receiving a research grant from Novartis. Judith James reported OMRF has licensed her IP to Progentec Biosciences, has received grant support from Progentec Biosciences, and serves on Advisory Committees to Glaxo Smith Klein, Merck and Novartis. Arthur Kim reports providing educational materials to Clinical Care Options and UpToDate and serving on a Data Safety Monitoring board for Kintor Pharmaceuticals, Ltd. Bruce Levy reported serving as a consultant for AstraZeneca, Entrinsic Biosciences, Gossamer Bio and Nocion Therapeutics and receiving research support from Amgen, Genentech, GlaxoSmithKline, Pieris Pharmaceuticals, SRA and Sanofi unrelated to the current work. Vincent Marconi reported receiving grants from NIH during the conduct of the study and grants from NIH, Veteran Affairs, and Centers for Disease Control and Prevention; grants, personal fees, nonfinancial support, and other from Lilly and Gilead; grants and personal fees from ViiV; and nonfinancial support from Bayer outside the submitted work. Grace McComsey reported serving as consultant for Merck, Gilead, ViiV, Janssen and have received research support from Pfizer, Vanda, Genentech, Roche, Redhill and Cognivue. Torri Metz reported being a site PI and a participant in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She also reported being a site PI for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Janet Mullington reported support for investigator-initiated research by "Open Medicine Foundation and the Patient-Led Research Collaborative" Princess Ogbogu reported research support from Astrazeneca, GSK, Blueprint medical; advisory board for Astrazeneca, GSK, Sanofi, Kalvista; and consulting for Astrazeneca, GSK Sairam Parthasarathy reported research funding to Institution from Sergey Brin foundation of COVID and Long-COVID research. Michael Peluso reported consulting fees from Gilead Sciences and AstraZeneca, and service on data safety monitoring board for American Gene Technologies. Sean Quigley reported service on speaker Board for Servier, Alnylam, Agios; service on advisory board for Recordati, Alexion. Franz Rischard reported research support from NIH/NHLBI, United Therapeutics, Acceleron/Merck, Janssen, Insmed, Aerovate, and Bayer; and consulting/advisory compensation from Acceleron and Bayer. Nadine Rouphael reported being a consultant for ICON and EMMES as a safety consultant for clinical trials; service on the advisory boards for Moderna; funds to institution from Sanofi, Lilly, Merck, Quidel and Pfizer. PJ Utz reported stock ownership of Gilead and PI of biomarker studies for Pfizer STOP-PASC paxlovid trial Juan Wisnivesky received receiving consulting honorarium from Sanofi, Banook, Prospero, PPD and Atea and research grants from Sanofi, Regeneron, Axella, and Arnold Consultants., (Copyright: © 2023 Horwitz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Modification of thin-film composite (TFC) nanofiltration (NF) membranes to increase permeability and improve separation performance remains a significant challenge for water scarcity. This study aimed to enhance the permeability and selectivity of two commercial polyamide (PA) NF membranes, NF90 and NF270, by modifying them with carbon nanotubes (CNTs) using microwave (MW)-assisted in-situ growth. The conducting polymer, polypyrrole (Ppy), and a ferrocene catalyst were used to facilitate the growth process. Chemical and morphological analyses confirmed that the surface of both membranes was modified. The NF270-Ppy-CNT membrane was selected for ion rejection testing due to its superior permeability compared to the NF90-Ppy-CNT. The modified NF270 membrane showed a 14% increase in ion rejection while maintaining constant water permeability. The results demonstrated that it is feasible to attach CNTs to a polymeric surface without compromising its functional properties. The Spliegler-Kedem model was employed to model the rejection and permeate flux of NF270-Ppy-CNT and NF270 membranes, which indicated that diffusive transport contributes to the modification to increase NaCl rejection. The present study provides a promising approach for modifying membranes by in-situ CNT growth to improve their performance in water treatment applications, such as desalination.

Introduction: The expression of PD-L1 in renal cell carcinoma (RCC) is associated with worse survival and prognostic clinical-pathological features. However, they seem to respond better to new therapeutic agents. Knowing the behavior of RCC according to the presence of PD-L1 has implications for medical counseling and therapeutic approaches., Objective: To identify the presence of PD-L1 in renal tumor cells and analyze its association with patients' prognostic factors, overall survival (OS) and cancer-specific survival (CSS)., Methodology: Retrospective analysis of RCC tissue samples, obtained between 2018 and 2021. Immunohistochemistry analysis with mouse monoclonal Anti PD-L1, clone 22C3. Definition of PD-L1 "positive" as a Tumor Proportion Score ≥1%. Comparison of prognostic factors according to the presence or absence of PD-L1, and univariate analysis for OS and CSS., Results: 14% (n = 11) of the sample were PD-L1(+). Average age was 59 years. There were no statistically significant differences between PD-L1 status and TNM stages, nuclear grade and histology. PD-L1(+) had worse OS with a HR of 5.27 (CI: 1.1-23.7; P = .03) and CSS showed a unfavorable tendency for PD-L1(+) with a HR of 4.79 (CI: 0.79-28.95; P = .08)., Conclusion: The prevalence of PD-L1 in RCC is considerable. In this study PD-L1(+) was associated with unfavorable OS and CSS. It seems reasonable to incorporate its routine use in RCC., (Copyright © 2023 AEU. Published by Elsevier España, S.L.U. All rights reserved.)

The addition of probiotic bacteria to a meat batter allows the development of functional fermented sausages. The aim of this work was to study the effect of microencapsulated Lactiplantibacillus plantarum BFL (EP) and as free cells (FP) on microbiological, physicochemical, and sensory parameters of fermented sausages during the drying stage and on the product ready for consumption. The microencapsulation of L. plantarum BFL did not improve its viability during the drying stage. In addition, sausages inoculated with L. plantarum BFL (FP and EP) caused lower residual nitrites values, pH values and Escherichia coli counts than the Control (C). However, only the presence of free cells of L. plantarum BFL (FP) caused a decrease in the Enterobacteriaceae and mannitol salt-positive Staphylococcus counts. In the sensory analysis, no significant differences were found in the acceptability of the different sausages. However, the acidity in probiotic sausages (FP and EP) was an attribute that consumers highlighted. The probiotic L. plantarum BFL could adapt and survive at high doses in the matrix of an industrial fermented sausage. Therefore, its use could represent a strategy both for biocontrol of pathogens and for the development of functional meat products., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Published by Elsevier Ltd.)