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Loneliness is recognized as a significant public health concern, affecting quality of life and health outcomes, including cancer-related outcomes. Thus, it is essential to understand the prevalence and risk factors for loneliness in people with cancer. Through an exploratory analysis of secondary data from the Health Information National Trends Survey, we investigated the prevalence and correlates of loneliness among adult cancer survivors (N = 1,234). An estimated 35.9% of participants experienced moderate to severe loneliness. In a series of multiple logistic regression models, we identified differences in sociodemographic, cancer-related factors, non-cancer comorbidities, social isolation, social support, and social media use behaviors in the odds of reporting moderate-severe loneliness. In our fully adjusted model, years since cancer diagnosis, fair-poor overall health, moderate-high psychological distress, and having children living in the household were all positively and independently associated with moderate-severe loneliness. In this same model, being married and reporting some types of social support were negatively associated with moderate-severe loneliness. This study underscores the multifaceted nature of loneliness among cancer survivors, revealing a complex interplay of demographic, health-related, and social factors., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

High-refractive-index (HRI) dielectrics are gaining increasing attention as building blocks for compact lasers. Their ability to simultaneously support both electric and magnetic modes provides greater versatility as compared to plasmonic platforms. Moreover, their reduced absorption loss minimizes heat generation, further enhancing their performance. Here, we employ a scalable soft nanoimprinting lithography method to create a series of two-dimensional (2D) periodic square hole arrays in polymeric films (SU-8), which are coated with an HRI dielectric layer (TiO 2 ). These structures exhibit low-threshold lasing from an organic dye-doped SU-8 layer deposited on top. We study arrays with different lattice parameters and a sample with a random distribution of holes, finding that the optimal laser performance occurs when the optical resonances of the array align with the emission wavelength range of the dye. Furthermore, we observe that the anisotropy in the TiO 2 coating breaks the polarization degeneracy of the square arrays, leading to the emergence of new modes and enabling the simultaneous appearance of multiple lasing peaks. Our work shows that, despite the simplicity of their fabrication process, the HRI structures studied here exhibit a high degree of complexity, leading to a rich optical response and enabling multiband lasing. This offers an innovative approach to building robust HRI platforms for lasing with improved control over their emission properties.

Alzheimer's disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies and infectious agents, with herpes simplex virus 1 (HSV-1) being a leading candidate. Our investigation, using metagenomics, mass spectrometry, western blotting, and decrowding expansion pathology, detects HSV-1-associated proteins in human brain samples. Expression of the herpesvirus protein ICP27 increases with AD severity and strongly colocalizes with p-tau but not with Aβ. Modeling in human brain organoids shows that HSV-1 infection elevates tau phosphorylation. Notably, p-tau reduces ICP27 expression and markedly decreases post-infection neuronal death from 64% to 7%. This modeling prompts investigation into the cGAS-STING-TBK1 pathway products, nuclear factor (NF)-κB and IRF-3, which colocalizes with ICP27 and p-tau in AD. Furthermore, experimental activation of STING enhances tau phosphorylation, while TBK1 inhibition prevents it. Together, these findings suggest that tau phosphorylation acts as an innate immune response in AD, driven by cGAS-STING., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Telomere length is an important indicator of biological age and a complex multi-factor trait. To date, the telomere interactome for comprehending the high-dimensional biological aspects linked to telomere regulation during childhood remains unexplored. Here we describe the multi-omics signatures associated with childhood telomere length., Methods: This study included 1001 children aged 6 to 11 years from the Human Early-life Exposome (HELIX) project. Telomere length was quantified via qPCR in peripheral blood of the children. Blood DNA methylation, gene expression, miRNA expression, plasma proteins and serum and urinary metabolites were measured through microarrays or (semi-) targeted assays. The association between each individual omics feature and telomere length was assessed in omics-wide association analyses. In addition, a literature-guided, sparse supervised integration method was applied to multiple omics, and latent components were extracted as predictors of child telomere length. The association of these latent components with early-life aging risk factors (child lifestyle, body mass index (BMI), exposure to smoking, etc.), were interrogated., Results: After multiple-testing correction, only two CpGs (cg23686403 and cg16238918 at PARD6G gene) out of all the omics features were significantly associated with child telomere length. The supervised multi-omics integration approach revealed robust associations between latent components and child BMI, with metabolites and proteins emerging as the primary contributing features. In these latent components, the contributing molecular features were known as involved in metabolism and immune regulation-related pathways., Conclusions: Findings of this multi-omics study suggested an intricate interplay between telomere length, metabolism and immune responses, providing valuable insights into the molecular underpinnings of the early-life biological aging., Competing Interests: Declarations. Ethics approval and consent to participate: The HELIX study complies with the Declaration of Helsinki. All six cohorts existed for several years before HELIX started, and had undergone the required evaluation by national ethics committees: EDEN received approval from the ethics committee (CCPPRB) of Kremlin Bicêtre and from CNIL (Commission Nationale Informatique et Liberté), the French data privacy institution; BiB received ethics approval from the Bradford Research Ethics Committee; INMA obtained the approval of the ethics committee of each involved hospital or health center; the research protocol of KANC was approved by the Lithuanian Bioethics Committee; MoBa received approval from a Norwegian regional committee for medical and health research ethics; and the ethics committee of the university hospital at Heraklion approved the study protocols of RHEA. An informed consent has been signed by all participants at recruitment and at the follow-up visit for clinical examinations and biospecimen collection. Each cohort also confirmed that relevant informed consent and approval were in place for the secondary use of data from pre-existing data. The work in HELIX was covered by new ethics approvals in each country. The HELIX project received ethical approvals from the Comité Ético de investigación Clínica Parc de Salut MAR. At follow-up enrolment in the HELIX subcohort and panel studies, participants were asked to sign an informed consent for clinical examination and biospecimen collection and analysis. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objective: The complex mix of factors, including hemodynamic forces and wall remodeling mechanisms, that drive intracranial aneurysm growth is unclear. This study focuses on the specific regions within aneurysm walls where growth occurs and their relationship to the prevalent hemodynamic conditions to reveal critical mechanisms leading to enlargement., Methods: The authors examined hemodynamic models of 67 longitudinally followed aneurysms, identifying 88 growth regions. These regions (of enlargement) were pinpointed through alignment and distance mapping between baseline and follow-up models. Aneurysm wall subdivisions were created based on saccular anatomy and flow-related characteristics, which were used to assess local hemodynamics. The distribution of growing regions across these subdivisions was then studied and stratified by aneurysm location and morphology to reveal distinct growth patterns. Statistical significance was evaluated using the Kruskal-Wallis and Mann-Whitney tests., Results: Growth predominantly occurred in the body (p < 0.0001) of aneurysms, with anterior communicating artery (ACom) (p < 0.0001) and lateral (p = 0.002) aneurysms showing a significantly greater tendency for growth in this region. In comparison, middle cerebral artery (MCA) (p < 0.0001) and bifurcation (p = 0.0001) aneurysms demonstrated growth in both the dome and the body. Notable differences in growth distribution across saccular regions included ACom versus MCA (neck, p = 0.038), bifurcation versus lateral (neck, p = 0.008), and so forth. The central flow region saw the most growth (p < 0.0001); although not significant, ACom (p = 0.196) and lateral (p = 0.218) aneurysms showed a tendency for growth in inflow and central zones, while MCA (p = 0.001) and bifurcation (p < 0.0001) aneurysms were more likely to grow in the central flow region., Conclusions: Two primary mechanisms seem to influence aneurysm growth: high-flow impingement jets in the neck, body, and inflow zones leading to wall degeneration/thinning, mainly in ACom aneurysms; and slow, oscillatory flow conditions in the dome and central flow zones promoting wall remodeling/thickening, mainly in MCA aneurysms. This latter mechanism is also observed as secondary flows in ACom aneurysms. These findings emphasize the need to understand the distinct and sometimes concurrent mechanisms of aneurysm growth, advocating for targeted monitoring and interventions that mitigate rupture risks by considering the unique hemodynamic environments within different aneurysm regions and locations.

Background: Postmastectomy radiation therapy (PMRT) improves disease-free survival in breast cancer but reduces aesthetic satisfaction. Proton PMRT has gained popularity because it results in fewer systemic complications. There is a lack of data regarding revision surgeries for prepectoral implant-based breast reconstruction (PP-IBBR) following radiation., Objectives: The aim of this study was to compare revision surgeries in PP-IBBR with photon vs proton PMRT., Methods: A single-institution retrospective cohort study was performed that included breast cancer patients undergoing mastectomy and PP-IBBR with PMRT between January 2020 and October 2022. The mean follow-up duration for the cohort was 1056.4 days (2.89 years). Revision surgeries evaluated were fat grafting, conversion to autologous flaps, implant replacement, implant removal, capsulectomy, and scar revision., Results: The 116 PP-IBBR subjects were divided into 2 cohorts, receiving either photon (75, 64.66%) or proton (41, 35.34%) radiation. Overall corrective surgeries were higher with photon therapy (27.5% overall; 32.4% photon vs 19.5% proton, P = .132). The odds of any revision surgery were nearly double with photon therapy (odds ratio [OR] = 1.98), and the conversion to an autologous flap was significantly more likely with photon therapy (OR = 4.55, P = .025). Multivariable analysis showed an increased tendency for photon therapy patients to require any revision surgeries (OR = 1.62, P = .359), autologous flaps (OR = 5.97, P = .049), fat grafting (OR = 1.52, P = .664), and scar revision (OR = 4.51, P = .273)., Conclusions: Compared to proton therapy, traditional photon therapy has a higher conversion rate to autologous flaps with PP-IBBR. Photon therapy had higher rates of overall revision surgeries, but the difference was not statistically significant. Proton therapy is safer and requires fewer revision surgeries, warranting larger studies and broader utilization., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Childhood obesity poses a significant public health challenge, yet the molecular intricacies underlying its pathobiology remain elusive. Leveraging extensive multi-omics profiling (methylome, miRNome, transcriptome, proteins and metabolites) and a rich phenotypic characterization across two parts of Europe within the population-based Human Early Life Exposome project, we unravel the molecular landscape of childhood obesity and associated metabolic dysfunction. Our integrative analysis uncovers three clusters of children defined by specific multi-omics profiles, one of which characterized not only by higher adiposity but also by a high degree of metabolic complications. This high-risk cluster exhibits a complex interplay across many biological pathways, predominantly underscored by inflammation-related cascades. Further, by incorporating comprehensive information from the environmental risk-scape of the critical pregnancy period, we identify pre-pregnancy body mass index and environmental pollutants like perfluorooctanoate and mercury as important determinants of the high-risk cluster. Overall, our work helps to identify potential risk factors for prevention and intervention strategies early in the life course aimed at mitigating obesity and its long-term health consequences., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects women of reproductive age and requires better treatment. N -acetylcysteine (NAC) is known to be beneficial under such conditions owing to its antioxidant potential and insulin-sensitizing properties. The effect of NAC on the reproductive outcomes of PCOS patients was examined in this meta-analysis., Methods: In accordance with PRISMA standards, this meta-analysis included studies that compared N -acetylcysteine, metformin, clomiphene citrate, and a placebo in patients with POCS. The main indicators were follicular growth, endometrial thickness, and hormone level. The risk of bias was evaluated using the Cochrane ROB2 tool., Results: Twenty-two studies ( n = 2515) were included. NAC was associated with a statistically significant increase in progesterone (SMD 0.95, 95% CI: 0.13-1.77, p = 0.02) and endometrial thickness (SMD 0.58, 95% CI: 0.10-1.06, p = 0.02) compared to the placebo and other drugs (SMD 0.71, 95% CI: 0.48-0.94, p < 0.0001). LH levels were significantly increased by NAC compared to metformin (SMD 0.67, 95% CI: 0.23-1.12, p = 0.003). However, no significant differences were observed in the estradiol, SHBG, or FSH levels., Conclusions: NAC had a major effect on progesterone, endometrial thickness, and LH levels in women with PCOS. Therefore, it may be a potential treatment option., Competing Interests: Authors Isabel Vi&ntilde;a and Macarena Carranza were employed by the company IVB Wellness Lab. 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.

Introduction: Silicone Lymphadenopathy (SL) is a complication of breast implants that involves migration of silicone to nearby soft tissue/lymph nodes. Data on its clinical features and management is scarce. We aimed to identify the clinical presentation and management of SL., Methods: A single-institution retrospective cohort study was conducted from our institutional imaging system where search terms "Silicone lymphadenopathy", "silicone adenitis" and "silicone adenopathy" were used to identify patients with SL (January 2016-September 2023). Patient demographics, clinical features, imaging findings, pathological investigation, and treatment were obtained from the medical records., Results: Of 52 patients with SL, breast augmentation accounted for 90.4% of the implant placements. All patients had silicone implants placed at some time. A significant portion of patients (69.3%) were asymptomatic, while 7.7% had non-tender lymphadenopathy, 19.2% experienced painful lymphadenopathy, and 1.9% presented with mixed symptoms. Implant rupture was observed in 88.7% of cases; 13.0% intracapsular, 26.1% extracapsular, 15.2% both, and unknown in 45.7%. Axillary nodes were the most commonly involved (86.5%), and ultrasonography was most commonly used to detect SL (80.7%). Biopsy was performed in 17.3% of cases, confirming benign pathology in all cases. No patients required surgical excision of lymph nodes for management of SL., Conclusion: Most patients with SL are asymptomatic and are managed with observation. Biopsy and surgical intervention should be reserved for those patients with abnormal imaging or persistent symptoms. Evaluation of lymphadenopathy is essential to exclude malignancy in patients with a history of breast cancer., Level of Evidence Iii: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., Competing Interests: Declarations. Conflict of interest: DPS is a consultant to Solventum and IC Surgical. KER has worked as a consultant for Roche Diagnostic Solutions, Merck. She has received honoraria from Pacira Pharmaceuticals. She has also received funding from Bristol Myers Squibb Foundation. All remaining authors have declared no conflicts of interest. Human Participants or Animals: This article does not contain any studies with human participants or animals performed by any of the authors. Informed Consent: For this type of study informed consent is not required, (© 2025. The Author(s).)

Background: Kidney transplant (KT) recipients at intermediate risk for cytomegalovirus (CMV) infection constitute a potential target for individualized prevention strategies informed by the CMV-specific cell-mediated immunity (CMV-CMI). The optimal method for the functional assessment of CMV-CMI in this group remains unclear., Methods: We included 74 CMV-seropositive KT recipients that did not receive T-cell-depleting induction and were managed by preemptive therapy. CMV-CMI was monitored at baseline and months 1, 3, 6, and 12 by intracellular cytokine staining (ICS) and a interferon (IFN)-γ-release assay (QuantiFERON-CMV [QTF-CMV]). Both methods were compared for discriminative capacity (areas under the receiving operating characteristic curve [auROCs]) and diagnostic accuracy to predict protection against high-level (≥1000 IU/mL) CMV DNAemia and/or disease., Results: Eighteen patients (24.3%) experienced high-level CMV DNAemia or disease. There were no significant differences in the discriminative capacity to predict protection of CMV-specific CD8+ (auROC: 0.719) and CD4+ T-cell counts (auROC: 0.664) enumerated by ICS and IFN-γ production measured by QTF-CMV (auROC: 0.666). Optimal cutoff values of ≥9.8 CMV-specific CD4+ T-cells/µL and ≥5.7 CD8+ T-cells/µL by ICS yielded excellent specificity (95.7% and 86.9%, respectively) and positive predictive values (PPVs) (>98.0%), but a sensitivity below 60%. A reactive QTF-CMV (IFN-γ ≥0.2 IU/mL) provided good sensitivity (81.6%) and PPV (92.5%), at the expense of a poor specificity (22.2%)., Conclusions: The discriminative capacity to predict immune protection against clinically relevant CMV infection among intermediate-risk KT recipients was comparable for ICS and QTF-CMV. A selected ICS threshold may provide better specificity than the interpretative cut-off values currently recommended for QTF-CMV., (© 2025 Wiley Periodicals LLC.)

Aims: The Peri-Implant and PeriProsthetic Survival AnalysiS (PIPPAS) study aimed to investigate the risk factors for one-year mortality of femoral peri-implant fractures (FPIFs)., Methods: This prospective, multicentre, observational study involved 440 FPIF patients with a minimum one-year follow-up. Data on demographics, clinical features, fracture characteristics, management, and mortality rates were collected and analyzed using both univariate and multivariate analyses. FPIF patients were elderly (median age 87 years (IQR 81 to 92)), mostly female (82.5%, n = 363), and frail: median clinical frailty scale 6 (IQR 4 to 7), median Pfeiffer 4 (1 to 7), median age-adjusted Charlson Comorbidity Index (CCI) 6 (IQR 5 to 7), and 58.9% (n = 250) were American Society of Anesthesiologists grade III., Results: Overall, 90.5% (n = 398) of the patients were treated surgically, 57.0% (n = 227) retained the implant, and 88.7% (n = 353) managed with fixation. Mortality rates were 8.2% (n = 3.6) in-hospital, 11.4% (n = 50) at 30 days, 21.1% (n = 93) at six months, and 21.6% (n = 95) at 12 months. Medical complications, mainly delirium, were common in the acute setting (52.7%, n = 215). The nonunion rate was 4.1% (n = 18). Mortality risk factors in the univariate analysis were age, living at a nursing home, no walking outdoors, frailty variables, fractures in the distal epiphysis, fractures around a proximal nail, discharge to a healthcare facility, and no osteoporotic treatment at discharge. Protective factors against mortality in the univariate analysis were surgical treatment by an experienced surgeon, management without an arthroplasty, allowing full weightbearing, mobilization in the first 48 hours postoperatively, and geriatric involvement. Risk factors for mortality in the multivariate analysis were cognitive impairment (Pfeiffer's questionnaire) (hazard ratio (HR) 1.14 (95% CI 1.05 to 1.23), p = 0.002), age-adjusted CCI (HR 1.18 (95% CI 1.07 to 1.30), p = 0.001), and antiaggregant or anticoagulant medication at admission (HR 2.00 (95% CI 1.19 to 3.38), p = 0.009). Haemoglobin level at admission was protective against mortality (HR 0.85 (95% CI 0.74 to 0.97), p = 0.018)., Conclusion: Mortality in FPIFs occurs mainly within the first six months of follow-up. Early co-management and clinical optimization, particularly targeting frail older patients, is crucial in reducing mortality following these fractures., Competing Interests: H. J. Aguado reports funding from SACYL (GRS 2371/A/21) and the AO Foundation (AO Trauma Spain) (PI-20-2041)., (© 2025 Aguado et al.)

We investigate the emergence of self-hybridized thermal magnetoplasmons in doped graphene nanodisks at finite temperatures upon being subjected to an external magnetic field. Using a semianalytical approach, which fully describes the eigenmodes and polarizability of the graphene nanodisks, we show that the hybridization originates from the coupling of transitions between thermally populated Landau levels and localized magnetoplasmon resonances of the nanodisks. Owing to their origin, these modes combine the extraordinary magneto-optical response of graphene with the strong field enhancement of plasmons, making them an ideal tool for achieving strong chiral light-matter interactions, with the additional advantage of being tunable through carrier concentration, magnetic field, and temperature. As a demonstration of their capabilities, we show that the thermal magnetoplasmons supported by an array of graphene nanodisks enable chiral perfect absorption and chiral thermal emission.

The impact of human cytomegalovirus (HCMV) infection on the mid- and long-term balance between pro-inflammatory and anti-inflammatory cytokines among kidney transplant recipients (KTRs) remains unclear. We measured plasma levels of 12 Th1/Th2-type cytokines (granulocyte-macrophage colony-stimulating factor, interferon-γ, interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-18 and tumor necrosis factor-α) in a cohort of 290 KTRs at four time points through month 12 after transplantation. Cytokine levels at each point were compared according to the previous documentation of HCMV replication by two approaches: "cumulative exposure" from the time of transplantation and "recent exposure" within the 2-3 months preceding cytokine assessment. Significance levels were Bonferroni-corrected for multiple pairwise comparisons. Plasma levels of IL-6, IL-10, and IL-12p70 at month 1 were significantly increased in KTRs that had experienced HCMV infection during the first 30 days. By month 3, IL-6 and IL-10 remained increased in KTRs with cumulative exposure through day 90. Cumulative exposure to HCMV replication through day 180 was also associated to increased IL-10 levels at month 6. In addition, KTRs with recent HCMV exposure had increased IL-10 levels at months 3 and 6. After multivariable adjustment, cumulative exposure to HCMV infection and/or the area under curve of HCMV DNAemia during the corresponding period were associated to IL-10 levels within the highest quartile at months 1, 3, and 6. Preceding HCMV infection induces sustained changes in the plasma cytokine milieu of KTRs, with elevated IL-6 and IL-10 levels throughout the first 6 months after transplantation., (© 2025 Wiley Periodicals LLC.)

As the number of cerebral aneurysms treated with flow diverters continues to increase, it is important to understand what factors influence not only thrombus formation within the aneurysm cavity but also fibrin accumulation across the device and its associated disruption and blockage of the inflow stream. Both processes contribute to the eventual occlusion of the aneurysm or its continued patency and incomplete occlusion which may require future re-treatment. To investigate fibrin accumulation on flow diverters placed across the neck of cerebral aneurysms, a previously developed computational model that couples flow and fibrin dynamics is used in combination with experimental in vitro models of cerebral aneurysms treated with flow diverters. Fibrin accumulation was previously investigated in four glass models of cerebral aneurysms with varying parent artery geometries placed in a flow loop at different flow rates. Corresponding computational models were constructed and compared with the experimental findings. The computational model based on fibrin production stimulated from flow shear stress and subsequent adhesion to device wires was able to reproduce and explain the fibrin accumulation patterns observed in the experimental aneurysms treated with flow diverters. Specifically, these models indicated that increasing vessel curvature, flow rate, and thrombin concentration induced faster fibrin accumulation and associated aneurysm inflow disruption and blockage. The models described and tested in this paper are valuable to understand the detailed mechanisms leading to aneurysm occlusion and healing or incomplete occlusions after treatment with flow diverting devices., (© 2024 The Author(s). International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)

The Cullin-3 E3 ligase adaptor protein SPOP targets proteins for ubiquitination and proteasomal degradation. We previously established the β-cell transcription factor (TF) and human diabetes gene PDX1 as an SPOP substrate, suggesting a functional role for SPOP in the β cell. Here, we generated a β-cell-specific Spop deletion mouse strain ( Spop βKO ) and found that Spop is necessary to prevent aberrant basal insulin secretion and for maintaining glucose-stimulated insulin secretion through impacts on glycolysis and glucose-stimulated calcium flux. Integration of proteomic, TF-regulatory gene network, and biochemical analyses identified XBP1 as a functionally important SPOP substrate in pancreatic β cells. Furthermore, loss of SPOP strengthened the IRE1α-XBP1 axis of unfolded protein response (UPR) signaling. ER stress promoted proteasomal degradation of SPOP, supporting a model whereby SPOP fine-tunes XBP1 activation during the UPR. These results position SPOP as a regulator of β-cell function and proper UPR activation., (© 2025 Oguh et al.; Published by Cold Spring Harbor Laboratory Press.)

Tauopathies, a group of neurodegenerative disorders, are characterized by the abnormal aggregation of tau proteins into neurofibrillary tangles (NFTs), driving synaptic dysfunction, neuronal loss, and disease progression through tau aggregate propagation. Graphene quantum dots (GQDs) functionalized with D - cysteine ( D -GQDs) have shown promise in inhibiting tau aggregation and transmission via π-π stacking and electrostatic interactions with tau proteins. However, the non-specific binding of GQDs to various proteins in the physiological environment, such as serum albumin, limits their clinical translation. In this study, we aim to enhance the specificity of D -GQDs toward tau protein by incorporating a tau-targeting N- amino peptide, mxyl-NAP2. The mxyl-NAP2/ D -GQD complex demonstrated improved selectivity for tau protein over serum albumin, effectively enhancing the inhibition of tau aggregation. To further minimize off-target effects and optimize therapeutic delivery, we loaded the mxyl-NAP2/ D -GQD complex into small extracellular vesicles (sEVs), followed by functionalization of sEVs with neuron targeting ligand, rabies viral glycoprotein peptides. This strategy not only reduced off-target effects, but also enhanced uptake by neuron cells, which further improved inhibition of tau transmission between neurons. Our results indicated that mxyl-NAP2/ D -GQD-loaded sEVs hold great promise for overcoming the off-target limitations of D - GQDs and advancing the development of precision therapeutics for neurodegenerative diseases.

HIV-1 assembly is initiated by the binding of Gag polyproteins to the inner leaflet of the plasma membrane, mediated by the myristylated matrix (MA) domain of Gag. Subsequent to membrane binding, Gag oligomerizes and buds as an immature, non-infectious virus particle, which, upon cleavage of the Gag precursor by the viral protease, transforms into a mature, infectious virion. During maturation, the MA lattice underlying the viral membrane undergoes a structural rearrangement and the newly released capsid (CA) protein forms a mature capsid that encloses the viral genome. While it is well established that formation of the mature capsid is essential to particle infectivity, the functional role of MA structural maturation remains unclear. Here, we examine MA maturation of an MA triple mutant, L20K/E73K/A82T, which exhibits distinct biochemical behaviours. The L20K/E73K/A82T mutant is a revertant derived by propagating the L20K mutant, which exhibits reduced infectivity and increased association of the Gag polyprotein with membranes. L20K/E73K/A82T replicates similarly to wild type but retains the increased Gag membrane binding properties of L20K. L20K/E73K/A82T MA also sediments to high-density fractions in sucrose gradients after detergent treatment under conditions that fully solubilize WT MA, suggesting enhanced MA-MA interactions. Cryo-electron tomography with subtomogram averaging reveals that the immature MA lattice of L20K/E73K/A82T closely resembles the wild type. However, mature virions of the triple mutant lack a detectable MA lattice, in stark contrast to both the wild type and L20K mutant. All-atom molecular dynamics simulations suggest that this absence results from destabilized inter-trimer interactions in the mature L20K/E73K/A82T MA. Furthermore, introducing additional mutations designed to disrupt the mature MA lattice does not impair particle infectivity. These findings suggest that an ordered, membrane-associated mature MA lattice is not essential for HIV-1 infectivity, providing new insights into the structural plasticity of the matrix during maturation and its functional role in the viral lifecycle.

Introduction: Secondary forests and coffee cultivation systems with shade trees might have great potential for carbon sequestration as a means of climate change adaptation and mitigation. This study aimed to measure carbon stocks in coffee plantations under different managements and secondary forest systems in the Peruvian Amazon rainforest (San Martín Region)., Methods: The carbon stock in secondary forest trees was estimated using allometric equations, while carbon stocks in soil, herbaceous biomass, and leaf litter were determined through sampling and laboratory analysis., Results: The biomass carbon stock in secondary forests was 132.2 t/ha, while in coffee plantations with Inga sp. shade trees was 118.2 t/ha. Carbon stocks were 76.5 t/ha in coffee with polyculture farming, while the lowest amount of carbon was found in coffee without shade trees (31.1 t/ha). The carbon sequestered by coffee plants in all agroforestry systems examined had an average of 2.65 t/ha, corresponding to 4.63 % of the total carbon sequestered, being the highest stored in the coffee system with Inga sp. shade trees. A higher content of glomalin-related soil proteins (GRSP) was found in coffee without shade trees, with 18.5 mg/g., Discussion: These results point to Inga sp. as a compatible model of shade system for coffee farms. However, broader-scale time-average measurements and carbon dioxide emissions should be assessed in these study systems to have a full understanding of their climate impacts., Competing Interests: The 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 Vallejos-Torres, Gaona-Jimenez, Pichis-García, Ordoñez, García-Gonzales, Quinteros, Lozano, Saavedra-Ramírez, Tuesta-Hidalgo, Reategui, Macedo-Córdova, Baselly-Villanueva and Marín.)

Background: Soybeans are a widely consumed legume, essential in Western diets and especially prominent in vegan and vegetarian nutrition. However, environmental contamination from anthropogenic sources, such as industrial emissions, wastewater, and pesticide use, has led to the accumulation of non-essential and toxic elements in legumes, potentially impacting human health. Method: This study quantified the levels of 11 potential toxic elements (Al, B, Ba, Cd, Co, Cr, Li, Ni, Pb, Sr, V) in 90 samples of four soybean species ( Glycine max , Vigna radiata , Vigna angularis , Vigna mungo ) using inductively coupled plasma optical emission spectrometry (ICP-OES). Results: Results showed that boron had the highest mean content (9.52 mg/kg ww), followed by aluminum (6.73 mg/kg ww). Among the toxic metals, cadmium was most concentrated in green soybeans (0.03 mg/kg ww), and black soybeans had the highest level of lead (0.07 mg/kg ww). Based on an average soybean consumption of 50 g/day, no immediate health risk was detected. However, lithium and nickel were present in substantial amounts, with lithium contributing 31.43-48.57% and nickel 6.81-39.56% of their respective provisional daily intake limits, especially from red soybeans ( V. angularis ). Conclusions: This study highlights the importance of monitoring toxic elements in soybeans and calls for stricter environmental management practices to minimize contamination, ensuring the safety of soy products as their global consumption rises.

Obstructive Sleep Apnea (OSA) is a widespread disease, but usually is an underdiagnosed and undertreated public health problem. Nowadays its study is expensive. Collaboration and involvement of all specialties are necessary, also the implementation of simplified diagnostic methods to try to improve detection, increase the diagnosis and treatment ratio. In the Osona region (Barcelona), it has been developed a protocol that defines a new care process that shortens and reduces the cost of the OSA's diagnosis process. This new care process also favors better knowledge of the pathology of OSA by all the specialists involved, resulting in an increase in community health, in addition to generating knowledge. This new care process could be implemented in other health areas around all the country and it would improve the management of this pathology and improve national community health., Competing Interests: Conflicto de intereses Los autores del estudio no tienen conflicto de intereses., (Copyright © 2024 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.)

The importance of maintaining data privacy and complying with regulatory requirements is highlighted especially when sharing omic data between different research centers. This challenge is even more pronounced in the scenario where a multi-center effort for collaborative omics studies is necessary. OmicSHIELD is introduced as an open-source tool aimed at overcoming these challenges by enabling privacy-protected federated analysis of sensitive omic data. In order to ensure this, multiple security mechanisms have been included in the software. This innovative tool is capable of managing a wide range of omic data analyses specifically tailored to biomedical research. These include genome and epigenome wide association studies and differential gene expression analyses. OmicSHIELD is designed to support both meta- and mega-analysis, so that it offers a wide range of capabilities for different analysis designs. We present a series of use cases illustrating some examples of how the software addresses real-world analyses of omic data., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Escriba-Montagut 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.)

Background: Transperitoneal approach to robot-assisted pyeloplasty (RAP) have been preferred in the last decades because of the use of multi-port robotic platforms. However, this approach is linked to notable issues, such as pneumoperitoneum and lateral decubitus position, which is associated with potential soft tissues injuries, and it is a time-consuming procedure. Single-port (SP) platform was introduced to potentially address these issues. Our aim was to describe perioperative surgical and functional outcomes of SP-RAP, including our preliminary results comparing the transperitoneal and LAA approaches., Methods: Data from a prospectively maintained dataset of all consecutive patients undergoing SP-RAP between 2019 and 2024 were retrospectively reviewed. Early procedures were performed using transperitoneal midline access, while later procedures utilized the low anterior access (LAA) approach. Patients' demographics, perioperative data, and surgical and functional outcomes were collected., Results: Overall, 34 patients underwent the procedure without intraoperative complications or conversion to an alternative approach. The median age was 46.5 (range: 35-56) years. The transperitoneal approach was used for the first 17 (50%) procedures, while the remaining 17 (50%) underwent LAA SP-RAP. Nonoperative room time, postoperative opioid dose, and length of hospital stay were significantly lower in the LAA group (P<0.001 in all cases), with all patients in the LAA group being discharged on the same day. No differences were observed in operative time or postoperative renal function., Conclusions: Outcomes for SP pyeloplasties appear promising, and the LAA approach may help optimize operating room time, promote faster patient recovery, and reduce postoperative opioid use.

Background: Infection remains a relevant complication after kidney transplantation (KT). A well-established strategy in modern medicine is the application of bundles of evidence-based practice in clinical settings. The objective of this study is to explore the application of a personalized bundle of measures aimed to reduce the incidence of infection in the first 12 months after KT., Methods: A single-center prospective cohort of 148 patients undergoing KT between February 2018 and September 2019 that received an individualized infection prevention strategy was compared to a preintervention cohort (n = 159). The bundle comprised a review of the patient's immunization history, infection risk by country of origin, screening for latent tuberculosis infection (LTBI), antimicrobial prophylaxis, and immunological assessment. Individualized recommendations were accordingly provided at a scheduled visit at day +30 after transplantation., Results: The intervention cohort showed a higher compliance rate with the recommended vaccine schedule, screening for geographically restricted infections and LTBI, and intravenous immunoglobulin and vitamin D supplementation (p values <.001). The 1-year incidence rate of infection was lower in the intervention cohort (42.6% vs. 57.9%; p value = .037), as was the rate of infection-related hospitalization (17.6% vs. 32.1%; p value = .003) and the incidence of severe bacterial infection. There were no differences in graft rejection or mortality rates between groups., Conclusions: A multifaceted intervention, including a bundle of evidence-based practices, enhanced compliance with recommended preventive measures and was correlated with a reduction in the 12-month incidence of infection after KT., (© 2024 The Author(s). Transplant Infectious Disease published by Wiley Periodicals LLC.)

Cytomegalovirus (CMV) infection remains a significant challenge in solid organ transplantation (SOT). The last international consensus guidelines on the management of CMV in SOT were published in 2018, highlighting the need for revision to incorporate recent advances, notably in cell-mediated immunity monitoring, which could alter the current standard of care. A working group including members from the Group for the Study of Infection in Transplantation and the Immunocompromised Host (GESITRA-IC) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and the Spanish Society of Transplantation (SET), developed consensus-based recommendations for managing CMV infection in SOT recipients. Recommendations were classified based on evidence strength and quality using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The final recommendations were endorsed through a consensus meeting and approved by the expert panel., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Julian Torre-Cisneros reports administrative support, article publishing charges, travel, and writing assistance were provided by Spanish Society of Infectious Diseases and Clinical Microbiology. Julian Torre-Cisneros reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory and speaking and lecture fees. Julian Torre-Cisneros reports a relationship with Takeda Pharmaceutical Company Limited that includes: consulting or advisory. Julian Torre-Cisneros reports a relationship with Biotest AG that includes: consulting or advisory and speaking and lecture fees. Julian Torre-Cisneros reports a relationship with QIAGEN GmbH that includes: consulting or advisory, funding grants, and speaking and lecture fees. Jose Maria Aguado reports a relationship with Mundipharma International Limited that includes: consulting or advisory and speaking and lecture fees. Jose Maria Aguado reports a relationship with Pfizer that includes: consulting or advisory and speaking and lecture fees. Jose Maria Aguado reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory and speaking and lecture fees. Jose Maria Aguado reports a relationship with Takeda Pharmaceutical Company Limited that includes: consulting or advisory and speaking and lecture fees. Sara Cantisan reports a relationship with QIAGEN GmbH that includes: funding grants and speaking and lecture fees. Juan Jose Caston reports a relationship with Pfizer Inc. that includes: funding grants and speaking and lecture fees. Juan Jose Caston reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: speaking and lecture fees. Juan Jose Caston reports a relationship with A Menarini International Pharmaceutics that includes: speaking and lecture fees. Juan Jose Caston reports a relationship with Novartis Pharmaceuticals Corporation that includes: speaking and lecture fees. Juan Jose Caston reports a relationship with QIAGEN GmbH that includes: funding grants and speaking and lecture fees. Carme Facundo reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory. Mirian Fernandez-Alonso reports a relationship with Roche Diagnostics Corporation that includes: travel reimbursement. Mirian Fernandez-Alonso reports a relationship with Werfen that includes: travel reimbursement. Mirian Fernandez-Alonso reports a relationship with QIAGEN GmbH that includes: non-financial support. Mario Fernandez-Ruiz reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory. Mario Fernandez-Ruiz reports a relationship with Biotech that includes: consulting or advisory. Sabina Herrera reports a relationship with Pfizer Inc. that includes: speaking and lecture fees and travel reimbursement. Sabina Herrera reports a relationship with Shionogi Inc. that includes: speaking and lecture fees. Sabina Herrera reports a relationship with Shire that includes: travel reimbursement. Sabina Herrera reports a relationship with A Menarini International Pharmaceutics that includes: travel reimbursement. Oscar Len reports a relationship with Pfizer that includes: funding grants and speaking and lecture fees. Oscar Len reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: funding grants and speaking and lecture fees. Oscar Len reports a relationship with Astellas Pharma Inc. that includes: speaking and lecture fees. Oscar Len reports a relationship with Novartis Pharmaceuticals Corporation that includes: speaking and lecture fees. Ibai Los-Arcos reports a relationship with Pfizer Inc. that includes: speaking and lecture fees and travel reimbursement. Ibai Los-Arcos reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: speaking and lecture fees and travel reimbursement. Ibai Los-Arcos reports a relationship with Gilead Sciences Inc. that includes: travel reimbursement. Ibai Los-Arcos reports a relationship with A Menarini International Pharmaceutics that includes: travel reimbursement. David Navarro reports a relationship with Roche Diagnostics Corporation that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Abbott that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with bioMérieux SA that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Beckton Dickinson that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Gilead Sciences Inc. that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Takeda Pharmaceutical Company Limited that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: consulting or advisory and speaking and lecture fees. David Navarro reports a relationship with Pfizer Inc. that includes: consulting or advisory and speaking and lecture fees. Maricela Valerio reports a relationship with Pfizer Inc. that includes: speaking and lecture fees and travel reimbursement. Maricela Valerio reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: speaking and lecture fees and travel reimbursement. Maricela Valerio reports a relationship with Shionogi and Co Ltd. that includes: speaking and lecture fees and travel reimbursement. Maricela Valerio reports a relationship with GSK that includes: speaking and lecture fees. If there are other authors, they 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 Authors. Published by Elsevier Inc. All rights reserved.)

Background: Preventive management of tuberculosis in liver transplantation (LT) is challenging due to difficulties in detecting and treating latent tuberculosis infection (LTBI). The aim of this study was to analyze the safety and efficacy of a screening strategy for LTBI with the inclusion of moxifloxacin as treatment., Methods: We performed a retrospective single-center study of all LTs performed between 2016 and 2019 with a minimum 4-year follow-up and a standardized protocol for the evaluation of LTBI., Results: Pretransplant LTBI screening was performed in 191/218 (87.6%) patients, and LTBI was diagnosed in 27.2% of them. Treatment for LTBI was administered to 71.2% of the patients and included moxifloxacin in 75.6% of the cases. After a median follow-up of 1628 days, no cases of active tuberculosis occurred among moxifloxacin-treated patients. The incidence of Clostridioides difficile (0.46 vs. 0.38 episodes/1000 transplant-days; p =  .8) and multidrug-resistant gram-negative bacilli infection (0 vs. 0.7 episodes per 1000 transplant-days; p =  .08) were not significantly higher in comparison to patients who did not receive moxifloxacin., Conclusion: A preventive strategy based on systematic LTBI screening and moxifloxacin treatment before LT in positive cases appears safe and effective in preventing the development of tuberculosis in LT recipients. However, our findings are limited by a small sample size; thus, larger studies are required to validate our observations., (© 2024 Wiley Periodicals LLC.)

The mechanisms leading to aneurysm occlusion after treatment with flow-diverting devices are not fully understood. Flow modification induces thrombus formation within the aneurysm cavity, but fibrin can simultaneously accumulate and cover the device scaffold, leading to further flow modification. However, the interplay and relative importance of these processes are not clearly understood. A computational model of fibrin accumulation and flow modification after flow diversion treatment of cerebral aneurysms has been developed under the guidance of in vitro experiments and observations. The model is based on the loose coupling of flow and transport-reaction equations that are solved separately by independent codes. Interaction or reactive terms account for thrombin production from prothrombin stimulated by thrombogenic metallic wires and inhibition by antithrombin as well as fibrin production from fibrinogen stimulated by thrombin and flow shear stress, and fibrin adhesion to device wires and already attached fibrin. The computational model was demonstrated and tested on idealized vessel and aneurysm geometries. The model was able to reproduce the salient features of fibrin accumulation after the deployment of flow-diverting devices in idealized in vitro models of cerebral aneurysms. Namely, fibrin production in regions of high shear stress, initial accumulation at the inflow zone, and progressive occlusion of the device and corresponding flow attenuation. The computational model linking flow dynamics to fibrin production, transport, and adhesion can be used to investigate and better understand the effects that lead to fibrin accumulation and the resulting aneurysm inflow reduction and intra-aneurysmal flow modulation., (© 2024 The Author(s). International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)

The increasing consumption of chia seeds is followed by a growing interest in their nutritional and toxicological characterization. To assess the characterization of the essential and PTEs of this novel food, 20 samples of conventional and organic chia seeds available on the European market were analyzed using ICP-OES. Then, the dietary exposure to these elements was assessed. An exhaustive investigation into the metal content of this food serves to elucidate the paucity of existing knowledge. The results show that the levels of essential elements are similar in both types of production, while the levels of PTEs are higher in the organic samples. The exposure assessment indicates that Mn contributes the most among the essential elements, followed by Cu in women. Exposure to PTEs through doses of 50 g/day of chia seeds analyzed would hardly pose short-term health risks as the contributions are below 10%, except for Sr, although they could produce a long-term toxicological risk. To promote safety in chia seed consumption, it is recommended to encourage responsible and moderate consumption, continue monitoring PTE levels in this novel food, and establish concentration limits for PTEs in future European regulations.

We report the synthesis of the antimicrobial cyclodepsipeptides marformycin A ( 1 ) and marformycin D ( 2 ) using a solid-phase approach. A scalable solution-phase synthesis of the γ-hydroxypiperazic acid subunit in 2 , starting from cis -hydroxyproline, is also described. Structural analysis of 1 and its Leu- epi congener demonstrates conformational differences that may underlie their divergent antimicrobial activities. The described approach enables further development of conformation-activity relationships within this class of depsipeptide natural products.

The gene editing field has advanced rapidly since the development of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system because of its applicability in precisely modifying the genome. Among its multiple applications, the correction of genetic diseases has emerged as a potential curative treatment for many disorders that have eluded a cure to date. Despite its efficiency in achieving therapeutic levels of correction, the unexpected adverse effects of editing due to CRISPR/Cas9 nuclease activity are a major concern when translating these new strategies to the clinic. Multiple in silico tools and empirical methods have been developed to evaluate these off-target edits as well as other adverse alterations of the genome, including rearrangements, not only in ex vivo experiments but also in in vivo experiments. In this review, we summarize the available methods for the assessment of off-target effects of CRISPR/Cas9 systems, highlighting their advantages and limitations. Special attention will be paid to their application in pre-clinical studies and clinical trials, both in the manufacturing product and in the long-term follow-up of patients., Competing Interests: Declaration of competing interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Robot-Assisted Simple Prostatectomy (RASP) is recommended for the treatment of large prostate glands. The introduction of the Single-Port (SP) platform in 2018 has enabled transvesical approach to SP-RASP with promising outcomes. Our aim was to describe the functional and urinary continence outcomes of SP-RASP., Methods: Clinical and surgical data from all consecutive patients who underwent transvesical SP-RASP between February 2020 and March 2024 were collected in a prospectively maintained institutional dataset and retrospectively analyzed. All procedures were performed using the da Vinci SP platform without any conversions to open surgery. Postoperative outcomes were gathered and analyzed, with a particular focus on the incidence of urinary incontinence (UI) and the time to continence recovery., Results: Overall, 89 patients underwent SP-RASP, with a median prostate size of 110 grams (90-171.5) and a median PSA level of 5.5 mg/dl (2.77-10.93). All patients were on at least one prostate medication prior to surgery. Preoperative evaluations showed a median International Prostate Symptoms Score (IPSS) of 23 (20-27), Quality of Life (QoL) of 4 (3-5), and Post-voiding Residual (PVR) of 153 ml (60-400). The median operative time was 180 min (164-200), with a median estimated blood loss of 100 ml (30-180). Postoperatively, no patients required continuous bladder irrigation. The median postoperative opioid intake was 6.5 morphine equivalents (0-10), with over 78% not requiring narcotics after discharge. Overall, 77.5% were same day discharged. No Clavien-Dindo > 2 complications were recorded. The median follow-up time was 18 (7-35) months. At the last postoperative urological evaluation, the median IPSS was 5 (3-7), QoL was 1 (0-2), and PVR was 10 ml (0-25). Only 4 patients (4.5%) experienced UI postoperatively, and all were continent within 3 months., Conclusions: The UI incidence rate and functional outcomes of SP-RASP are very encouraging, likely due to precise adenoma and urethra dissection and bladder neck reconstruction. This approach also allows for same-day discharge., Competing Interests: Competing interests Dr. Simone Crivellaro is a consultant for Intuitive, other authors have nothing to disclose. Ethics approval and consent to participate Institutional review board approval (protocol n° 2017-0152 from Office of Vice Chancellor for Research, University of Illinois at Chicago) was obtained previously to data collecting and analysis. This study was conducted in accordance with ethical principles given by the Helsinki Declaration about clinical studies on human participants, and written informed consent was obtained from all subjects., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive lung disease urgently needing new therapies. Current treatments only delay disease progression, leaving lung transplant as the sole remaining option. Recent studies support a model whereby IPF arises because alveolar epithelial type II (AT2) cells, which normally mediate distal lung regeneration, acquire airway and/or mesenchymal characteristics, preventing proper repair. Mechanisms driving this abnormal differentiation remain unclear. We performed integrated transcriptomic and epigenomic analysis of purified AT2 cells which revealed genome-wide alterations in IPF lungs. The most prominent epigenetic alteration was activation of an enhancer in thyroid receptor interactor 13 (TRIP13), although TRIP13 was not the most significantly transcriptionally upregulated gene. TRIP13 is broadly implicated in epithelial-mesenchymal plasticity. In cultured human AT2 cells and lung slices, small molecule TRIP13 inhibitor DCZ0415 prevented acquisition of the mesenchymal gene signature characteristic of IPF, suggesting TRIP13 inhibition as a potential therapeutic approach to fibrotic disease., 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. Published by Elsevier B.V.)

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents that potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into phase 2a clinical trials. Previous cell culture-based viral breakthrough assays identified the HIV-1 (Y99H/A128T IN) variant that confers substantial resistance to this inhibitor. Here, we have elucidated the unexpected mechanism of viral resistance to PIR. Although both Tyr99 and Ala128 are positioned within the inhibitor binding V-shaped cavity at the IN catalytic core domain (CCD) dimer interface, the Y99H/A128T IN mutations did not substantially affect the direct binding of PIR to the CCD dimer or functional oligomerization of full-length IN. Instead, the drug-resistant mutations introduced a steric hindrance at the inhibitor-mediated interface between CCD and C-terminal domain (CTD) and compromised CTD binding to the CCD Y99H/A128T + PIR complex. Consequently, full-length IN Y99H/A128T was substantially less susceptible to the PIR-induced hyper-multimerization than the WT protein, and HIV-1 (Y99H/A128T IN) conferred >150-fold resistance to the inhibitor compared with the WT virus. By rationally modifying PIR, we have developed its analog EKC110, which readily induced hyper-multimerization of IN Y99H/A128T in vitro and was ~14-fold more potent against HIV-1 (Y99H/A128T IN) than the parent inhibitor. These findings suggest a path for developing improved PIR chemotypes with a higher barrier to resistance for their potential clinical use.IMPORTANCEAntiretroviral therapies save the lives of millions of people living with HIV (PLWH). However, the evolution of multi-drug-resistant viral phenotypes is a major clinical problem, and there are limited or no treatment options for heavily treatment-experienced PLWH. Allosteric HIV-1 integrase inhibitors (ALLINIs) are a novel class of antiretroviral compounds that work by a unique mechanism of binding to the non-catalytic site on the viral protein and inducing aberrant integrase multimerization. Accordingly, ALLINIs potently inhibit both wild-type HIV-1 and all drug-resistant viral phenotypes that have so far emerged against currently used therapies. Pirmitegravir, a highly potent and safe investigational ALLINI, is currently advancing through clinical trials. Here, we have elucidated the structural and mechanistic bases behind the emergence of HIV-1 integrase mutations in infected cells that confer resistance to pirmitegravir. In turn, our findings allowed us to rationally develop an improved ALLINI with substantially enhanced potency against the pirmitegravir-resistant virus., Competing Interests: Kyungjin Kim was the chief executive officer of ST Pharm Co. Ltd. No other authors declare a potential conflict of interest.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is often asymptomatic and underdiagnosed; consequently, there is a demand for simple, non-invasive diagnostic tools. In this study, we developed a method to quantify liver steatosis based on miRNAs, present in liver and serum, that correlate with liver fat. The miRNAs were analyzed by miRNAseq in liver samples from two cohorts of patients with a precise quantification of liver steatosis. Common miRNAs showing correlation with liver steatosis were validated by RT-qPCR in paired liver and serum samples. Multivariate models were built using partial least squares (PLS) regression to predict the percentage of liver steatosis from serum miRNA levels. Leave-one-out cross validation and external validation were used for model selection and to estimate predictive performance. The miRNAseq results disclosed (a) 144 miRNAs correlating with triglycerides in a set of liver biobank samples ( n = 20); and (b) 124 and 102 miRNAs correlating with steatosis by biopsy digital image and MRI analyses, respectively, in liver samples from morbidly obese patients ( n = 24). However, only 35 miRNAs were common in both sets of samples. RT-qPCR allowed to validate the correlation of 10 miRNAs in paired liver and serum samples. The development of PLS models to quantitatively predict steatosis demonstrated that the combination of serum miR-145-3p, 122-5p, 143-3p, 500a-5p, and 182-5p provided the lowest root mean square error of cross validation (RMSECV = 1.1, p -value = 0.005). External validation of this model with a cohort of mixed MASLD patients ( n = 25) showed a root mean squared error of prediction (RMSEP) of 5.3. In conclusion, it is possible to predict the percentage of hepatic steatosis with a low error rate by quantifying the serum level of five miRNAs using a cost-effective and easy-to-implement RT-qPCR method.

To develop and validate a novel Comorbidity score for Robotic Surgery (CRS) in predicting severe complications after robot-assisted radical prostatectomy (RARP). Furthermore, we investigated the impact of the surgical platform (Multi-Port - MP vs Single-Port - SP) according to this score. We included 2085 ("development cohort") and 595 ("validation cohort") patients undergoing RARP at two tertiary referral centers between 2014 and March 2024 in a retrospective study. Statistical analyses included validation of the Charlson Comorbidity Index (CCI) to predict 30-day severe complications (Clavien-Dindo ≥ 3a), development and external validation of CRS using calibration plots and decision curve analysis. Lastly, locally weighted scatterplot smoothing (LOWESS) analysis was used to graphically explore the impact of the robotic platform according to novel CRS. CCI exhibited limited predictive ability for severe complications (60% in the validation cohort). In multivariable logistic regression analyses testing the correlation between each condition included in CCI and severe complications, diabetes and myocardial infarction resulted as independent predictors (OR 1.75 [95%CI 1.05-2.82]; OR 1.92 [95%CI 1.26-2.88]) and were subsequently fitted into a multivariable logistic model including age, previous abdominal surgery and obesity (BMI > 30). The resulting predictive model demonstrated superior discrimination and clinical net benefit in predicting severe complications compared to CCI (AUC 64 vs 60%). At LOWESS analysis, SP platform was associated with lower risk of severe complications as CRS increased compared to MP system. The validated CRS showed better accuracy compared to CCI in predicting severe complications after RARP. Additionally, the use of SP robotic platform may reduce the risk of severe complications in highly comorbid patients according to CRS., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Background: Trauma is a leading cause of global death, with 200 000 deaths and over 3 million non-fatal injuries/year in the United States. We aim to assess trauma care value for patients who underwent urgent laparotomies (LAP) and thoracotomies (THO) in our Health Network System., Methods: Clinical variables (v = 84) from trauma patients (>18 yo) were retrieved retrospectively (Jan-2010 to July-2016) and prospectively (Aug-2016 to Sept-2021) from a Health System warehouse under IRB-approved protocols. Patients were divided according to their Injury Severity Score (ISS) into mild/moderate cases (ISS <15) and severe cases (ISS >15). Value was assessed using quality and cost domains. Quality surrogates included graded postoperative complications (PCs), length of stay (LOS), 30-day readmission (RA), patient satisfaction (PS), and textbook (TB) cases. Total charges (TCs) and reimbursement index ( RI) were included as surrogates for cost. Value domains were displayed in scorecards comparing Observed (O) with Expected (E) (using the ACS risk calculator) outcomes. Uni-/multivariate analyses were performed using SPSS., Results: 41,927 trauma evaluations were performed, leading to 16 044 admissions, with 528 (3.2%) patients requiring urgent surgical procedures (LAP = 413 and THO = 115). Although the M:F ratio (7:3) was similar in LAP vs THO groups, age and BMI were significantly different (41.8 ± 19.1 vs 51.8 ± 19.9 years, 28.6 ± 9.9 vs 27.4 ± 7 Kg/m 2 , respectively, P < .05). Blunt trauma was involved in 68.8/77.3% of the LAP/THO procedures, respectively ( P < .05). Multivariate analyses showed ISS, age, ASA class, and medical center as factors significantly predicting PC ( P < .05). Postoperative complication grades from the LAP/THO groups showed above-average outcomes; nonetheless, LOS was higher than the national averages., Conclusions: The Trauma Program holds high value in our Health Network System. Protocols for decreasing LOS are being implemented., 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.

Hematological cancers encompass a diverse group of malignancies affecting the blood, bone marrow, lymph nodes, and spleen. These disorders present unique challenges due to their complex etiology and varied clinical manifestations. Despite significant advancements in understanding and treating hematological malignancies, innovative therapeutic approaches are continually sought to enhance patient outcomes. This review highlights the application of RNA nanoparticles (RNA-NPs) in the treatment of hematological cancers. We delve into detailed discussions on in vitro and preclinical studies involving RNA-NPs for adult patients, as well as the application of RNA-NPs in pediatric hematological cancer. The review also addresses ongoing clinical trials involving RNA-NPs and explores the emerging field of CAR-T therapy engineered by RNA-NPs. Finally, we discuss the challenges still faced in translating RNA-NP research to clinics., 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.)

Background: The lymphatic microsurgical preventive healing approach reduces the risk of lymphedema after axillary lymph node dissection. We identified surgical factors of Lymphatic Microsurgical Preventive Healing Approach (LYMPHA) that influence lymphedema rates focusing on the vein caliber used., Methods: A single-institution retrospective cohort study included breast cancer patients undergoing axillary lymph node dissection and LYMPHA (April 2021-November 2022) with a follow-up of at least 1 year. Lymphedema was defined as an increase of ≥10 units in the lymphedema index (measured using bioimpedance spectroscopy) from baseline. The primary outcome was the correlation between the lymphedema index of patients with a vein caliber of ≤2 mm vs > 2 mm., Results: Forty-eight patients with documented vein caliber were analyzed. The median baseline lymphedema index in patients with a vein caliber ≤2 mm was 2 (SD 3.04) and 2.2 (SD 2.03) for vein caliber >2 mm. (P = .57). After 1-year follow-up, the L-dex was 6.20 (SD 7.48) for vein caliber ≤2 mm and 1.60 (SD 5.85) for vein caliber >2 mm (P = .02). The L-dex difference from baseline was higher for vein caliber ≤2 mm compared to >2 mm (2.9 vs 0.10, P = .02). Larger vein caliber was associated with a lower L-dex at 3 months (P = .04) and a lesser difference from the baseline after 1 year (P = .03). This was maintained on univariate analysis and multivariate analysis controlling for radiation, chemotherapy, and number of lymph nodes excised., Conclusion: Vein caliber >2 mm during LYMPHA axillary lymph node dissection is associated with a lower postoperative lymphedema index. These results can be enhanced by a multi-institutional study to improve standardization of this technique., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Invasive aspergillosis (IA) is a rare but fatal disease among liver transplant recipients (LiTRs). We performed a multicenter 1:2 case-control study comparing LiTRs diagnosed with proven/probable IA and controls with no invasive fungal infection. We included 62 IA cases and 124 matched controls. Disseminated infection occurred only in 8 cases (13%). Twelve-week all-cause mortality of IA was 37%. In multivariate analyses, systemic antibiotic usage (adjusted odds ratio [aOR], 4.74; P = .03) and history of pneumonia (aOR, 48.7; P = .01) were identified as independent risk factors associated with the occurrence of IA. Moreover, reoperation (aOR, 5.99; P = .01), systemic antibiotic usage (aOR, 5.03; P = .04), and antimold prophylaxis (aOR, 11.9; P = .02) were identified as independent risk factors associated with the occurrence of early IA. Among IA cases, Aspergillus colonization (adjusted hazard ratio [aHR], 86.9; P < .001), intensive care unit stay (aHR, 3.67; P = .02), disseminated IA (aHR, 8.98; P < .001), and dialysis (aHR, 2.93; P = .001) were identified as independent risk factors associated with 12-week all-cause mortality, while recent receipt of tacrolimus (aHR, 0.11; P = .001) was protective. Mortality among LiTRs with IA remains high in the current era. The identified risk factors and protective factors may be useful for establishing robust targeted antimold prophylactic and appropriate treatment strategies against IA., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. J. Hand reports research grant funding from Pfizer, Janssen, Scynexis, and GlaxoSmithKline. D. Neofytos has received research support from MSD and Pfizer and consulting fees from MSD, Pfizer, Basilea, and Gilead. N.J. Mueller is on the scientific advisory board of Takeda MSD, and Pfizer and has received travel support from Biotest. M. Luong is on the Scientific Advisory Board of Takeda and Merck. S. Husain reports grant funding from Merck, Astellas, ScynexisInc, Pulmocide, Ltd, and Gilead Sciences Inc, outside the submitted work. All other authors have no potential conflicts., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: Because angiotensin (Ang) II is an essential vasoconstrictive peptide, we analyzed the impact of its post-translational modification to pyruvamide-Ang II (Ang P) by pyridoxal-5'-phosphate (PLP) on blood pressure. PLP is a less expensive vitamin B 6 derivative and, therefore, could be a cost-effective drug against hypertension., Methods: Effect of Ang P on calcium ion entry into vascular smooth muscle cells (VSMCs) was analyzed. Binding affinity of Ang P to angiotensin II type 1 receptor (AT 1 R) was measured. Vasoconstrictive effect of Ang P was investigated using the bioassay of isolated perfused rat kidneys. Spontaneously hypertensive rats (SHR) were administered PLP. Additionally, Wistar Kyoto rats (WKY) received Ang II and PLP. Blood pressure was measured time-dependently., Results: Ang II, incubated with PLP, was post-translationally modified to Ang P. Calcium ion entry in VSMCs was significantly lower with Ang P compared to Ang II. Binding affinity of Ang P to AT 1 R was lower compared to Ang II. Perfusion pressure of isolated perfused rat kidneys increased less by Ang P than by Ang II. Blood pressure of SHR treated with PLP decreased significantly. Blood pressure of WKY rats treated with Ang II was increased to hypertensive values, whereas blood pressure of WKY rats cotreated with Ang II and PLP was not., Conclusion: PLP induces a post-translational modification of Ang II decreasing blood pressure in rats. Assuming that increased PLP intake in the form of vitamin B 6 might reduce blood pressure in hypertensive patients, PLP might be a cost-effective drug against hypertension., (© 2024 The Author(s). Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Frailty is associated with poor clinical outcomes in heart failure patients. The impact of frailty on outcomes following left ventricular assist device (LVAD) implantation, however, is less clearly defined. We therefore sought to conduct a systematic review to evaluate current frailty assessment strategies and their significance for patients undergoing LVAD implantation. We conducted a comprehensive electronic search of PubMed, Embase, and CINAHL databases from inception until April 2021 for studies examining frailty in patients undergoing LVAD implantation. Study characteristics, patient demographics, type of frailty measurement, and outcomes were extracted. Outcomes were organized into 5 basic categories: implant length of stay (iLOS), 1-year mortality, rehospitalization, adverse events, and quality of life (QOL). Of the 260 records retrieved, 23 studies involving 4935 patients satisfied the inclusion criteria. Approaches to measuring frailty varied, with the 2 most common being sarcopenia determined by computed tomography and Fried's frailty phenotype assessment. Outcomes of interest were also widely variable, with iLOS stay and mortality being the most frequently reported, albeit with differing definitions of both between studies. The heterogeneity among included studies precluded quantitative synthesis. Narrative synthesis showed that frailty by any measure is more likely to be associated with higher mortality, longer iLOS, more adverse events and worse QOL post-LVAD implant. Frailty can be a valuable prognostic indicator in patients undergoing LVAD implantation. Further studies are needed to determine the most sensitive frailty assessment, as well as the ways in which frailty may serve as a modifiable target to improve outcomes following LVAD implantation., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Mesoscale eddies have attracted increased attention due to their central role in ocean energy and mass transport. The observations of their three-dimensional structure will facilitate the understanding of nonlinear eddy dynamics. In this paper, we propose a novel framework, the mesoscale eddy characterization from ordinal modalities recurrence networks method (MeC-OMRN), that utilizes a Petrel-II underwater glider for in situ observations and vertical structure characterization of a moving mesoscale eddy in the northern South China Sea. First, higher resolution continuous observation profile data collected throughout the traversal by the underwater glider are acquired and preprocessed. Subsequently, we analyze and compute these nonlinear data. To further amplify the hidden structural features of the mesoscale eddy, we construct ordinal modalities sequences rich in spatiotemporal characteristics based on the measured vertical density of the mesoscale eddy. Based on this, we employ ordinal modalities recurrence plots (OMRPs) to depict the vertical structure inside and outside the eddy, revealing significant differences in the OMRPs and the unevenness of density stratification within the eddy. To validate our intriguing findings from the perspective of complex network theory, we build the multivariate weighted ordinal modalities recurrence networks, through which network measures exhibit a more random distribution of vertical density stratification within the eddy, possibly due to more intense vertical convection and oscillations within the eddy's seawater micelles. These framework and intriguing findings are anticipated to be applied to more data-driven in situ observation tasks of oceanic phenomena., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids 1-3 . Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8 + T cells 4,5 . However, the mechanisms that govern this immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer transgelin 2 (TAGLN2) is necessary for optimal fatty acid uptake, mitochondrial respiration and anticancer function in CD8 + T cells. TAGLN2 interacts with FABP5 to facilitate its cell surface localization and function in activated CD8 + T cells. Analyses of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses induced by the tumour microenvironment repress TAGLN2 in infiltrating CD8 + T cells, thereby enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8 + T cells increased their lipid uptake, mitochondrial respiration and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumour-induced ER stress and demonstrated therapeutic efficacy in mice with metastatic ovarian cancer. Our study establishes the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis., Competing Interests: Competing interests: J.R.C.-R. holds patents on the targeting of ER stress responses for the treatment of disease, as well as on the use of immune modulators for OC therapy. J.R.C.-R. is a scientific consultant for Moderna, Immagene, Autoimmunity Biologic Solutions, and Emerald Bioventures, and holds stock options in Vescor Therapeutics. D.Z. reports institutional grants from Merck, Genentech, AstraZeneca, Plexxikon, and Synthekine, and personal fees from AstraZeneca, Xencor, Memgen, Takeda, Synthekine, Immunos, Tessa Therapeutics, Miltenyi, and Calidi Biotherapeutics. D.Z. owns a patent on use of oncolytic Newcastle Disease Virus for cancer therapy. J.R.C.-G. has stock options in Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics; receives licensing fees from Anixa Biosciences for the patent of FSHCER T cells; receives honorarium from Alloy Therapeutics; has intellectual property with Compass Therapeutics and Anixa Biosciences; and is co-founder of Cellepus Therapeutics, a company that develops allogeneic γδ CAR T cells. All other authors declare no potential conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

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The QuantiFERON-Monitor assay (QTF-Monitor) is intended to assess innate and adaptive immune responses by quantifying interferon (IFN)-γ release upon whole blood stimulation with a TLR7/8 agonist and an anti-CD3 antibody. We performed the QTF-Monitor in 126 kidney transplant recipients (KTRs) at different points during the first 6 post-transplant months. The primary outcome was overall infection, whereas secondary outcomes included bacterial infection, opportunistic infection and de novo cancer. The association between IFN-γ production and outcomes was analyzed as "low" immune responses (<15 IU/mL) and as a continuous variable to explore alternative thresholds. There were no significant differences in the occurrence of overall infection according to the QTF-Monitor at any monitoring point. Regarding secondary outcomes, KTRs with a low response at week 2 experienced a higher incidence of bacterial infection (50.8% versus 24.4%; P -value = 0.006). Low response at month 1 was also associated with opportunistic infection (31.6% versus 14.3%; P -value = 0.033). The discriminative capacity of IFN-γ levels was poor (areas under the ROC curve: 0.677 and 0.659, respectively). No differences were observed for the remaining points or post-transplant cancer. In conclusion, the QTF-Monitor may have a role to predict bacterial and opportunistic infection in KTRs when performed early after transplantation., Competing Interests: The 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 Fernández-Ruiz, Ruiz-Merlo, Rodríguez-Goncer, Caso, López-Medrano, Parra, San Juan, Polanco, González, Andrés, Aguado and Redondo.)

Hepatocytes-like cells (HLC) derived from human induced pluripotent stem cells show great promise for cell-based liver therapies and disease modelling. However, their application is currently hindered by the low production yields of existing protocols. We aim to develop a bioprocess able to generate high numbers of HLC. We used stirred-tank bioreactors with a rational control of dissolved oxygen concentration (DO) for the optimization of HLC production as 3D aggregates. We evaluated the impact of controlling DO at physiological levels (4%O 2 ) during hepatic progenitors' stage on cell proliferation and differentiation efficiency. Whole transcriptome analysis and biochemical assays were performed to provide a detailed characterization of HLC quality attributes. When DO was controlled at 4%O 2 during the hepatic progenitors' stage, cells presented an upregulation of genes associated with hypoxia-inducible factor pathway and a downregulation of oxidative stress genes. This condition promoted higher HLC production (maximum cell concentration: 2 × 10 6 cell/mL) and improved differentiation efficiencies (80% Albumin-positive cells) when compared to the bioreactor operated under atmospheric oxygen levels (21%O 2 , 0.6 × 10 6 cell/mL, 43% Albumin positive cells). These HLC exhibited functional characteristics of hepatocytes: capacity to metabolize drugs, ability to synthesize hepatic metabolites, and inducible cytochrome P450 activity. Bioprocess robustness was confirmed with HLC derived from different donors, including a primary hyperoxaluria type 1 (PH1) patient. The generated PH1.HLC showed metabolic features of PH1 disease with higher secretion of oxalate compared with HLC generated from healthy individuals. This work reports a reproducible bioprocess, that shows the importance of controlling DO at physiological levels to increase HLC production, and the HLC capability to display PH1 disease features., (© 2024. The Author(s).)

HIV-1 inhibitors, such as Bevirimat (BVM) and Lenacapavir (LEN), block the production and maturation of infectious virions. However, their mechanisms remain unclear due to the absence of high-resolution structures for BVM complexes and LEN's structural data being limited to the mature capsid. Utilizing perforated virus-like particles (VLPs) produced from mammalian cells, we developed an approach to determine in situ cryo-electron microscopy (cryo-EM) structures of HIV-1 with inhibitors. This allowed for the first structural determination of the native immature HIV-1 particle with BVM and LEN bound inside the VLPs at high resolutions. Our findings offer a more accurate model of BVM engaging the Gag lattice and, importantly, demonstrate that LEN not only binds the mature capsid but also targets the immature lattice in a distinct manner. The binding of LEN induces a conformational change in the capsid protein (CA) region and alters the architecture of the Gag lattice, which may affect the maturation process. These insights expand our understanding of the inhibitory mechanisms of BVM and LEN on HIV-1 and provide valuable clues for the design of future inhibitors.

Iron accumulation in tumors contributes to disease progression and chemoresistance. Although targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone reprogrammed ovarian cancer cells toward an immunostimulatory state characterized by the production of type-I IFN and overexpression of molecules that activate NK cells. Mechanistically, these effects were driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses triggered upon iron chelation. Deferiprone synergized with chemotherapy and prolonged the survival of mice with ovarian cancer by bolstering type-I IFN responses that drove NK cell-dependent control of metastatic disease. Hence, iron chelation may represent an alternative immunotherapeutic strategy for malignancies that are refractory to current T-cell-centric modalities. Significance: This study uncovers that targeting dysregulated iron accumulation in ovarian tumors represents a major therapeutic opportunity. Iron chelation therapy using an FDA-approved agent causes immunogenic stress responses in ovarian cancer cells that delay metastatic disease progression and enhance the effects of first-line chemotherapy. See related commentary by Bell and Zou, p. 1771., (©2024 American Association for Cancer Research.)

This work proposes a high-efficiency High-Brightness LED (HB-LED) driver for Visible Light Communication (VLC) based on a Two-Input Buck (TIBuck) DC/DC converter. This solution not only outperforms previous approaches based on Buck DC/DC converters, but also simplifies previous proposals for VLC drivers that use the split power technique with two DC/DC converters: one is in charge of the communication tasks and the other controls the biasing of the HB-LED (i.e., lighting tasks). The real implementation of this scheme requires either two input voltage sources, one of which is isolated, or one DC/DC converter with galvanic isolation. The proposed implementation of splitting the power is based on a TIBuck DC/DC converter that avoids the isolation requirement, overcoming the major drawback of this technique, keeping high-efficiency and high communication capability thanks to the lower voltage stress both across the switches and at the switching node. This fact allows for the operation at very high frequency for communication purposes, minimizing switching power losses, achieving high efficiency and providing lower filtering effort. Moreover, the duty ratio range can also be adapted to the useful voltage range of the HB-LED load to maximize the resolution on the tracking of the output volage. The power is split by means of an auxiliary Buck DC/DC converter operating at low switching frequency, which generates the secondary voltage source needed by the TIBuck DC/DC converter. This defines a natural split of power by only processing the power delivered for communications purposes at high frequency. A 7 W output-power experimental prototype of the proposed VLC driver was built and tested. Based on the experimental results, the prototype achieved 94% efficiency, reproducing a 64-QAM digital modulation scheme and achieving a bit rate of 1.5 Mbps with error in communication of 12%.

High-grade serious ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here, we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1α in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1α in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in ~ 50% of the treated hosts. Hence, neutrophil-intrinsic IRE1α facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease., Competing Interests: J.R.C.-R. holds patents on the targeting of ER stress responses for the treatment of disease, as well as on the use of immune modulators for ovarian cancer therapy. J.R.C.-R serves as scientific consultant for Moderna, Immagene B.V., Autoimmunity Biologic Solutions, Inc., and Emerald Bioventures, LLC, and holds stock options in Vescor Therapeutics. All other authors declare no potential conflicts of interest., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Respiratory syncytial virus-associated acute respiratory infection (RSV-ARI) constitutes an emerging cause of morbidity in the adult population. The present retrospective study was aimed at identifying factors predictive of poor outcome that may be assessed at the first evaluation in the Emergency Department (ED). We included 275 adult patients with laboratory-confirmed RSV-ARI that required hospital admission from the ED between January 2018 and December 2019. Poor outcome (composite of progression to high-flow oxygen therapy, non-invasive or invasive mechanical ventilation, or intensive care unit admission, and/or 30-day all-cause mortality) occurred in 31 patients (11.2%). Immunosuppression was present in 59 patients (21.5%). Although bacterial co-infection was rare, antibiotic therapy was commonly initiated. Ribavirin was administered in 10 patients. Cognitive impairment (odds ratio [OR]: 2.452; 95% confidence interval [CI]: 0.990-6.072), concurrent oral anticoagulation (OR: 3.099; 95 CI: 1.287-7.464) and a pulse oximetry oxygen saturation to fraction of inspired oxygen ratio (SpO 2 /FiO 2 ) ratio <382 at ED admission (OR: 3.013; 95 CI: 1.306-6.950) were independent risk factors for poor outcome, whereas influenza vaccination in the current season was protective (OR: 0.324; 95% CI: 0.138-0.763). Various factors easily available at the ED are useful for early risk stratification in adult patients with RSV-ARI., (© 2024 Wiley Periodicals LLC.)