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Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer's disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [ 11 C]CNY-10 is reported, which may enable brain RIPK1 imaging. [ 11 C]CNY-10 is radiosynthesized with a high radiochemical yield (41.8%) and molar activity (305 GBq/µmol). [ 11 C]CNY-10 is characterized by PET imaging in rodents and a non-human primate, demonstrating good brain penetration, binding specificity, and a suitable clearance kinetic profile. It is performed autoradiography of [ 11 C]CNY-10 in human AD and healthy control postmortem brain tissues, which shows strong radiosignal in AD brains higher than healthy controls. Subsequently, it is conducted further characterization of RIPK1 in AD using [ 11 C]CNY-10-based PET studies in combination with immunohistochemistry leveraging the 5xFAD mouse model. It is found that AD mice revealed RIPK1 brain signal significantly higher than WT control mice and that RIPK1 is closely related to amyloid plaques in the brain. The studies enable further translational studies of [ 11 C]CNY-10 for AD and potentially other RIPK1-related human studies., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Vascular endothelial growth factor is associated with reduced immune response and impaired anti-tumor activity. Combining antiangiogenic agents with immune checkpoint inhibition can overcome this immune suppression and enhance treatment efficacy., Methods: This study investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment. Baseline and on-treatment plasma and PBMC samples were analyzed by multiplex protein assay and mass cytometry, respectively., Results: In this Phase 1B study (NCT02298959), ten patients with advanced PD-1-resistant melanoma were treated with a combination of ziv-aflibercept (at 2-4 mg/kg) plus pembrolizumab (at 2 mg/kg), administered intravenously every 2 weeks. Two patients (20%) achieved a partial response, and two patients (20%) experienced stable disease (SD) as the best response. The two responders had mucosal melanoma, while both patients with SD had ocular melanoma. The combination therapy demonstrated clinical activity and acceptable safety, despite the occurrence of adverse events. Changes in plasma analytes such as platelet-derived growth factor and PD-L1 were explored, indicating potential alterations in myeloid cell function. Higher levels of circulating CXCL10 in non-responding patients may reflect pro-tumor activity. Specific subsets of γδ T cells were associated with poor clinical outcomes, suggesting impaired γδ T-cell function in non-responding patients., Conclusions: Although limited by sample size and follow-up, these findings highlight the potential of the combination of ziv-aflibercept antiangiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment and the need for further research to improve outcomes in anti-PD-1-resistant melanoma., Trial Registration Number: NCT02298959., (© 2024. The Author(s).)

We developed a comprehensive method for functional assessment of the changes in immune populations and killing activity of peripheral blood mononuclear cells after cocultures with cancer cells using mass cytometry. In this study, a 43-marker mass cytometry panel was applied to a coculture of immune cells from healthy donors' peripheral blood mononuclear cells with diverse cancer cell lines. DNA content combined with classical CD45 surface staining was used as gating parameters for cocultures of immune cells (CD45 high /DNA low ) with hematological (CD45 low /DNA high ) and solid cancer cell lines (CD45 neg /DNA high ). This strategy allows for universal discrimination of cancer cells from immune populations without the need for a specific cancer cell marker and simultaneous assessment of phenotypical changes in both populations. The use of mass cytometry allows for simultaneous detection of changes in natural killer, natural killer T cell, and T cell phenotypes and degranulation of immune populations upon target recognition, analysis of target cells for cytotoxic protein granzyme B content, and cancer cell death. These findings have broad applicability in research and clinical settings with the aim to phenotype and assess functional changes following not only NK-cancer cell interactions but also the effect of those interactions on other immune populations., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients with smoldering multiple myeloma (SMM) are observed until progression, but early treatment may improve outcomes. We conducted a phase II trial of elotuzumab, lenalidomide, and dexamethasone (EloLenDex) in patients with high-risk SMM and performed single-cell RNA and T cell receptor (TCR) sequencing on 149 bone marrow (BM) and peripheral blood (PB) samples from patients and healthy donors (HDs). We find that early treatment with EloLenDex is safe and effective and provide a comprehensive characterization of alterations in immune cell composition and TCR repertoire diversity in patients. We show that the similarity of a patient's immune cell composition to that of HDs may have prognostic relevance at diagnosis and after treatment and that the abundance of granzyme K (GZMK) + CD8 + effector memory T (TEM) cells may be associated with treatment response. Last, we uncover similarities between immune alterations observed in the BM and PB, suggesting that PB-based immune profiling may have diagnostic and prognostic utility., Competing Interests: Declaration of interests N.J.H. is a consultant for Constellation Pharmaceuticals. F.A. is an employee of Illumina Inc. O.Z. is an employee of Ikena Oncology and a stockholder in Ikena Oncology and Morphosys AG. G.G. receives research funds from IBM and Pharmacyclics and is an inventor on patent applications filed by the Broad Institute related to MSMuTect, MSMutSig, POLYSOLVER, SignatureAnalyzer-GPU, and MSIDetect. He is also a founder and consultant of and holds privately held equity in Scorpion Therapeutics. I.M.G. has a consulting or advisory role with AbbVie, Adaptive, Amgen, Aptitude Health, Bristol Myers Squibb, GlaxoSmithKline, Huron Consulting, Janssen, Menarini Silicon Biosystems, Oncopeptides, Pfizer, Sanofi, Sognef, Takeda, The Binding Site, and Window Therapeutics and has received speaker fees from Vor Biopharma and Veeva Systems, Inc., and her spouse is the CMO and equity holder of Disc Medicine. S.M. has a consulting role with Abbvie, Adaptive Biotechnology, Amgen, Celgene/BMS, GlaxoSmithKline, Janssen, Novartis, Oncopeptides, Regeneron, Roche, and Takeda and has received research funding from Abbvie, Adaptive Biotechnology, Amgen, Celgene/BMS, GlaxoSmithKline, Janssen, Novartis, Oncopeptides, Regeneron, Roche, and Takeda. A.J.Y. has a consulting role with Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK, Janssen, Karyopharm, Oncopeptides, Sanofi, and Takeda and has received research funding from Amgen, Janssen, and Takeda. M.B. is a consultant for Sanofi, Genzyme, and Janssen and has received research funding from MedImmune, Janssen, Legend Biotech, Amgen, Celularity, Bristol Myers Squibb, Celgene, Bluebird bio, Millennium, Takeda, Cerecor (currently Avalo Therapeutics), and C4 Therapeutics. M.B has an advisory role and received honoraria from Bristol Myers Squibb, Takeda, Janssen, and Menarini. T.H.M. received advisory board fees from Legend Biotech. R.S.-P., G.G., and I.M.G. are co-inventors on a patent application related to this work (PCT/US22/74839)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

With the increasing use of mass cytometry in clinical research, a simplified and standardized protocol for immunophenotyping human peripheral blood mononuclear cells (PBMCs) in clinical trials is needed. We present a simplified in-plate staining protocol for up to 80 samples, for laboratories of all mass cytometry expertise levels, aimed to generate reproducible datasets for large clinical cohorts. In this protocol, we provide details on the requirements to obtain meaningful results, spanning from sample quality, barcoding, and batch-freezing of stained samples., Competing Interests: Dr. Hodi reports grants and/or personal fees from Bristol-Myers Squibb, Merck, EMD Serono, Novartis, Surface, Compass Therapeutics, Apricity, Sanofi, Pionyr, 7 Hills Pharma, Torque, Bicara, Pieris Pharmaceutical, Checkpoint Therapeutics, Genentech/Roche, Bioentre, Gossamer, Iovance, Trillium, Catalym, Immunocore, Amgen, and Zumutor outside the submitted work. In addition, Dr. Hodi has a patent (#20100111973) with royalties paid and patents (#7250291, #9402905, #10279021, #10106611, #20170248603, #20160046716, #20140004112, #20170022275, #20170008962, and #20170343552) pending., (© 2022 The Author(s).)

This protocol details a staining technique optimized for immunophenotyping of human bone marrow immune populations using mass cytometry. The protocol accounts for the limitations of working with human bone marrow, such as reduced viability, low cell counts, and fragile cell pellets, to successfully acquire single viable cells ready for downstream analysis. This assay can be used to characterize the activation, exhaustion, and cytotoxicity of immune populations and ensure comprehensive immunophenotyping of human bone marrow clinical samples., Competing Interests: Hodi FS: Dr. Hodi reports grants and/or personal fees from Bristol-Myers Squibb, Merck, EMD Serono, grants and Novartis, Surface, Compass Therapeutics, Apricity, Sanofi, Pionyr, 7 Hills Pharma, Torque, Bicara, Pieris Pharmaceuticals, Checkpoint Therapeutics, Genentech/Roche, Bioentre, Gossamer, Iovance, Trillium, Catalym, Immunocore, Amgen, Zumutor, outside the submitted work; in addition, Dr. Hodi has a patent (#20100111973) with royalties paid, patents (#7250291) (#9402905) (# 10279021) (#10106611) (#20170248603) (#20160046716) (#20140004112) (#20170022275) (#20170008962) and (#20170343552) pending. Ghobrial IM : Dr Ghobrial has the following potential conflicts of interest to disclose: Honoraria: Celgene, Bristol-Myers Squibb, Takeda, Amgen, Janssen; Consulting or Advisory Role: Bristol-Myers Squibb, Novartis, Amgen, Takeda, Celgene, Cellectar, Sanofi, Janssen, Pfizer, Menarini Silicon Biosystems Oncopeptides, The Binding Site, GlazoSmithKlein, AbbVi Adaptive; Travel, Accommodations, Expenses: Bristol-Myers Squibb, Novartis, Celgene, Takeda, and Janssen Oncology., (© 2022 The Authors.)

Assesses the effect of glyceryl trinitrate (GTN) on the smooth muscle of the sphincter of Oddi, in terms of ease of cannulation at endoscopic retrograde cholangiopancreatography. Side effects of GTN; Effect of GTN among the experienced endoscopists and trainees; Difference in the average time taken to achieve cannulation of the desired duct.

Background: People living with HIV (PLWH), especially immunological non-responders (INRs), may experience adverse neurologic events. However, the extent of neurological impairment in INRs remains uncertain. This study evaluates brain structure and function, immune dysregulation, and peripheral immunomarkers in INRs and immunological responders (IRs) among PLWH, classified according to immunological response criteria, within a clinical research setting. Methods: This study utilized multi-modal MRI to assess brain structure and function in INRs (n = 25) and IRs (n = 53). Mass cytometry and Luminex/ELISA assays were employed to analyze peripheral blood monocytes, T cell subpopulations, cytokines, chemokines, neurotrophic factors, and endocrine factors. Results: Neuroimaging findings revealed notable changes in brain structure and function in INRs, including increased fractional amplitude of low-frequency fluctuations and regional homogeneity in the left middle temporal gyrus, as well as decreased grey matter volume in the left middle temporal gyrus, left lingual gyrus, and right rolandic operculum. Furthermore, INRs exhibited significant alterations in functional connectivity in the temporal and occipital gyrus. Mass cytometry analysis demonstrated significant immune dysregulation in INRs, characterised by increased levels of senescent and activated T cells, and heightened monocyte activation. Additionally, noteworthy associations were found between neurological abnormalities and peripheral levels of immunomarkers, inflammatory cytokines, chemokines, neurotrophic factors, and endocrine factors in INRs. Conclusion: These findings underscore the associations between immune dysfunction and changes in brain structure and function, emphasizing the importance of further investigations in this field. [ABSTRACT FROM AUTHOR]

The share of wind power in power systems is increasing dramatically, and this is happening in parallel with increased penetration of solar photovoltaics, storage, other inverter-based technologies, and electrification of other sectors. Recognising the fundamental objective of power systems, maintaining supply–demand balance reliably at the lowest cost, and integrating all these technologies are significant research challenges that are driving radical changes to planning and operations of power systems globally. In this changing environment, wind power can maximise its long-term value to the power system by balancing the needs it imposes on the power system with its contribution to addressing these needs with services. A needs and services paradigm is adopted here to highlight these research challenges, which should also be guided by a balanced approach, concentrating on its advantages over competitors. The research challenges within the wind technology itself are many and varied, with control and coordination internally being a focal point in parallel with a strong recommendation for a holistic approach targeted at where wind has an advantage over its competitors and in coordination with research into other technologies such as storage, power electronics, and power systems. [ABSTRACT FROM AUTHOR]

Within days of taking office in January 2021, President Biden signed an executive order establishing the Justice40 initiative, which directed federal agencies to ensure that at least 40% of the benefits of federal investments flow to historically marginalized communities. This article traces how Justice40, as interpreted and enacted by government bureaucrats, academics, industry researchers, and activists, intervenes in the governance of the energy transition it seeks to put into motion. Drawing from ongoing critical participation in energy research and development arenas and taking inspiration from Kim Fortun's notion of the "informating of environmentalism," this article argues that Justice40 can be understood as an attempt to informate justice, rendering it into problems that can be understood, manipulated, and audited through information systems. Scrambling to manage their accountabilities to the executive branch, Congress, and the American taxpayers footing the bill for massive infrastructure investments, Department of Energy programs are rolling out intricate systems of quantification, whose objectives of commensurability obscure local conceptions and prioritizations of justice. While Justice40 articulates lofty goals of energy transition enhancing the wellbeing of people who have otherwise been harmed by or excluded from the country's existing energy infrastructure, its everyday practice has the ironic effect of undermining both epistemic and procedural justice. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Endograft repair of abdominal aortic aneurysms (AAA) has become a viable alternative to open surgical repair in the last decade. We report here our experience and analysis of the surgical outcomes associated with endograft AAA repair., Methods: Patients suffering from significant abdominal aortic aneurysms (> 5cm in diameter) underwent endovascular repair. We report our experience with 342 consecutive patients from June 1998 to December 2004. Outcomes such as perioperative mortality, length of admission, length of ICU admission, operative blood loss, rates of transfusion postoperatively, rates of postoperative myocardial infarction (MI), rates of lower extremity ischemia, rates of conversion to open surgery, and the incidence of postoperative endoleaks were reviewed and analyzed. These results were compared to our patients undergoing open AAA repair during the same time period. Differences in the rates of perioperative mortality (2.0% vs 5.3%, NS) were not significant. However, the length of admission (4.8 vs 11.6 days, P=<0.001), length of ICU admission (0.6 vs 3.8 days, P=<0.001), blood transfusion (0.27 vs 1.83 units, P=<0.001), rates of postoperative MI (0.9% vs 5.0%, P=<0.001), and the incidence of postoperative renal insufficiency (4.1% vs 22.2%, P=<0.001) were superior in our endovascular group as compared to our open subset. In addition, most of our results were comparable to those results reported in recent major trials of endograft AAA repair., Conclusions: Endograft repair of AAA demonstrated superior outcomes when compared to our patients undergoing open AAA repair. However, these results must be weighed against the risk of endoleaks, secondary interventions, and routine radiographic surveillance required for the endovascular approach.

Purpose: Colonic bleeding has historically been controlled by the use of localization procedures and surgery. Since our initial experience with superselective embolization of colonic bleeding, it has become our preferred method for the control of lower gastrointestinal hemorrhage. This follow-up study evaluates the Hartford Hospital experience using angiographic methods as the primary modality for the treatment of colonic bleeding., Methods: From March 1993 to September 1999, 27 patients who had angiographically visualized colonic hemorrhage underwent arterial embolization procedures. Diagnostic arteriography was performed in all patients using digital subtraction imaging and selective contrast injections into the superior and inferior mesenteric arteries. Once the bleeding site was identified, superselective arteriogram and embolization was performed. Platinum-fibered coils, Hilal coils, or polyvinyl alcohol particle emboli were then fluoroscopically guided into the bleeding vessel. A repeat arteriogram was performed to confirm occlusion and the absence of any collateral channels., Results: All 27 patients were initially controlled with arterial embolization; 6 patients rebled (22.2 percent), and 5 of these patients required surgery. Two patients demonstrated ischemia (7.4 percent), one of which required surgical intervention. The other patient was followed up by colonoscopy. There was no mortality in this study., Conclusion: Superselective embolization is effective in controlling colonic hemorrhage and is associated with a low rate of postembolization ischemia. Our experience with angiography reinforces the paradigm shift from its use as a diagnostic tool to the primary method for the control of colonic bleeding. Because patients have been followed up for as long as seven years, this approach remains effective for the long-term treatment of colonic bleeding.

Vaccination reduces morbidity and mortality due to infections, but efficacy may be limited due to distinct immunogenicity at the extremes of age. This raises the possibility of employing adjuvants to enhance immunogenicity and protection. Early IFNγ production is a hallmark of effective vaccine immunogenicity in adults serving as a biomarker that may predict effective adjuvanticity. We utilized mass cytometry (CyTOF) to dissect the source of adjuvant-induced cytokine production in human blood mononuclear cells (BMCs) from newborns (~39-week-gestation), adults (~18-63 years old) and elders (>65 years of age) after stimulation with pattern recognition receptors agonist (PRRa) adjuvants. Dimensionality reduction analysis of CyTOF data mapped the BMC compartment, elucidated age-specific immune responses and profiled PRR-mediated activation of monocytes and DCs upon adjuvant stimulation. Furthermore, we demonstrated PRRa adjuvants mediated innate IFNγ induction and mapped NK cells as the key source of TLR7/8 agonist (TLR7/8a) specific innate IFNγ responses. Hierarchical clustering analysis revealed age and TLR7/8a-specific accumulation of innate IFNγ producing γδ T cells. Our study demonstrates the application of mass cytometry and cutting-edge computational approaches to characterize immune responses across immunologically distinct age groups and may inform identification of the bespoke adjuvantation systems tailored to enhance immunity in distinct vulnerable populations. An in vitro mass cytometry study focusing on age and adjuvant-specific activation of human blood mononuclear cells reveals NK cells as the key source of TLR7/8 agonist induced innate IFNγ responses. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the advancement of molecular biology and Next-Generation Sequencing (NGS), the study of the tumor microenvironment continues to have paradigmatic importance in research applied to malignant melanoma, and neoangiogenesis continues to exert a significant influence. In this review, we discuss the most updated knowledge about neoangiogenesis in melanoma, address the role of the TME in progression, and outline future therapeutic perspectives. Angiogenesis plays a pivotal role in tumor progression, particularly in melanoma, the deadliest form of skin cancer. This review synthesizes current knowledge on the intricate interplay between angiogenesis and tumor microenvironment (TME) in melanoma progression. Pro-angiogenic factors, including VEGF, PlGF, FGF-2, IL-8, Ang, TGF-β, PDGF, integrins, MMPs, and PAF, modulate angiogenesis and contribute to melanoma metastasis. Additionally, cells within the TME, such as cancer-associated fibroblasts, mast cells, and melanoma-associated macrophages, influence tumor angiogenesis and progression. Anti-angiogenic therapies, while showing promise, face challenges such as drug resistance and tumor-induced activation of alternative angiogenic pathways. Rational combinations of anti-angiogenic agents and immunotherapies are being explored to overcome resistance. Biomarker identification for treatment response remains crucial for personalized therapies. This review highlights the complexity of angiogenesis in melanoma and underscores the need for innovative therapeutic approaches tailored to the dynamic TME. [ABSTRACT FROM AUTHOR]

Rechargeable aqueous zinc metal batteries (RAZMBs) have received extensive attention for large-scale energy storage systems due to the merits of Zn anodes, including moderate volumetric and gravimetric energy density, low redox potential, abundant reserve, low cost and impressive intrinsic safety. However, Zn anodes suffer from a series of adverse reactions (dendrite growth, hydrogen evolution, and surface passivation) resulting in low Coulombic efficiency, large polarization, and unsatisfied cycling performance, which inevitably hinder the wide application of RAZMBs. To address the above issues, cellulose-based materials are widely used for Zn anode protection because of their unique physical and chemical properties and other advantages such as biocompatibility, non-toxicity, degradability and easy extraction. In order to better understand the current progress in cellulose-based materials for the Zn anode protection, we have classified and summarized the relevant literatures. In this review, we summarize and elaborate the causes of poor reversibility for Zn anodes, including dendrite formation, hydrogen evolution, and surface passivation. Subsequently, the effective strategies (anode interfacial engineering, gel electrolyte optimization, and separator modification) of cellulose-based materials toward stabilizing Zn anodes are overviewed. In the end, the existing challenges and prospects of cellulose-based materials in Zn anode protection are summarized to shed light on future work. [ABSTRACT FROM AUTHOR]

Background: People living with HIV (PLWH) fail to achieve normalization of CD4+ T cell counts and function, especially in immunological non-responders (INRs). The frequencies of Ki67+CD4+ T cells were inversely associated with CD4+ T cell counts in HIV infected patients. Early ART did not normalize CD4+ T cell proliferation. However, the features of the abnormal proliferation CD4+ T cell in INRs are far from known. Method: PLWH were divided into INRs (n= 16) and immunological responders (IRs, n= 53) groups. Mass cytometry was applied to peripheral blood T cells to profile the immune cells and liquid chip technique was used to measure plasma levels of cytokines and chemokines. Correlation analyses were conducted to evaluate associations between the degree of CD4+ T cell proliferation and immune function. Results: The percentage of Ki67+ CD4+ T cells were significant higher in INRs, and we defined these cells with significant higher level of Ki67, as overproliferating cells. No significant difference of markers' expression (HLA-DR, CD38, CD57, PD-1, PD-L1, CD107a, perforin) was found between INRs and IRs. Compared with naïve CD4+ T cells in INRs, Ki67+ CD4+ T cells exhibited lower levels of CD57 and CD38. Whereas Ki67+ T cells exhibited higher levels of CD38 and CD57 and activation compared with differentiated mature central memory CD4+ T cells and effector memory CD4+ T cells. Ki67+ cells did not show higher levels of senescence and activation compared to certain Ki67- CD4+ central memory T cells in IRs. Furthermore, Ki67+ CD4+ Tcm cells exhibited positive correlations with pro-inflammatory cytokines. Conclusion: We proposed and validated the hypothesis of "pathological proliferation" in INRs: excessive proliferation of CD4+ T cells in INRs may be accompanied by aberrant activation, senescence and loss of immune function. Eventually, such over-proliferating but poor-quality cells in INRs result in incomplete recovery of both CD4+ T cell counts and function. An intervention that enhancing the proliferative capacity or functional ability or both of CD4+ T cell in INRs might therefore be beneficial. [ABSTRACT FROM AUTHOR]

With the rapid evolution of the wind energy sector, there is an ever-increasing need to create value from the vast amounts of data made available both from within the domain and from other sectors. This article addresses the challenges faced by wind energy domain experts in converting data into domain knowledge, connecting and integrating them with other sources of knowledge, and making them available for use in next-generation artificial intelligence systems. To this end, this article highlights the role that knowledge engineering can play in the digital transformation of the wind energy sector. It presents the main concepts underpinning knowledge-based systems and summarises previous work in the areas of knowledge engineering and knowledge representation in a manner that is relevant and accessible to wind energy domain experts. A systematic analysis of the current state of the art on knowledge engineering in the wind energy domain is performed with available tools put into perspective by establishing the main domain actors and their needs, as well as identifying key problematic areas. Finally, recommendations for further development and improvement are provided. [ABSTRACT FROM AUTHOR]

Background/Aim: Elotuzumab, an anti-SLAMF7 monoclonal antibody, can enhance immune activity via elevated antibody-dependent cellular cytotoxicity and reduced SLAMF7+CD8+CD57+ regulatory T-cells (Tregs). This multicenter observational study investigated the kinetics of lymphocytes in myeloma patients treated with elotuzumab, lenalidomide, and dexamethasone (ERd) by two-color flow cytometry using peripheral blood samples. Patients and Methods: Twenty-one patients were included in this study. The median duration of ERd was 22.6 months, and the cutoff time for long-duration ERd was two years. Results: The CD2+CD16+ and CD16+CD57- NK cells were significantly increased over time in the long-duration ERd group compared to those in the short-duration ERd group (p=0.035 and p<0.001). The CD8+ and CD16-CD57+ lymphocytes, identified as low-activity NK cells or SLAMF7+ Tregs, were significantly increased in the patients whose ERd outcome was progressive disease (PD) compared to those in the non- PD group (p=0.023 and p<0.001). The mean CD4/CD8 ratio and CD19+ lymphocyte counts in the long-duration ERd group were significantly lower than those in the shortduration ERd group, although the kinetics of them did not change over time (p=0.016 and p=0.011). When the cutoff value of CD4/CD8 ratio was 0.792 according to ROC curves, the two-year time to next treatment (TTNT) in the low CD4/CD8 group was significantly longer than that in the high CD4/CD8 group (80.0% vs. 15.0%, p=0.024). Conclusion: The change in NK cells and CD8+ Tregs predicted long-duration ERd and PD, and maintaining low CD4/8 ratio predicted long TTNT, suggesting that these lymphocyte fractions might be biomarkers for a durable therapeutic effect of ERd in myeloma patients. [ABSTRACT FROM AUTHOR]

A major issue in quantifying potential power generation from prospective wind energy sites is the lack of observations from heights relevant to modern wind turbines, particularly for offshore where blade tip heights are projected to increase beyond 250 m. We present analyses of uniquely detailed data sets from lidar (light detection and ranging) deployments in New York State and on two buoys in the adjacent New York Bight to examine the relative power generation potential and power quality at these on- and offshore locations. Time series of 10 min wind power production are computed from these wind speeds using the power curve from the International Energy Agency 15MW reference wind turbine. Given the relatively close proximity of these lidar deployments, they share a common synoptic-scale meteorology and seasonal variability with lowest wind speeds in July and August. Time series of power production from the on- and offshore location are highly spatially correlated with the Spearman rank correlation coefficient dropping below 0.4 for separation distances of approximately 350 km. Hence careful planning of on- and offshore wind farms (i.e., separation of major plants by >350 km) can be used reduce the system-wide probability of low wind energy power production. Energy density at 150m height at the offshore buoys is more than 40%higher, and theWeibull scale parameter is 2ms-1 higher than at all but one of the land sites. Analyses of power production time series indicate annual energy production is almost twice as high for the two offshore locations. Further, electrical power production quality is higher from the offshore sites that exhibit a lower amplitude of diurnal variability, plus a lower probability of wind speeds below the cut-in and of ramp events of any magnitude. Despite this and the higher resource, the estimated levelized cost of energy (LCoE) is higher from the offshore sites mainly due to the higher infrastructure costs. Nonetheless, the projected LCoE is highly competitive from all sites considered. [ABSTRACT FROM AUTHOR]

Achieving national targets on renewable energy poses several challenges, especially in multi-level governance environments. Incentives and specifications on wind energy development might cause uneven progress or even discrepancies. Therefore, governments have commenced adopting 'positive planning' to combine energy targets with spatial and land-use planning. Yet detailed discussions regarding wind energy development remain scarce. In this paper, I explore three explanatory case studies in Germany and Sweden, aiming to provide policymakers and planners with essential knowledge while presenting significant challenges and key lessons learned. Positive planning appears to center on a strong energy target focus, limited space, and a balanced approach, shaped by the sociopolitical context. While Germany has recently embraced positive planning, Sweden started ambitiously but is encountering planning and policy challenges. Planning agencies play a vital role in promoting wind energy targets at mid-scale levels, yet legally binding targets matter. Striking a balance between energy targets and addressing land-use concerns without disregarding them requires managing a delicate trade-off. Early communication and inter-agency collaboration, as seen in Sweden, might facilitate identifying compromises, navigating trade-offs between species protection and renewable energy and offering municipal incentives. Nonetheless, negotiating satisfactory spatial trade-offs for a long-term proof of concept remains a challenge. [ABSTRACT FROM AUTHOR]

Introduction: Monitoring of innate myeloid cells (IMC) is broadly applied in basic and translational research, as well as in diagnostic patient care. Due to their immunophenotypic heterogeneity and biological plasticity, analysis of IMC populations typically requires large panels of markers. Currently, two cytometry-based techniques allow for the simultaneous detection of ≥40 markers: spectral flow cytometry (SFC) and mass cytometry (MC). However, little is known about the comparability of SFC and MC in studying IMC populations. Methods: We evaluated the performance of two SFC and MC panels, which contained 21 common markers, for the identification and subsetting of blood IMC populations. Based on unsupervised clustering analysis, we systematically identified 24 leukocyte populations, including 21 IMC subsets, regardless of the cytometry technique. Results: Overall, comparable results were observed between the two technologies regarding the relative distribution of these cell populations and the staining resolution of individual markers (Pearson’s ρ=0.99 and 0.55, respectively). However, minor differences were observed between the two techniques regarding intra-measurement variability (median coefficient of variation of 42.5% vs. 68.0% in SFC and MC, respectively; p<0.0001) and reproducibility, which were most likely due to the significantly longer acquisition times (median 16 min vs. 159 min) and lower recovery rates (median 53.1% vs. 26.8%) associated with SFC vs. MC. Discussion: Altogether, our results show a good correlation between SFC and MC for the identification, enumeration and characterization of IMC in blood, based on large panels (>20) of antibody reagents. [ABSTRACT FROM AUTHOR]

Molecular heterogeneity has great significance in the disease biology of multiple myeloma (MM). Thus, the analysis combined single-cell RNA-seq (scRNA-seq) and bulk RNA-seq data were performed to investigate the clonal evolution characteristics and to find novel prognostic targets in MM. The scRNA-seq data were analyzed by the Seurat pipeline and Monocle 2 to identify MM cell branches with different differentiation states. Marker genes in each branch were uploaded to the STRING database to construct the Protein-Protein Interaction (PPI) network, followed by the detection of hub genes by Cytoscape software. Using bulk RNA-seq data, Kaplan-Meier (K-M) survival analysis was then carried out to determine prognostic biomarkers in MM. A total of 342 marker genes in two branches with different differentiation states were identified, and the top 20 marker genes with the highest scores in the network calculated by the MCC algorithm were selected as hub genes in MM. Furthermore, K-M survival analysis revealed that higher NDUFB8, COX6C, NDUFA6, USMG5, and COX5B expression correlated closely with a worse prognosis in MM patients. Moreover, ssGSEA and Pearson analyses showed that their expression had a significant negative correlation with the proportion of Tcm (central memory cell) immune cells. Our findings identified NDUFB8, COX6C, NDUFA6, USMG5, and COX5B as novel prognostic biomarkers in MM, and also revealed the significance of genetic heterogeneity during cell differentiation in MM prognosis. [ABSTRACT FROM AUTHOR]

Gastric cancer is characterized by the growth of cancerous cells within the lining of the stomach. Traditionally, this condition has been challenging to diagnose. However, today artificial intelligence (AI) is becoming more widely used across healthcare sectors because it offers significant improvements in the speed and accuracy of data discovery, extraction, and personalized recommendations for treatments. At present, AI research on the identification and treatment of gastric malignant growth, helicobacter pylori bacteria, and throat disease is advancing; the connections between these sub-fields and those of gastric tumors and oesophageal diseases indicates that AI can also be utilized for diagnosis in these areas. PRISMA standards were used to identify publications published between 2009 and 2021 on Web of Science, EBSCO, and EMBASE. This study conducted an efficient search and included research publications that used AI-based learning algorithms for gastric cancer prediction. A total of 110 studies are regarded as important for gastric cancer prediction using traditional machine and deep learning-based classifications. In this work, we offer a survey of the work currently performed on AI-enabled diagnosis at different stages of gastric cancers. We also outline the symptoms of gastric cancer, the various means of diagnosis of gastric cancers, and the roles played by conventional machine learning (ML) and the ML subset of deep learning (DL) models for early detection of gastric cancer. Furthermore, we summarize the work done by different researchers in AI techniques for early prediction of gastric cancers and compare their work by using parameters such as prediction rate, accuracy, sensitivity, specificity, the area under the curve, and F1-score. [ABSTRACT FROM AUTHOR]

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Minimally invasive endovascular embolization is a widely used clinical technique used for the occlusion of blood vessels to treat various diseases. Different occlusive agents ranging from gelatin foam to synthetic polymers such as poly(vinyl alcohol) (PVA) have been commercially used for embolization. However, these agents have some drawbacks, such as undesired toxicity and unintended and uncontrolled occlusion. To overcome these issues, several polymer-based embolic systems are under investigation including biocompatible and biodegradable microspheres, gelling liquid embolic with controlled occlusive features, and trackable microspheres with enhanced safety profiles. This review aims to summarize recent advances in current and emerging polymeric materials as embolization agents with varying material architectures. Furthermore, this review also explores the potential of combining injectable embolic agents and cell therapy to achieve more effective embolization with the promise of outstanding results in treating various devastating diseases. Finally, limitations and challenges in developing next-generation multifunctional embolic agents are discussed to promote advancement in this emerging field. [ABSTRACT FROM AUTHOR]

Herein, we report two cases of duodenal ulcers that developed after transcatheter procedures for the treatment of unruptured artery aneurysms. Both patients recovered after the administration of nothing by mouth, intravenous fluids, and proton-pump inhibitors. Notably, the duodenal ulcer was unchanged in one patient six days after endovascular treatment and improved in the other patient 13 days after angiography. These cases suggest that conservative treatment is acceptable in patients with duodenal ischemia that develops as an adverse effect of endovascular procedures. The usefulness of esophagogastroduodenoscopy in such patients has also been highlighted. [ABSTRACT FROM AUTHOR]

Background and Objectives. Benign strictures are the main cause of esophageal strictures in children. They can be managed by different modalities but endoscopic dilatation is the standard therapy. This study is aimed at reviewing the efficacy and safety of endoscopic dilatations in children with esophageal strictures. Materials and Methods. In this retrospective cross-sectional single center study, records of patients with esophageal strictures presented to the pediatric department, Salmaniya Medical Complex, Bahrain, in the period between 1995 and 2019 were reviewed. Demographic data, indications of endoscopic dilatations, the procedure success rate, and possible complications were assessed. Results. Forty-six children were found to have esophageal strictures. Twenty-five (54.3%) patients were males. Most patients presented during infancy (86.5%, 32/37 patients). Twenty-six (56.5%) patients required 88 dilatation sessions, while the remaining 20 (43.5%) patients did not require dilatations. The median number of dilatation sessions per patient was three (interquartile range = 2 –5). Savary-Gilliard bougienages were the main dilators used (80.8%, 21/26 patients). Anastomotic stricture (post esophageal atresia/tracheoesophageal fistula repair) was the main cause of esophageal strictures and was found in 35 (76.1%) patients. Patients with nonanastomotic strictures had more frequent dilatations compared to those with anastomotic strictures (P = 0.007). The procedure success rate was 98.8%. Yet, it was operator dependent (P = 0.047). Complete response to dilatation was found in 18 (69.2%) patients, satisfactory in seven (26.9%), and an inadequate response in one (3.9%). Those with satisfactory responses still require ongoing dilatations based on their symptoms and radiological and endoscopic findings. No perforation or mortality was reported. Patients with dilatations had more recurrent hospitalization (P < 0.0001), more dysphagia (P = 0.001), but shorter hospital stay (P = 0.046) compared to those without dilatations. Surgical intervention was required in one patient with caustic strictures. The median follow-up period was six years (interquartile range = 2.25 –9.0). Conclusions. Endoscopic esophageal dilatation in children with esophageal strictures is effective and safe. Yet, it was operator dependent. Nonanastomotic strictures require more dilatations compared to anastomotic strictures. Findings of this study are comparable to those reported worldwide. [ABSTRACT FROM AUTHOR]

Background: Acute cholecystitis (AC), frequently responsible for presentation to the emergency department, requires expedient diagnosis and definitive treatment by a general surgeon. Ultrasonography, usually performed by radiology technicians and reported by radiologists, is the first-line imaging study for the assessment of AC. Targeted point-of-care ultrasound (POCUS), particularly in the hands of the treating surgeon, may represent an evolution in surgical decision-making and may expedite care, reducing morbidity and cost. Methods: This consensus guideline was written under the auspices of the European Society of Trauma and Emergency Surgery (ESTES) by the POCUS working group. A systematic literature search identified relevant papers on the diagnosis and treatment of AC. Literature was critically-appraised according to the GRADE evidence-based guideline development method. Following a consensus conference at the European Congress of Trauma & Emergency Surgery (Valencia, Spain, May 2018), final recommendations were approved by the working group, using a modified e-Delphi process, and taking into account the level of evidence of the conclusion. Recommendations: We strongly recommend the use of ultrasound as the first-line imaging investigation for the diagnosis of AC; specifically, we recommend that POCUS may be adopted as the primary imaging adjunct to surgeon-performed assessment of the patient with suspected AC. In line with the Tokyo guidelines, we strongly recommend Murphy's sign, in conjunction with the presence of gallstones and/or wall thickening as diagnostic of AC in the correct clinical context. We conditionally recommend US as a preoperative predictor of difficulty of cholecystectomy. There is insufficient evidence to recommend contrast-enhanced ultrasound or Doppler ultrasonography in the diagnosis of AC. We conditionally recommend the use of ultrasound to guide percutaneous cholecystostomy placement by appropriately-trained practitioners. Conclusions: Surgeons have recently embraced POCUS to expedite diagnosis of AC and provide rapid decision-making and early treatment, streamlining the patient pathway and thereby reducing costs and morbidity. [ABSTRACT FROM AUTHOR]

Lower gastrointestinal bleeding (LGIB) is a common entity encountered by the surgeon. Though most LGIB stops on its own, familiarity with the diagnoses and their treatments is critical to optimal patient care. Even in 2016, surgery may be required. Advances in imaging have led to an enhanced ability to localize bleeding. Newer anticoagulants have developed which provide ease of use to the patient, but challenges to caregivers when bleeding arises. [ABSTRACT FROM AUTHOR]

Objective:Easy common bile duct (CBD) cannulation is associated with low complication rate. This study aimed to investigate the potential impact of nitroglycerin and glucagon administration on selective CBD cannulation and prevention of post-ERCP pancreatitis. Methods:A prospective single center, double–blind randomized study in which a total of 455 patients were randomly assigned to CBD cannulation by receiving 6 puffs (2.4 mg) sublingual nitroglycerin and glucagon 1 mg intravenously (n = 227, group A) or 6 puffs sterile water and 20 mg hyoscine-n-butyl bromide intravenously (n = 228, group B). After ERCP, patients were followed for the development of drugs’ side-effects and post-ERCP complications. Results:There were no statistically significant differences between the two groups regarding demographic data and ERCP findings. Success rate of selective CΒD cannulation was 95.15% in group A versus 82.29% in group B (p < .001). Time required for CBD cannulation was 2.82 ± 2.31 min in group A versus 4.27 ± 3.84 min in group B (p = .021). Needle-knife papillotomy was used in 11 (4.85%) patients of group A and 39 (17.11%) patients of group B (p = .001). The frequency of post-ERCP pancreatitis was significantly lower in group A than in group B (3.08% versus 7.46%,p = .037). No difference was observed between the two groups with regard to the occurrence of post-procedure hemorrhage. There was no procedure-related mortality; no adverse event related to the combination regimen was observed. Conclusions:Combined nitroglycerin and glucagon administration achieves a high selective CBC cannulation rates with concomitant reduction of post-ERCP pancreatitis incidence. However, further relative large-scale studies are needed to confirm our findings before definite conclusions can be drawn (Clinical trial registration number: NT: 4321). [ABSTRACT FROM PUBLISHER]

Background: Ischaemic colitis is an infrequent but serious complication following repair of abdominal aortic aneurysm (AAA), with high mortality rates. This systematic review set out to identify risk factors for the development of ischaemic colitis after AAA surgery. Methods: A systematic search of the MEDLINE, EMBASE and CINAHL databases was performed. This search was limited to studies published in the English language after 1990. Abstracts were screened by two authors. Eligible studies were obtained as full text for further examination. Data was extracted by two authors, and any disputes were resolved via consensus. Extracted data was pooled using Mantel-Haenszel random effects models. Bias was assessed using two Cochrane-approved tools. Effect sizes are expressed as relative risk ratios alongside the 95 % confidence interval. Statistical significance was defined at the level of p < 0.05. Results: From 388 studies identified in the initial search, 33 articles were included in the final synthesis and analysis. Risk factors were grouped into patient (female gender, disease severity) and operative factors (peri-procedural hypotension, operative modality). The risk of ischaemic colitis was significantly higher when undergoing emergency repair versus elective (risk ratio (RR) 7.36, 3.08 to 17.58, p < 0.001). Endovascular repair reduced the likelihood of ischaemic colitis (RR 0.22, 0.12 to 0.39, p < 0.001). Discussion: The quality of published evidence on this subject is poor with many retrospective datasets and inconsistent reporting across studies. Despite this, emergency presentation and open repair should prompt close monitoring for the development of IC. [ABSTRACT FROM AUTHOR]

Despite staging laparoscopy ( SL) with peritoneal lavage is recommended in US Guidelines in patients with potentially resectable gastroesophageal adenocarcinoma, this procedure is not systematically proposed in French Guidelines. Therefore, we decided to analyze the results of systematic SL in patients considered for preoperative chemotherapy. From 2005 to 2011, 116 consecutive patients with distal esophagus, esogastric junction, and gastric adenocarcinoma ≥ T3 or N+ without detectable metastatic dissemination by computed tomography ( CT) scan imaging underwent SL before neoadjuvant chemotherapy. Positive and negative SLs were compared according to tumor characteristics. SL was positive in 15 cases (12.9%) including 14 with peritoneal seeding (localized in five, diffuse in nine). SL was positive in 7 (24.1%) of 29 patients with poorly differentiated tumor, in 9 (32.1%) of 28 patients with signet ring cells, in 7 (50%) of 14 patients with gastric linitis tumor, and in 15 (16.3%) of 92 patients with T3 or T4 tumor. All the lesions of distal esophagus extending to the cardia had a negative SL. Among the 14 patients with peritoneal carcinomatosis at SL, nine (65%) had signs of peritoneal seeding on initial CT scan. One (0.8%) patient had a small bowel perforation closed laparoscopically. If systematic SL before preoperative chemotherapy does not seem justified because of its low accuracy, it should be performed in patients with poorly differentiated tumor, signet ring cell, and gastric linitis plastica components on biopsy and when CT scan is suggestive of T4 tumor, ascites, or peritoneal nodule. [ABSTRACT FROM AUTHOR]