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Aims/hypothesis: The majority of hybrid closed-loop systems still require carbohydrate counting (CC) but the evidence for its justification remains limited. Here, we evaluated glucose control with simplified meal announcement (SMA) vs CC in youth and young adults with type 1 diabetes using the mylife CamAPS FX system., Methods: We conducted a two-centre, randomised crossover, non-inferiority trial in two University Hospitals in Switzerland in 46 participants (aged 12-20 years) with type 1 diabetes using multiple daily injections (n=35), sensor-augmented pump (n=4) or hybrid closed-loop (n=7) therapy before enrolment. Participants underwent two 3 month periods with the mylife CamAPS FX system (YpsoPump, Dexcom G6) to compare SMA (individualised carbohydrate meal sizes) with CC, in a randomly assigned order using computer-generated sequences. The primary endpoint was the proportion of time glucose was in target range (3.9-10.0 mmol/l) with a non-inferiority margin of 5 percentage points. Secondary endpoints were other sensor glucose and insulin metrics, usability and safety endpoints., Results: Forty-three participants (18 women and girls) completed the trial. In the intention-to-treat analysis, time in range (mean±SD) was 69.9±12.4% with SMA and 70.7±13.0% with CC (estimated mean difference -0.6 percentage points [95% CI -2.4, 1.1], demonstrating non-inferiority). Time <3.9 mmol/l (median [IQR] 1.8 [1.2-2.2]% vs 1.9 [1.6-2.5]%) and >10.0 mmol/l (28.2±12.6% vs 27.2±13.4%) was similar between periods. Total daily insulin dose was higher with SMA (54.0±14.7 U vs 51.7±12.1 U, p=0.037). Three participants experienced serious adverse events, none of which were intervention-related., Conclusions/interpretation: Glucose control using the CamAPS FX algorithm with SMA was non-inferior to its use with CC in youth and young adults with type 1 diabetes., Trial Registration: ClinicalTrials.gov NCT05481034., Funding: The study was supported by the Swiss Diabetes Foundation and by a YTCR grant from the Bangerter-Rhyner Foundation and the Swiss Academy of Medical Sciences. Dexcom and Ypsomed provided product support., Competing Interests: Acknowledgements: We are grateful to study volunteers for their participation. We acknowledge support by L. Cavalli, E. Leu, C. Gisler (UDEM, Inselspital, Bern, Switzerland), M. Vajner and S. Rocha (Division of Paediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland) who contributed to participant care, logistical and administrative management of the study. An abstract of study results was presented in March 2024 at the Advanced Technologies & Treatments for Diabetes conference in Florence, Italy and at the Swiss Society of Paediatrics annual meeting in June 2024 in Lucerne, Switzerland. Data availability: De-identified subject level dataset will be made available on a case-by-case basis on reasonable request to the corresponding author for research purposes 6 months after publication. Funding: Open access funding provided by University of Bern. The study was supported by the Swiss Diabetes Foundation and by a YTCR grant from the Bangerter-Rhyner Foundation and the Swiss Academy of Medical Sciences. Dexcom and Ypsomed provided product support. Authors’ relationships and activities: CIL received a travel grant from the Swiss Society of Endocrinology and Diabetology to present the present work at the Advanced Technologies & Treatments for Diabetes conference in Florence, Italy (Abstract no. 181). KB-K has received research funding from Dexcom, Embecta, Novo Nordisk and Eli Lilly, as well as honoraria from Tandem, Dexcom, Sanofi and Roche. MEW reports patents related to closed-loop (US9402953B2, US9579456B2), and being a consultant at CamDiab. RH reports having received speaker honoraria from Eli Lilly, Dexcom and Novo Nordisk, receiving license fees from BBraun, patents related to closed-loop, and being a director at CamDiab. LB reports having received speaker and advisory board honoraria from Eli Lilly, Dexcom, Novo Nordisk, Ypsomed, Roche, Sanofi and Oviva. Contribution statement: CIL, CP, FN, NS, KB-K, LK, DH, DK and LB were involved in the conception, design and conduct of the study and the analysis and interpretation of the results. CIL, CP, FN, NS, LK, KB-K, TZ, DH, DK and LB were involved in the conception of the study and data acquisition. DH, CTN, CIL, KB-K, MEW, RH and LB were involved in the analysis and interpretation of the results. CIL, DH and LB wrote the first draft of the manuscript, and all authors edited, reviewed and approved the final version of the manuscript. CIL, DH, DK and LB are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis., (© 2024. The Author(s).)

Protein-Protein Interaction (PPI) prediction plays a pivotal role in understanding cellular processes and uncovering molecular mechanisms underlying health and disease. Structure-based PPI prediction has emerged as a robust alternative to sequence-based methods, offering greater biological accuracy by integrating three-dimensional spatial and biochemical features. This work summarizes the recent advances in computational approaches leveraging protein structure information for PPI prediction, focusing on machine learning (ML) and deep learning (DL) techniques. These methods not only improve predictive accuracy but also provide insights into functional sites, such as binding and catalytic residues. However, challenges such as limited high-resolution structural data and the need for effective negative sampling persist. Through the integration of experimental and computational tools, structure-based prediction paves the way for comprehensive proteomic network analysis, holding promise for advancements in drug discovery, biomarker identification, and personalized medicine. Future directions include enhancing scalability and dataset reliability to expand these approaches across diverse proteomes.

Zinc is an essential micronutrient that participates in a multitude of cellular and biochemical processes. It is indispensable for normal growth and the maintenance of physiological functions. As one of the most significant trace elements in the body, zinc fulfills three primary biological roles: catalytic, structural, and regulatory. It serves as a cofactor in over 300 enzymes, and more than 3000 proteins require zinc, underscoring its crucial role in numerous physiological processes such as cell division and growth, immune function, tissue maintenance, as well as synthesis protein and collagen synthesis. Zinc deficiency has been linked to increased oxidative stress and inflammation, which may contribute to the pathogenesis of a multitude of diseases, like neurological disorders and cancer. In addition, zinc is a key constituent of zinc-binding proteins, which play a pivotal role in maintaining cellular zinc homeostasis. This review aims to update and expand upon the understanding of zinc biology, highlighting the fundamental roles of zinc in biological processes and the health implications of zinc deficiency. This work also explores the diverse functions of zinc in immune regulation, cellular growth, and neurological health, emphasizing the need for further research to fully elucidate the therapeutic potential of zinc supplementation in disease prevention and management., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Receiver operating characteristic (ROC) curve analysis is widely used in evaluating the effectiveness of a diagnostic test/biomarker or classifier score. A parametric approach for statistical inference on ROC curves based on a Box-Cox transformation to normality has frequently been discussed in the literature. Many investigators have highlighted the difficulty of taking into account the variability of the estimated transformation parameter when carrying out such an analysis. This variability is often ignored and inferences are made by considering the estimated transformation parameter as fixed and known. In this paper, we will review the literature discussing the use of the Box-Cox transformation for ROC curves and the methodology for accounting for the estimation of the Box-Cox transformation parameter in the context of ROC analysis, and detail its application to a number of problems. We present a general framework for inference on any functional of interest, including common measures such as the AUC, the Youden index, and the sensitivity at a given specificity (and vice versa). We further developed a new R package (named 'rocbc') that carries out all discussed approaches and is available in CRAN., (© 2024 John Wiley & Sons Ltd.)

The present study investigated the oxidative and cytogenotoxic potential of Tetraethylene glycol dimethyl ether (known as Tetraglyme) on healthy human peripheral blood lymphocytes, widely used as an in vitro model for assessing the human health risk posed by different chemical compounds. In a first step, Nuclear Magnetic Resonance ( 1 H NMR) spectroscopy, and Ultra-High Performance Liquid Chromatography-Mass Spectrometry (UHPLC-MS) were employed to estimate Tetraglyme's stability under a wide range of pH values (4-12), and thus to identify potential by-products. Thereafter, isolated lymphocytes were treated with different concentrations of Tetraglyme (0.02-20 mg L -1 ) for assessing its oxidative (using the DCFH-DA staining), and cytogenotoxic potential (using the trypan blue exclusion test for estimating cell viability, Comet assay, as well as the cytokinesis-block micronucleus assay, with or without the addition of S9 metabolic activation system). According to the results, Tetraglyme remains stable at pH 4, but two additional derivatives (i.e. 1-[2-(2-ethoxyethoxy)ethoxy]-2-methoxyethane [C 9 H 20 O 4 ] and 1-ethoxy-2-(2-ethoxyethoxy)ethane (Diethylene glycol diethyl ether) [C 8 H 18 O 3 ]) were found in traces, under alkaline conditions (pH ≥7). Moreover, although Tetraglyme (and/or its derivatives) showed negligible alterations of cell viability (>92 %) in all cases, the pronounced ROS formation, DNA damage, cell proliferation arrest, and MN frequencies in challenged cells are indicative of its oxidative and cytogenotoxic potential. The significant alterations of Cytokinesis-Block Proliferation Index (CBPI) and Micronucleus (MN) frequencies in S9 challenged cells give further evidence for the potential involvement of Tetraglyme's metabolites in the observed cytogenotoxic mode of action. Although not conclusive, the present findings give rise to further research, utilizing different cell types and biological models, for elucidating Tetraglyme's toxic mode of action, as well as its environmental and human risk., Competing Interests: Declaration of competing interest Authors have nothing to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

At altitude, factors such as decreased barometric pressure, low temperatures, and acclimatization might affect lung function. The effects of exposure and acclimatization to high-altitude on lung function were assessed in 39 subjects by repetitive spirometry up to 6022 m during a high-altitude expedition. Subjects were classified depending on the occurrence of acute mountain sickness (AMS) and summit success to evaluate whether lung function relates to successful climb and risk of developing AMS. Peak expiratory flow (PEF), forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) increased with progressive altitude (max. +20.2 %pred, +9.3 %pred, and +6.7 %pred, all p<0.05). Only PEF improved with acclimatization (BC1 vs. BC2, +7.2 %pred, p=0.044). At altitude FEV1 (p=0.008) and PEF (p<0.001) were lower in the AMS group. The risk of developing AMS was associated with lower baseline PEF (p<0.001) and longitudinal changes in PEF (p=0.008) and FEV1 (p<0.001). Lung function was not related to summit success (7126 m). Improvement in PEF after acclimatization might indicate respiratory muscle adaptation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, and respiratory syncytial virus (RSV) are significant global health threats. The need for low-cost, easily synthesized oral drugs for rapid deployment during outbreaks is crucial. Broad-spectrum therapeutics, or pan-antivirals, are designed to target multiple viral pathogens simultaneously by focusing on shared molecular features, such as common metal cofactors or conserved residues in viral catalytic domains. This study introduces a new generation of potent sartans, known as bisartans, engineered in our laboratories with negative charges from carboxylate or tetrazolate groups. These anionic tetrazoles interact strongly with cationic arginine residues or metal cations (e.g., Zn 2+ ) within viral and host target sites, including the SARS-CoV-2 ACE2 receptor, influenza H1N1 neuraminidases, and the RSV fusion protein. Using virtual ligand docking and molecular dynamics, we investigated how bisartans and their analogs bind to these viral receptors, potentially blocking infection through a pan-antiviral mechanism. Bisartan, ACC519TT, demonstrated stable and high-affinity docking to key catalytic domains of the SARS-CoV-2 NSP3, H1N1 neuraminidase, and RSV fusion protein, outperforming FDA-approved drugs like Paxlovid and oseltamivir. It also showed strong binding to the arginine-rich furin cleavage sites S1/S2 and S2', suggesting interference with SARS-CoV-2's spike protein cleavage. The results highlight the potential of tetrazole-based bisartans as promising candidates for developing broad-spectrum antiviral therapies.

(1) Background: "Kidney Disease: Improving Global Outcomes" (KDIGO) provides guidelines for identifying the stages of acute kidney injury (AKI) and chronic kidney disease (CKD). A data-driven rule-based engine was developed to determine KDIGO staging compared to KD-related keywords in discharge letters. (2) Methods: To assess potential differences in outcomes, we compare the patient subgroups with exact KDIGO staging to imprecise or missing staging for all-cause mortality, in-hospital mortality, selection bias and costs by applying Kaplan-Meier analysis and the Cox proportional hazards regression model. We analysed 63,105 in-patient cases from 2016 to 2023 at a tertiary hospital with AKI, CKD and acute-on-chronic KD. (3) Results: Imprecise and missing CKD staging were associated with an 85% higher risk of all-cause and in-hospital mortality (CI: 1.7 to 2.0 and 1.66 to 2.03, respectively) compared to exact staging for any given disease status; imprecise or missing AKI staging increased in-hospital mortality risk by 56% and 57% (CI: 1.43 to 1.70 and 1.37 to 1.81, respectively) in patients with AKI. (4) Conclusions: Exact staging is associated with better outcomes in KD management. Our study provides valuable insight into potential quality and outcome improvements and lower costs, considering elderly patients, women and patients with acute-on-chronic KD as the most vulnerable.

Global warming concerns have led to emission regulations and various incentives for low-carbon technologies. Energy system models, which are used to examine how investments affect our ability to meet energy demand, are typically based on two assumptions: key parameters are assumed to be known deterministically and a multi-period energy transition plan is determined at one point in time. We argue that for a systematic generation and analysis of energy transition pathways, these assumptions should be relaxed and, accordingly, we propose methods to achieve that. First, we use stochastic programming (SP) to account for uncertainty in key parameters. Second, we pair SP with a sequential decision-making approach that represents how decisions can be updated as uncertainties unfold. Third, we use simulation-based methods to evaluate the quality of energy transitions. Importantly, we find that accounting for uncertainty, proactively and through feedback, yields pathways with diverse technology portfolios that are resilient to uncertainty., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

The binding affinities and interactions between eight drug candidates, both commercially available (candesartan; losartan; losartan carboxylic acid; nirmatrelvir; telmisartan) and newly synthesized benzimidazole-N-biphenyltetrazole (ACC519T), benzimidazole bis-N,N'-biphenyltetrazole (ACC519T(2) and 4-butyl-N,N-bis([2-(2H-tetrazol-5-yl)biphenyl-4-yl]) methyl (BV6), and the active site of angiotensin-converting enzyme-2 (ACE2) were evaluated for their potential as inhibitors against SARS-CoV-2 and regulators of ACE2 function through Density Functional Theory methodology and enzyme activity assays, respectively. Notably, telmisartan and ACC519T(2) exhibited pronounced binding affinities, forming strong interactions with ACE2's active center, favorably accepting proton from the guanidinium group of arginine273. The ordering of candidates by binding affinity and reactivity descriptors, emerged as telmisartan > ACC519T(2) > candesartan > ACC519T > losartan carboxylic acid > BV6 > losartan > nirmatrelvir. Proton transfers among the active center amino acids revealed their interconnectedness, highlighting a chain-like proton transfer involving tyrosine, phenylalanine, and histidine. Furthermore, these candidates revealed their potential antiviral abilities by influencing proton transfer within the ACE2 active site. Furthermore, through an in vitro pharmacological assays we determined that candesartan and the BV6 derivative, 4-butyl-N,N0-bis[20-2Htetrazol-5-yl)bipheyl-4-yl]methyl)imidazolium bromide (BV6(K + ) 2 ) also contain the capacity to increase ACE2 functional activity. This comprehensive analysis collectively underscores the promise of these compounds as potential therapeutic agents against SARS-CoV-2 by targeting crucial protein interactions., 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 Authors. Published by Elsevier Inc. All rights reserved.)

Building sustainable platforms to produce biofuels and specialty chemicals has become an increasingly important strategy to supplement and replace fossil fuels and petrochemical-derived products. Terpenoids are the most diverse class of natural products that have many commercial roles as specialty chemicals. Poplar is a fast growing, biomassdense bioenergy crop with many species known to produce large amounts of the hemiterpene isoprene, suggesting an inherent capacity to produce significant quantities of other terpenes. Here we aimed to engineer poplar with optimized pathways to produce squalene, a triterpene commonly used in cosmetic oils, a potential biofuel candidate, and the precursor to the further diversified classes of triterpenoids and sterols. The squalene production pathways were either re-targeted from the cytosol to plastids or co-produced with lipid droplets in the cytosol. Squalene and lipid droplet co-production appeared to be toxic, which we hypothesize to be due to disruption of adventitious root formation, suggesting a need for tissue specific production. Plastidial squalene production enabled up to 0.63 mg/g fresh weight in leaf tissue, which also resulted in reductions in isoprene emission and photosynthesis. These results were also studied through a technoeconomic analysis, providing further insight into developing poplar as a production host., (© 2024 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Background: Despite remarkable progress in diabetes technology, most systems still require estimating meal carbohydrate (CHO) content for meal-time insulin delivery. Emerging smartphone applications may obviate this need, but performance data in relation to patient estimates remain scarce., Objective: The objective is to assess the accuracy of two commercial CHO estimation applications, SNAQ and Calorie Mama, and compare their performance with the estimation accuracy of people with type 1 diabetes (T1D)., Methods: Carbohydrate estimates of 53 individuals with T1D (aged ≥16 years) were compared with those of SNAQ (food recognition + quantification) and Calorie Mama (food recognition + adjustable standard portion size). Twenty-six cooked meals were prepared at the hospital kitchen. Each participant estimated the CHO content of two meals in three different sizes without assistance. Participants then used SNAQ for CHO quantification in one meal and Calorie Mama for the other (all three sizes). Accuracy was the estimate's deviation from ground-truth CHO content (weight multiplied by nutritional facts from recipe database). Furthermore, the applications were rated using the Mars-G questionnaire., Results: Participants' mean ± standard deviation (SD) absolute error was 21 ± 21.5 g (71 ± 72.7%). Calorie Mama had a mean absolute error of 24 ± 36.5 g (81.2 ± 123.4%). With a mean absolute error of 13.1 ± 11.3 g (44.3 ± 38.2%), SNAQ outperformed the estimation accuracy of patients and Calorie Mama (both P > .05). Error consistency (quantified by the within-participant SD) did not significantly differ between the methods., Conclusions: SNAQ may provide effective CHO estimation support for people with T1D, particularly those with large or inconsistent CHO estimation errors. Its impact on glucose control remains to be evaluated., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: LB reports serving as a consultant for SNAQ.

Fusarium oxysporum f. sp. lentis ( Fol ) is considered the most destructive disease for lentil ( Lens culinaris Medik.) worldwide. Despite the extensive studies elucidating plants' metabolic response to fungal agents, there is a knowledge gap in the biochemical mechanisms governing Fol -resistance in lentil. Τhis study aimed at comparatively evaluating the metabolic response of two lentil genotypes, with contrasting phenotypes for Fol -resistance, to Fol -inoculation. Apart from gaining insights into the metabolic reprogramming in response to Fol -inoculation, the study focused on discovering novel biomarkers to improve early selection for Fol -resistance. GC-MS-mediated metabolic profiling of leaves and roots was employed to monitor changes across genotypes and treatments as well as their interaction. In total, the analysis yielded 178 quantifiable compounds, of which the vast majority belonged to the groups of carbohydrates, amino acids, polyols and organic acids. Despite the magnitude of metabolic fluctuations in response to Fol -inoculation in both genotypes under study, significant alterations were noted in the content of 18 compounds, of which 10 and 8 compounds referred to roots and shoots, respectively. Overall data underline the crucial contribution of palatinitol and L-proline in the metabolic response of roots and shoots, respectively, thus offering possibilities for their exploitation as metabolic biomarkers for Fol -resistance in lentil. To the best of our knowledge, this is the first metabolomics-based approach to unraveling the effects of Fol -inoculation on lentil's metabolome, thus providing crucial information related to key aspects of lentil- Fol interaction. Future investigations in metabolic aspects of lentil- Fol interactions will undoubtedly revolutionize the search for metabolites underlying Fol -resistance, thus paving the way towards upgrading breeding efforts to combat fusarium wilt in lentil.

The N-terminal portion of the octapeptide angiotensin II (DRVYIHPF; AngII), a vasopressor peptide that favorably binds to, and activates, AngII type 1 receptor (AT 1 R), has an important role in maintaining bioactive conformation. It involves all three charged groups, namely (i) the N-terminal amino group cation, (ii) the Asp sidechain anion and (iii) the Arg guanidino cation. Neutralization of any one of these three charged groups results in a substantial reduction (<5%) in bioactivity, implicating a specialized function for this cluster. In contrast, angiotensin A (ARVYIHPF; AngA) has reduced bioactivity at AT 1 R; however, replacement of Asp in AngII with sarcosine (N-methyl-glycine) not only restores bioactivity but increases the activity of agonist, antagonist, and inverse agonist analogues. A bend produced at the N-terminus by the introduction of the secondary amino acid sarcosine is thought to realign the functional groups that chaperone the C-terminal portion of AngII, allowing transfer of the negative charge originating at the C-terminus to be transferred to the Tyr hydroxyl-forming tyrosinate anion, which is required to activate the receptor and desensitizes the receptor (tachyphylaxis). Peptide (sarilesin) and nonpeptide (sartans) moieties, which are long-acting inverse agonists, appear to desensitize the receptor by a mechanism analogous to tachyphylaxis. Sartans/bisartans were found to bind to alpha adrenergic receptors resulting in structure-dependent desensitization or resensitization. These considerations have provided information on the mechanisms of receptor desensitization/tolerance and insights into possible avenues for treating addiction. In this regard sartans, which appear to cross the blood-brain barrier more readily than bisartans, are the preferred drug candidates.

Bone mechanotransduction is a critical process during skeletal development in embryogenesis and organogenesis. At the same time, the type and level of mechanical loading regulates bone remodeling throughout the adult life. The aberrant mechanosensing of bone cells has been implicated in the development and progression of bone loss disorders, but also in the bone-specific aspect of other clinical entities, such as the tumorigenesis of solid organs. Novel treatment options have come into sight that exploit the mechanosensitivity of osteoblasts, osteocytes, and chondrocytes to achieve efficient bone regeneration. In this regard, runt-related transcription factor 2 (Runx2) has emerged as a chief skeletal-specific molecule of differentiation, which is prominent to induction by mechanical stimuli. Polycystins represent a family of mechanosensitive proteins that interact with Runx2 in mechano-induced signaling cascades and foster the regulation of alternative effectors of mechanotransuction. In the present narrative review, we employed a PubMed search to extract the literature concerning Runx2, polycystins, and their association from 2000 to March 2024. The keywords stated below were used for the article search. We discuss recent advances regarding the implication of Runx2 and polycystins in bone remodeling and regeneration and elaborate on the targeting strategies that may potentially be applied for the treatment of patients with bone loss diseases.

Background: Hypertension worsens outcomes in SARS-CoV-2 patients. Sartans, a type of antihypertensive angiotensin receptor blocker-(ARB), reduce COVID-19 morbidity and mortality by targeting angiotensin-converting enzyme-2 (ACE2). This study aimed to evaluate the antiviral and antihypertensive effects of nirmatrelvir, commercial sartans (candesartan, losartan, and losartan carboxylic (Exp3174)), and newly synthesized sartans (benzimidazole-N-biphenyl carboxyl (ACC519C) and benzimidazole-N-biphenyl tetrazole (ACC519T)), compared to nirmatrelvir, the antiviral component of Paxlovid., Research Design and Methods: Surface plasmon resonance (SPR) and enzymatic studies assessed drug effects on ACE2. Antiviral abilities were tested with SARS-CoV-2-infected Vero E6 cells, and antihypertensive effects were evaluated using angiotensin II-contracted rabbit iliac arteries., Results: Benzimidazole-based candesartan and ACC519C showed antiviral activity comparable to nirmatrelvir (95% inhibition). Imidazole-based losartan, Exp3174, and ACC519T were less potent (75%-80% and 50%, respectively), with Exp3174 being the least effective. SPR analysis indicated high sartans-ACE2 binding affinity. Candesartan and nirmatrelvir combined had greater inhibitory and cytopathic effects (3.96%) than individually (6.10% and 5.08%). ACE2 enzymatic assays showed varying effects of novel sartans on ACE2. ACC519T significantly reduced angiotensin II-mediated contraction, unlike nirmatrelvir and ACC519T(2)., Conclusion: This study reports the discovery of a new class of benzimidazole-based sartans that significantly inhibit SARS-CoV-2, likely due to their interaction with ACE2.

We assessed the diagnostic potential of erythroferrone as a biomarker for iron homeostasis comparing iron deficiency cases with anaemia of inflammation and controls. The dysregulation of the hepcidin axis was observed by Latour et al. in a mouse model of malarial anaemia induced by prolonged Plasmodium infection leading to increased erythroferrone concentrations. In line with that, we found significantly higher erythroferrone levels in cases with malaria and anaemia in an African population, compared to asymptomatic controls. Therefore, our findings extend the previous ones of the mouse model, suggesting also a dysregulation of the hepcidin axis in humans, which should be further corroborated in prospective studies and may lay the basis for the development of improved treatment strategies according to ERFE concentrations in such patients., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The coordination chemistry of 2-pyridyl ketoximes continues to attract the interest of many inorganic chemistry groups around the world for a variety of reasons. Cadmium(II) complexes of such ligands have provided models of solvent extraction of this toxic metal ion from aqueous environments using 2-pyridyl ketoxime extractants. Di-2-pyridyl ketone oxime (dpkoxH) is a unique member of this family of ligands because its substituent on the oxime carbon bears another potential donor site, i.e., a second 2-pyridyl group. The goal of this study was to investigate the reactions of cadmium(II) halides and dpkoxH in order to assess the structural role (if any) of the halogeno ligand and compare the products with their zinc(II) analogs. The synthetic studies provided access to complexes {[CdCl 2 (dpkoxH)∙2H 2 O]} n ( 1 ∙2H 2 O), {[CdBr 2 (dpkoxH)]} n ( 2 ) and {[CdI 2 (dpkoxH)]} n ( 3 ) in 50-60% yields. The structures of the complexes were determined by single-crystal X-ray crystallography. The compounds consist of structurally similar 1D zigzag chains, but only 2 and 3 are strictly isomorphous. Neighboring Cd II atoms are alternately doubly bridged by halogeno and dpkoxH ligands, the latter adopting the η 1 :η 1 :η 1 :μ (or 2.0111 using Harris notation) coordination mode. A terminal halogeno group completes distorted octahedral coordination at each metal ion, and the coordination sphere of the Cd II atoms is {Cd II (η 1 - X)(μ - X) 2 (N pyridyl ) 2 (N oxime )} (X = Cl, Br, I). The trans -donor-atom pairs in 1 ∙2H 2 O are Cl terminal /N oxime and two Cl bridging /N pyridyl ; on the contrary, these donor-atom pairs are X terminal /N pyridyl , X bridging /N oxime, and X bridging /N pyridyl (X = Br, I). There are intrachain H-bonding interactions in the structures. The packing of the chains in 1 ∙2H 2 O is achieved via π-π stacking interactions, while the 3D architecture of the isomorphous 2 and 3 is built via C-H∙∙∙C g (C g is the centroid of one pyridyl ring) and π-π overlaps. The molecular structures of 1 ∙2H 2 O and 2 are different compared with their [ZnX 2 (dpkoxH)] (X = Cl, Br) analogs. The polymeric compounds were characterized by IR and Raman spectroscopies in the solid state, and the data were interpreted in terms of the known molecular structures. The solid-state structures of the complexes are not retained in DMSO, as proven via NMR ( 1 H, 13 C, and 113 Cd NMR) spectroscopy and molar conductivity data. The complexes completely release the coordinated dpkoxH molecule, and the dominant species in solution seem to be [Cd(DMSO) 6 ] 2+ in the case of the chloro and bromo complexes and [CdI 2 (DMSO) 4 ].

Open-source devices are nowadays used in a vast number of research fields like medicine, education, agriculture, and sports, among others. In this work, an open-source, portable, low-cost pH logger, appropriate for in situ measurements, was designed and developed to assist in experiments on agricultural produce manufacturing. Τhe device was calibrated manually using pH buffers for values of 4.01 and 7.01. Then, it was tested by manually measuring the pH from the juice of citrus fruits. A waterproof temperature sensor was added to the device for temperature compensation when measuring the pH. A formal method comparison process between the open-source device and a Hanna HI9024 Waterproof pH Meter was designed to assess their agreement. We derived indices of agreement and graphical assessment tools using mixed-effects models. The advantages and disadvantages of interpreting agreement through the proposed procedure are discussed. In our illustration, the indices reported mediocre agreement and the subsequent similarity analysis revealed a fixed bias of 0.22 pH units. After recalibration, agreement between the devices improved to excellent levels. The process can be followed in general to avoid misleading or over-simplistic results of studies reporting solely correlation coefficients for formal comparison purposes.

In silico approaches were employed to examine the characteristics of interactions between human mitochondrial thioredoxin 2 (HsTrx2) and its 38 previously identified mitochondrial protein ligands. All interactions appeared driven mainly by electrostatic forces. The statistically significant residues of HsTrx2 for interactions were characterized as "contact hot spots". Since these were identical/adjacent to putative thermodynamic hot spots, an energy network approach identified their neighbors to highlight possible contact interfaces. Three distinct areas for binding emerged: (i) one around the active site for covalent interactions, (ii) another antipodal to the active site for strong non-covalent interactions, and (iii) a third area involved in both kinds of interactions. The contact interfaces of HsTrx2 were projected as respective interfaces for Escherichia coli Trx1 (EcoTrx1), 2, and HsTrx1. Comparison of the interfaces and contact hot spots of HsTrx2 to the contact residues of EcoTx1 and HsTrx1 from existing crystal complexes with protein ligands supported the hypothesis, except for a part of the cleft/groove adjacent to Trp 30 preceding the active site. The outcomes of this study raise the possibility for the rational design of selective inhibitors for the interactions of HsTrx2 with specific protein ligands without affecting the entirety of the functions of the Trx system.

Several artificial larval diets have been developed, evaluated and used for mass-rearing of the Mediterranean fruit fly (medfly), Ceratitis capitata (Wiedemann) (Diptera: Teprhitidae). There are several efforts to reduce the cost of rearing and optimize the quality of the produced sterile males that are destined for release in sterile insect release programs. Survival, growth, longevity and reproductive capacity of sterile males are strongly connected with the most expensive ingredient, the brewer's yeast (protein), in the larval diet. The current study focused on settling the optimal content of brewer's yeast in a liquid diet and a gel diet. Egg hatch rates, developmental duration of immatures, pupation rate, pupae and adult survival were recorded as indicators of quantity and quality of the produced adults. Egg hatch was higher and larval developmental duration longer in the gel diet. In contrast to the liquid diet, an increase in brewer's yeast concentration was correlated with increased pupation rate and pupae survival in the gel diet. Reducing brewer's yeast up to 50% of its initial quantity had no significant effect on the survival of the emerging adults regardless of the diet type. Our findings may contribute to the production of low-cost and effective diets for use in mass-rearing facilities of medflies.

Background: The fumigant phosphine is used all over the world for disinfestation of stored grains and commodities. Adults of 23 different populations of Tribolium castaneum from 10 different countries were evaluated for phosphine resistance using a modification of the Detia Degesch Phosphine Tolerance Test Kit (DDPTTK). Adults were exposed to 3000 ppm and recorded for 5-270 min for their mobility., Results: Among the tested populations, high levels of phosphine resistance were recorded in populations from Brazil, Serbia, and Spain. No survivals were recorded after 7 days post exposure for eight of 23 in a tested population., Conclusions: Our work revealed four scenarios: 1, quick knockdown-low (or no) recovery; 2, Slow knockdown-high recovery; 3, Quick knockdown-high recovery; and 4, Slow knockdown-low recovery. Our data indicate that post exposure period is critical for the evaluation and characterization of phosphine resistance. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

Regular physical activity (PA) supports the long-term success of bariatric surgery. However, integrating health-enhancing physical activity in daily life requires specific competences. In this study, we evaluated a multimodal exercise programme to build these competences.Forty adults who underwent bariatric surgery were randomised to a multimodal exercise programme or control group. Primary outcomes were the facets of PA-related health competences, namely the control competence for physical training, PA-specific affect regulation, motivational competence and PA-specific self-control. Secondary outcomes were PA behaviour and subjective vitality. Outcomes were assessed before, directly after the intervention and at 3 months follow-up.Significant treatment effects were found for control competence for physical training and PA-specific self-control but not for PA-specific affect regulation and motivational competence. Significant treatment effects were further observed for self-reported exercise and subjective vitality, all in favour of the intervention group. In contrast, no treatment effect was found for device-based PA. Overall, this study provides a foundation for future research to optimise long-term post bariatric surgery outcomes., (© 2023. The Author(s).)

Aim: To evaluate the efficacy of nutritional hypoglycaemia correction strategies in postbariatric hypoglycaemia (PBH) after Roux-en-Y gastric bypass (RYGB)., Materials and Methods: In a randomized, controlled, three-arm crossover trial, eight post-RYGB adults (mean [SD] 7.0 [1.4] years since surgery) with PBH ingested a solid mixed meal (584 kcal, 85 g carbohydrates, 21 g fat, 12 g protein) to induce hypoglycaemia on three separate days. Upon reaching plasma glucose of less than 3.0 mmol/L, hypoglycaemia was corrected with 15 g of glucose (G15), 5 g of glucose (G5) or a protein bar (P10, 10 g of protein) in random order. The primary outcome was percentage of time spent in the target plasma glucose range (3.9-5.5 mmol/L) during 40 minutes after correction., Results: Postcorrection time spent in the target glucose range did not differ significantly between the interventions (P = .161). However, postcorrection time with glucose less than 3.9 mmol/L was lower after G15 than P10 (P = .007), whereas time spent with glucose more than 5.5 mmol/L, peak glucose and insulin 15 minutes postcorrection were higher after G15 than G5 and P10 (P < .001). Glucagon 15 minutes postcorrection was higher after P10 than after G15 and G5 (P = .002 and P = .003, respectively). G15 resulted in rebound hypoglycaemia (< 3.0 mmol/L) in three of eight cases (38%), while no rebound hypoglycaemia occurred with G5 and P10., Conclusions: Correcting hypoglycaemia with 15 g of glucose should be reconsidered in post-RYGB PBH. A lower dose appears to sufficiently increase glucose levels outside the critical range in most cases, and complementary nutrients (e.g. proteins) may provide glycaemia-stabilizing benefits., Registration Number of Clinical Trial: NTC05250271 (ClinicalTrials.gov)., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Furins are serine endoproteases that process precursor proteins into their biologically active forms, and they play essential roles in normal metabolism and disease presentation, including promoting expression of bacterial virulence factors and viral pathogenesis. Thus, furins represent vital targets for development of antimicrobial and antiviral therapeutics. Recent experimental evidence indicated that dichlorophenyl (DCP)-pyridine "BOS" drugs ( e.g. , BOS-318) competitively inhibit human furin by an induced-fit mechanism in which tryptophan W254 in the furin catalytic cleft (FCC) functions as a molecular gate, rotating nearly 180 o through a steep energy barrier about its chi-1 dihedral to an "open" orientation, exposing a buried ( i.e. , cryptic) hydrophobic pocket 1 . Once exposed, the non-polar DCP group of BOS-318, and similar halo-phenyl groups of analogs, enter the cryptic pocket, stabilizing drug binding. Here, we demonstrate flexible-receptor docking of BOS-318 (and various analogs) was unable to emulate the induced-fit motif, even when tryptophan was replaced with less bulky phenylalanine or glycine. While either substitution allowed access to the hydrophobic pocket for most ligands tested, optimal binding was observed only for W254, inferring a stabilizing effect of the indole sidechain. Furthermore, non-equilibrium steered molecular dynamics (sMD) in which the bound drugs (or their fragments) were extracted from the FCC did not cause closure of the open W254 gate, consistent with the thermodynamic stability of the open or closed W254 orientations. Finally, interactive molecular dynamics (iMD) revealed two putative conduits of drug entry and binding into the FCC, each coupled with W254 dihedral rotation and opening of the cryptic pocket. The iMD simulations further revealed ligand entry and binding in the FCC is likely driven in part by energy fluxes stemming from disruption and re-formation of ligand and protein solvation shells during drug migration from the solution phase into the FCC., Competing Interests: 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., (© 2023 The Authors.)

Background: Asymptomatic Plasmodium falciparum parasitaemia forms a reservoir for the transmission of malaria disease in West Africa. Certain haemoglobin variants are known to protect against severe malaria infection. However, data on the potential roles of haemoglobin variants and nongenetic factors in asymptomatic malaria infection is scarce and controversial. Therefore, this study investigated the associations of iron homeostasis, inflammation, nutrition, and haemoglobin mutations with parasitaemia in an asymptomatic cohort from a P. falciparum-endemic region during the high transmission season., Methods: A sub-study population of 688 asymptomatic individuals (predominantly children and adolescents under 15 years, n = 516) from rural Burkina Faso previously recruited by the NOVAC trial (NCT03176719) between June and October 2017 was analysed. Parasitaemia was quantified with conventional haemocytometry. The haemoglobin genotype was determined by reverse hybridization assays targeting a selection of 21 HBA and 22 HBB mutations. Demographics, inflammatory markers (interleukins 6 and 10, hepcidin), nutritional status (mid upper-arm circumference and body mass index), and anaemia (total haemoglobin, ferritin, soluble transferrin receptor) were assessed as potential predictors through logistic regression., Results: Malaria parasites were detected in 56% of subjects. Parasitaemia was associated most strongly with malnutrition. The effect size increased with malnutrition severity (OR = 6.26, CI 95 : 2.45-19.4, p < 0.001). Furthermore, statistically significant associations (p < 0.05) with age, cytokines, hepcidin and heterozygous haemoglobin S were observed., Conclusions: According to these findings, asymptomatic parasitaemia is attenuated by haemoglobin S, but not by any of the other detected genotypes. Aside from evidence for slight iron imbalance, overall undernutrition was found to predict parasitaemia; thus, further investigations are required to elucidate causality and inform strategies for interventions., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Zinc is a multipurpose trace element for the human body, as it plays a crucial part in various physiological processes, such as cell growth and development, metabolism, cognitive, reproductive, and immune system function. Its significance in human health is widely acknowledged, and this has led the scientific community towards more research that aims to uncover all of its beneficial properties, especially when compared to other essential metal ions. One notable area where zinc has shown beneficial effects is in the prevention and treatment of various diseases, including cancer. This review aims to explain the involvement of zinc in specific health conditions such as cancer, coronavirus disease 2019 (COVID-19) and neurological disorders like Alzheimer's disease, as well as its impact on the gut microbiome., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Kiouri et al.)

Recovery of carbon-based resources from waste is a critical need for achieving carbon neutrality and reducing fossil carbon extraction. We demonstrate a new approach for extracting volatile fatty acids (VFAs) using a multifunctional direct heated and pH swing membrane contactor. The membrane is a multilayer laminate composed of a carbon fiber (CF) bound to a hydrophobic membrane and sealed with a layer of polydimethylsiloxane (PDMS); this CF is used as a resistive heater to provide a thermal driving force for PDMS that, while a highly hydrophobic material, is known for its ability to rapidly pass gases, including water vapor. The transport mechanism for gas transport involves the diffusion of molecules through the free volume of the polymer matrix. CF coated with polyaniline (PANI) is used as an anode to induce an acidic pH swing at the interface between the membrane and water, which can protonate the VFA molecule. The innovative multilayer membrane used in this study has successfully demonstrated a highly efficient recovery of VFAs by simultaneously combining pH swing and joule heating. This novel technique has revealed a new concept in the field of VFA recovery, offering promising prospects for further advancements in this area. The energy consumption was 3.37 kWh/kg for acetic acid (AA), and an excellent separation factor of AA/water of 51.55 ± 2.11 was obtained with high AA fluxes of 51.00 ± 0.82 g.m -2 hr -1 . The interfacial electrochemical reactions enable the extraction of VFAs without the need for bulk temperature and pH modification.

Objective: During a high-altitude expedition, the association of cardiopulmonary exercise testing (CPET) parameters with the risk of developing acute mountain sickness (AMS) and the chance of reaching the summit were investigated., Methods: Thirty-nine subjects underwent maximal CPET at lowlands and during ascent to Mount Himlung Himal (7126 m) at 4844 m, before and after 12 days of acclimatisation, and at 6022 m. Daily records of Lake-Louise-Score (LLS) determined AMS. Participants were categorised as AMS+ if moderate to severe AMS occurred., Results: Maximal oxygen uptake (V̇O 2max ) decreased by 40.5%±13.7% at 6022 m and improved after acclimatisation (all p<0.001). Ventilation at maximal exercise (VE max ) was reduced at 6022 m, but higher VE max was related to summit success (p=0.031). In the 23 AMS+ subjects (mean LLS 7.4±2.4), a pronounced exercise-induced oxygen desaturation (ΔSpO 2exercise ) was found after arrival at 4844 m (p=0.005). ΔSpO 2exercise >-14.0% identified 74% of participants correctly with a sensitivity of 70% and specificity of 81% for predicting moderate to severe AMS. All 15 summiteers showed higher V̇O 2max (p<0.001), and a higher risk of AMS in non-summiteers was suggested but did not reach statistical significance (OR: 3.64 (95% CI: 0.78 to 17.58), p=0.057). V̇O 2max ≥49.0 mL/min/kg at lowlands and ≥35.0 mL/min/kg at 4844 m predicted summit success with a sensitivity of 46.7% and 53.3%, and specificity of 83.3% and 91.3%, respectively., Conclusion: Summiteers were able to sustain higher VE max throughout the expedition. Baseline V̇O 2max below 49.0 mL/min/kg was associated with a high chance of 83.3% for summit failure, when climbing without supplemental oxygen. A pronounced drop of SpO 2exercise at 4844 m may identify climbers at higher risk of AMS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To investigate the effect of empagliflozin on glucose dynamics in individuals suffering from postbariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). Methods: Twenty-two adults with PBH after RYGB were randomized to empagliflozin 25 mg or placebo once daily over 20 days in a randomized, double-blind, placebo-controlled, crossover trial. The primary efficacy outcome was the amplitude of plasma glucose excursion (peak to nadir) during a mixed-meal tolerance test (MMTT). Outcomes of the outpatient period were assessed using continuous glucose monitoring (CGM) and an event-tracking app. Results: The amplitude of glucose excursion during the MMTT was 8.1 ± 2.4 mmol/L with empagliflozin versus 8.1 ± 2.6 mmol/L with placebo (mean ± standard deviation, P  = 0.807). CGM-based mean amplitude of glucose excursion during the 20-day period was lower with empagliflozin than placebo (4.8 ± 1.3 vs. 5.2 ± 1.6. P  = 0.028). Empagliflozin reduced the time spent with CGM values >10.0 mmol/L (3.8 ± 3.5% vs. 4.7 ± 3.8%, P  = 0.009), but not the time spent with CGM values <3.0 mmol/L (1.7 ± 1.6% vs. 1.5 ± 1.5%, P  = 0.457). No significant difference was observed in the quantity and quality of recorded symptoms. Eleven adverse events occurred with empagliflozin (three drug-related) and six with placebo. Conclusions: Empagliflozin 25 mg reduces glucose excursions but not hypoglycemia in individuals with PBH. Clinical Trial Registration: Clinicaltrials.gov: NCT05057819.

Ammonia is considered a contaminant to be removed from wastewater. However, ammonia is a valuable commodity chemical used as the primary feedstock for fertilizer manufacturing. Here we describe a simple and low-cost ammonia gas stripping membrane capable of recovering ammonia from wastewater. The material is composed of an electrically conducting porous carbon cloth coupled to a porous hydrophobic polypropylene support, that together form an electrically conductive membrane (ECM). When a cathodic potential is applied to the ECM surface, hydroxide ions are produced at the water-ECM interface, which transforms ammonium ions into higher-volatility ammonia that is stripped across the hydrophobic membrane material using an acid-stripping solution. The simple structure, low cost, and easy fabrication process make the ECM an attractive material for ammonia recovery from dilute aqueous streams, such as wastewater. When paired with an anode and immersed into a reactor containing synthetic wastewater (with an acid-stripping solution providing the driving force for ammonia transport), the ECM achieved an ammonia flux of 141.3 ± 14.0 g.cm -2 .day -1 at a current density of 6.25 mA.cm -2 (69.2 ± 5.3 kg(NH 3 -N)/kWh). It was found that the ammonia flux was sensitive to the current density and acid circulation rate.

The potential of targeting the Renin-Angiotensin-Aldosterone System (RAAS) as a treatment for the coronavirus disease 2019 (COVID-19) is currently under investigation. One way to combat this disease involves the repurposing of angiotensin receptor blockers (ARBs), which are antihypertensive drugs, because they bind to angiotensin-converting enzyme 2 (ACE2), which in turn interacts with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. However, there has been no in silico analysis of the potential toxicity risks associated with the use of these drugs for the treatment of COVID-19. To address this, a network-based bioinformatics methodology was used to investigate the potential side effects of known Food and Drug Administration (FDA)-approved antihypertensive drugs, Sartans. This involved identifying the human proteins targeted by these drugs, their first neighbors, and any drugs that bind to them using publicly available experimentally supported data, and subsequently constructing proteomes and protein-drug interactomes. This methodology was also applied to Pfizer's Paxlovid, an antiviral drug approved by the FDA for emergency use in mild-to-moderate COVID-19 treatment. The study compares the results for both drug categories and examines the potential for off-target effects, undesirable involvement in various biological processes and diseases, possible drug interactions, and the potential reduction in drug efficiency resulting from proteoform identification.

This study is an extension of current research into a novel class of synthetic antihypertensive drugs referred to as "bisartans", which are bis-alkylated imidazole derivatives bearing two symmetric anionic biphenyltetrazoles. Research to date indicates that bisartans are superior to commercially available hypertension drugs, since the former undergo stronger docking to angiotensin-converting enzyme 2 (ACE2). ACE2 is the key receptor involved in SARS-CoV-2 entry, thus initiating COVID-19 infection and in regulating levels of vasoactive peptides such as angiotensin II and beneficial heptapeptides A(1-7) and Alamandine in the renin-angiotensin system (RAS). In previous studies using in vivo rabbit-iliac arterial models, we showed that Na + or K + salts of selected Bisartans initiate a potent dose-response inhibition of vasoconstriction. Furthermore, computational studies revealed that bisartans undergo stable binding to the vital interfacial region between ACE2 and the SARS-CoV-2 "receptor binding domain" (i.e., the viral RBD). Thus, bisartan homologs are expected to interfere with SARS-CoV-2 infection and/or suppress disease expression in humans. The primary goal of this study was to investigate the role of tetrazole in binding and the network of amino acids of SARS-CoV-2 Spike RBD-ACE2 complex involved in interactions with sartans. This study would, furthermore, allow the expansion of the synthetic space to create a diverse suite of new bisartans in conjunction with detailed computational and in vitro antiviral studies. A critical role for tetrazole was uncovered in this study, shedding light on the vital importance of this group in the binding of sartans and bisartans to the ACE2/Spike complex. The in silico data predicting an interaction of tetrazole-containing sartans with ACE2 were experimentally validated by the results of surface plasmon resonance (SPR) analyses performed with a recombinant human ACE2 protein.

The polymorphism of human insulin upon pH variation was characterized via X-ray powder diffraction, employing a crystallization protocol previously established for co-crystallization with phenolic derivatives. Two distinct rhombohedral (R3) polymorphs and one cubic (I2 1 3) polymorph were identified with increasing pH, corresponding to the T 6 , T 3 R 3 and T f conformations of insulin, respectively. The structure of the cubic T 2 conformations of insulin, respectively. The structure of the cubic T 2 polymorph was determined via multi-profile stereochemically restrained Rietveld refinement at 2.7 Å resolution. This constitutes the first cubic insulin structure to be determined from crystals grown in the presence of zinc ions, although no zinc binding was observed. The differences of the polycrystalline variant from other cubic insulin structures, as well as the nature of the pH-driven phase transitions, are discussed in detail., (open access.)

Aims/hypothesis: Post-bariatric hypoglycaemia is an increasingly recognised complication of bariatric surgery, manifesting particularly after Roux-en-Y gastric bypass. While hyperinsulinaemia is an established pathophysiological feature, the role of counter-regulation remains unclear. We aimed to assess counter-regulatory hormones and glucose fluxes during insulin-induced postprandial hypoglycaemia in patients with post-bariatric hypoglycaemia after Roux-en-Y gastric bypass vs surgical and non-surgical control individuals., Methods: In this case-control study, 32 adults belonging to four groups with comparable age, sex and BMI (patients with post-bariatric hypoglycaemia, Roux-en-Y gastric bypass, sleeve gastrectomy and non-surgical control individuals) underwent a postprandial hypoglycaemic clamp in our clinical research unit to reach the glycaemic target of 2.5 mmol/l 150-170 min after ingesting 15 g of glucose. Glucose fluxes were assessed during the postprandial and hypoglycaemic period using a dual-tracer approach. The primary outcome was the incremental AUC of glucagon during hypoglycaemia. Catecholamines, cortisol, growth hormone, pancreatic polypeptide and endogenous glucose production were also analysed during hypoglycaemia., Results: The rate of glucose appearance after oral administration, as well as the rates of total glucose appearance and glucose disappearance, were higher in both Roux-en-Y gastric bypass groups vs the non-surgical control group in the early postprandial period (all p<0.05). During hypoglycaemia, glucagon exposure was significantly lower in all surgical groups vs the non-surgical control group (all p<0.01). Pancreatic polypeptide levels were significantly lower in patients with post-bariatric hypoglycaemia vs the non-surgical control group (median [IQR]: 24.7 [10.9, 38.7] pmol/l vs 238.7 [186.3, 288.9] pmol/l) (p=0.005). Other hormonal responses to hypoglycaemia and endogenous glucose production did not significantly differ between the groups., Conclusions/interpretation: The glucagon response to insulin-induced postprandial hypoglycaemia is lower in post-bariatric surgery individuals compared with non-surgical control individuals, irrespective of the surgical modality. No significant differences were found between patients with post-bariatric hypoglycaemia and surgical control individuals, suggesting that impaired counter-regulation is not a root cause of post-bariatric hypoglycaemia., Trial Registration: ClinicalTrials.gov NCT04334161., (© 2023. The Author(s).)

In the current study, a mixed microbial culture (MMC) of polyhydroxyalkanoates (PHAs) producers was developed under nutrient stress and was assessed as biocatalyst for the production of high-yielding PHAs from fermented (acidified) discarded fruit juices (DFJ). The structure of the MMC was analyzed periodically to determine its microbial dynamics, revealing that Zoogloae sp. dominated throughout the operation of the system. The efficiency of PHAs production from the MMC was further optimized in batch mode by altering the ratio of C to N, the ratio of carbon sources (propionate and butyrate), and the initial pH, and subsequently different fermentation mixtures of acidified DFJ were assessed as substrates at optimal conditions. Upon solvent extraction, the properties of recovered PHAs were analyzed, showing that in all cases P(3HB-co-3HV) was produced, with T m ranging from 90.5 to 168.8 °C, and maximum obtained yields 54.61 ± 4.31 % and 43.27 ± 2.13 %, from synthetic substrates and DFJ, respectively. Overall, it was shown that the developed MMC can be efficiently applied as biocatalyst for the exploitation of sugary wastewaters, such as DFJ, towards bio-based and biodegradable plastics bearing the required properties to substitute fossil plastics, into the concept of a circular economy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gerasimos Lyberatos reports financial support was provided by General Secretariat for Research and Technology. Gerasimos Lyberatos reports a relationship with General Secretariat for Research and Technology that includes: funding grants., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background , Aims , Methods , Results , Conclusions: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. The molecular biology of this virus has been extensively studied and computational methods applied are an example paradigm for novel antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis by proteases, such as furin, trypsin, and the Transmembrane Serine Protease 2 (TMPRSS2) that augment infection rates, while inhibition of the 3-chymotrypsin-like protease (3CL pro ) can prevent the viral replication. Additionally, non-RBD and non-interfacial mutations may assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. This study aimed to report variant distribution of SARS-CoV-2 across European Union (EU)/European Economic Area (EEA) countries and relate mutations with the driving forces that trigger infections. Variants' distribution data for SARS-CoV-2 across EU/EEA countries were mined from the European Centre for Disease Prevention and Control (ECDC) based on the sequence or genotyping data that are deposited in the Global Science Initiative for providing genomic data (GISAID) and The European Surveillance System (TESSy) databases. Docking studies performed with AutoDock VINA revealed stabilizing interactions of putative antiviral drugs, e.g., selected anionic imidazole biphenyl tetrazoles, with the ACE2 receptor in the RBD-ACE2 complex. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Epsilon, Kappa, Lambda, and Omicron variants, which stabilize the RBD-ACE2 complex, were investigated by computational approaches. Arginine is the critical amino acid in the polybasic furin cleavage sites S1/S2 (681-PRRARS-686) S2' (814-KRS-816). Critical mutations into arginine residues that were found in the delta variant (L452R, P681R) and may be responsible for the increased transmissibility and morbidity are also present in two widely spreading omicron variants, named BA.4.6 and BQ.1, where mutation R346T in the S-protein potentially contributes to neutralization escape. Arginine binders, such as Angiotensin Receptor Blockers (ARBs), could be a class of novel drugs for treating COVID-19.

Background: There is conflicting evidence on the effect of exercise on systemic insulin concentrations in adults with type 1 diabetes., Methods: This prospective single-arm study examined the effect of exercise on systemic insulin degludec (IDeg) concentrations. The study involved 15 male adults with type 1 diabetes (age 30.7 ± 8.0 years, HbA1c 6.9 ± 0.7%) on stable IDeg regimen. Blood samples were collected every 15 minutes at rest, during 60 minutes of cycling (66% VO 2 max) and until 90 minutes after exercise termination. IDeg concentrations were quantified using high-resolution mass-spectrometry and analyzed applying generalized estimation equations., Results: Compared to baseline, systemic IDeg increased during exercise over time ( P  < .001), with the highest concentrations observed toward the end of the 60-minute exercise (17.9% and 17.6% above baseline after 45 minutes and 60 minutes, respectively). IDeg levels remained elevated until the end of the experiment (14% above baseline at 90 minutes after exercise termination, P  < .001)., Conclusions: A single bout of aerobic exercise increases systemic IDeg exposure in adults on a stable basal IDeg regimen. This finding may have important implications for future hypoglycemia mitigation strategies around physical exercise in IDeg-treated patients.

Background: The ubiquitin system is a modification process with many different cellular functions including immune signaling and antiviral functions. E3 ubiquitin ligases are enzymes that recruit an E2 ubiquitin-conjugating enzyme bound to ubiquitin in order to catalyze the transfer of ubiquitin from the E2 to a protein substrate. The RING E3s, the most abundant type of ubiquitin ligases, are characterized by a zinc (II)-binding domain called RING (Really Interesting New Gene). Viral replication requires modifying and hijacking key cellular pathways within host cells such as cellular ubiquitination. There are well-established examples where a viral proteins bind to RING E3s, redirecting them to degrade otherwise long-lived host proteins or inhibiting E3's ubiquitination activity. Recently, three binary interactions between SARS-CoV-2 proteins and innate human immune signaling Ε3 RING ligases: NSP15-RNF41, ORF3a-TRIM59 and NSP9-MIB1 have been experimentally established., Methods: In this work, we have investigated the mode of the previous experimentally supported NSP15-RNF41, ORF3a,-TRIM59 and NSP9-MIB1 binary interactions by in silico methodologies intending to provide structural insights of E3-virus interplay that can help identify potential inhibitors that could block SARS-CoV-2 infection of immune cells., Conclusion: In silico methodologies have shown that the above human E3 ligases interact with viral partners through their Zn(II) binding domains. This RING mediated formation of stable SARS-CoV-2-E3 complexes indicates a critical structural role of RING domains in immune system disruption by SARS-CoV-2-infection., Data Availability: The data used to support the findings of this research are included within the article and are labeled with references., Competing Interests: Conflict of interest The authors declare no potential conflicts of interest., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Cadmium (Cd) is a toxic metal for the human organism and for all ecosystems. Cd is naturally found at low levels; however, higher amounts of Cd in the environment result from human activities as it spreads into the air and water in the form of micropollutants as a consequence of industrial processes, pollution, waste incineration, and electronic waste recycling. The human body has a limited ability to respond to Cd exposure since the metal does not undergo metabolic degradation into less toxic species and is only poorly excreted. The extremely long biological half-life of Cd essentially makes it a cumulative toxin; chronic exposure causes harmful effects from the metal stored in the organs. The present paper considers exposure and potential health concerns due to environmental cadmium. Exposure to Cd compounds is primarily associated with an elevated risk of lung, kidney, prostate, and pancreatic cancer. Cd has also been linked to cancers of the breast, urinary system, and bladder. The multiple mechanisms of Cd-induced carcinogenesis include oxidative stress with the inhibition of antioxidant enzymes, the promotion of lipid peroxidation, and interference with DNA repair systems. Cd 2+ can also replace essential metal ions, including redox-active ones. A total of 12 cancer types associated with specific genes coding for the Cd-metalloproteome were identified in this work. In addition, we summarize the proper treatments of Cd poisoning, based on the use of selected Cd detoxifying agents and chelators, and the potential for preventive approaches to counteract its chronic exposure.

The SARS-CoV-2 infection was previously associated with the expression of the dopamine biosynthetic enzyme L-Dopa decarboxylase (DDC). Specifically, a negative correlation was detected between DDC mRNA and SARS-CoV-2 RNA levels in in vitro infected epithelial cells and the nasopharyngeal tissue of COVID-19 patients with mild/no symptoms. However, DDC, among other genes related to both DDC expression and SARS-CoV-2-infection ( ACE2 , dACE2 , EPO ), was upregulated in these patients, possibly attributed to an orchestrated host antiviral response. Herein, by comparing DDC expression in the nasopharyngeal swab samples of severe/critical to mild COVID-19 cases, we showed a 20 mean-fold reduction, highlighting the importance of the expression of this gene as a potential marker of COVID-19 severity. Moreover, we identified an association of SARS-CoV-2 infection with the expression of key catecholamine biosynthesis/metabolism-related genes, in whole blood samples from hospitalized patients and in cultured cells. Specifically, viral infection downregulated the biosynthetic part of the dopamine pathway (reduction in DDC expression up to 7.5 mean-fold), while enhanced the catabolizing part (increase in monoamine oxidases A and B expression up to 15 and 10 mean-fold, respectively) in vivo, irrespectively of the presence of comorbidities. In accordance, dopamine levels in the sera of severe cases were reduced (up to 3.8 mean-fold). Additionally, a moderate positive correlation between DDC and MAOA mRNA levels (r = 0.527, p < 00001) in the blood was identified upon SARS-CoV-2-infection. These observations were consistent to the gene expression data from SARS-CoV-2-infected Vero E6 and A549 epithelial cells. Furthermore, L-Dopa or dopamine treatment of infected cells attenuated the virus-derived cytopathic effect by 55% and 59%, respectively. The SARS-CoV-2 mediated suppression of dopamine biosynthesis in cell culture was, at least in part, attributed to hypoxia-like conditions triggered by viral infection. These findings suggest that L-Dopa/dopamine intake may have a preventive or therapeutic value for COVID-19 patients.

Orthopedic implants heal well without complications in most patients but fail for unclear reasons in some individuals. This study determined the relevance of metal hypersensitivity in patients with failed orthopedic implants and those requiring orthopedic implant surgery. The study included 35 patients with failed orthopedic implants and 15 subjects scheduled for orthopedic implant surgery. The production of selected pro-inflammatory cytokines was measured in patients with failed orthopedic implants. Metal hypersensitivity was measured in all subjects using the MELISA® test. Of common metals in orthopedic alloys, the patients with failed orthopedic implants responded most frequently to nickel, chromium, titanium, iron, and molybdenum. Hypersensitivity to metals found in implants was measured in 40% of patients with failed implants. The study also showed that titanium exposure in patients with titanium hypersensitivity might lead to implant failure. Metal hypersensitivity testing should be offered to patients before surgery to minimize the risk of implant failure., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests associated with this publication., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Bariatric surgery is a highly effective obesity treatment resulting in substantial weight loss and improved glucose metabolism. We hereby aimed to summarize available evidence of the effect of the 2 most common bariatric surgery procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), on dynamic measures of β-cell function (BCF). A systematic search of the literature was conducted in 3 bibliographic databases for studies reporting effects of RYGB and/or SG on BCF assessed using dynamic metabolic perturbation (oral or intravenous bolus stimulation), performed before and 1 year (±3 months) after surgery. Twenty-seven unique studies (6 randomized controlled trials and 21 observational studies), involving a total of 1856 obese adults, were included for final analysis. Twenty-five and 9 studies report effects of RYGB and SG on BCF, respectively (7 studies compared the 2 procedures). Seven studies report results according to presurgical diabetes status. Owing to variable testing procedures and BCF indices reported, no meta-analysis was feasible, and data were summarized qualitatively. For both surgical procedures, most studies suggest an increase in BCF and disposition index, particularly when using oral stimulation, with a more pronounced increase in diabetic than nondiabetic individuals. Additionally, limited indications for greater effects after RYGB versus SG were found. The quality of the included studies was, in general, satisfactory. The considerable heterogeneity of test protocols and outcome measures underscore the need for a harmonization of BCF testing in future research., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Two novel halogenated (Br- and F-) quinazoline derivatives, namely [( E )-4-(2-((6-bromopyridin-2-yl)methylene)hydrazinyl)quinazoline] (L1) and [( E )-4-(2-((3-fluoropyridin-2-yl)methylene)hydrazinyl) quinazoline] (L2), were synthesized and characterized. Their interaction with a series of metal(II) ions (= Mn(II), Ni(II), Cu(II), Zn(II) and Cd(II)) resulted in the formation of six mononuclear complexes characterized by spectroscopic techniques and single-crystal X-ray crystallography. The complexes bear the formulae [Ni(L 1 ) 2 ](NO 3 ) 2 (1), [Zn(L 2 ) 2 ](NO 3 )(PF 6 ) (2), [Cd(L 2 )(H 2 O)(CH 3 OH)(NO 3 )](NO 3 ) (3), [Cu(L 2 )Cl 2 ] (4), [Ni(L 2 ) 2 ](NO 3 ) 2 (5) and [Mn(L 2 )(CH 3 OH)(Cl) 2 ] (6). The biological activity of the compounds was further evaluated in vitro regarding their interaction with calf-thymus DNA, their cleavage ability towards supercoiled circular pBR322 plasmid DNA in the absence or presence of irradiation at various wavelengths (UVA, UVB and visible light), their affinity to bovine serum albumin and their ability to scavenge 1,1-diphenyl-picrylhydrazyl and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) radicals and to reduce H 2 O 2 . In silico molecular docking calculations were employed to study the behavior of the complexes towards calf-thymus DNA and bovine serum albumin.

The thioredoxin system, consisting of thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH, plays a fundamental role in the control of antioxidant defenses, cell proliferation, redox states, and apoptosis. Aberrations in the Trx system may lead to increased oxidative stress toxicity and neurodegenerative processes. This study reviews the role of the Trx system in the pathophysiology and treatment of Alzheimer's, Parkinson's and Huntington's diseases, brain stroke, and multiple sclerosis. Trx system plays an important role in the pathophysiology of those disorders via multiple interactions through oxidative stress, apoptotic, neuro-immune, and pro-survival pathways. Multiple aberrations in Trx and TrxR systems related to other redox systems and their multiple reciprocal relationships with the neurodegenerative, neuro-inflammatory, and neuro-oxidative pathways are here analyzed. Genetic and environmental factors (nutrition, metals, and toxins) may impact the function of the Trx system, thereby contributing to neuropsychiatric disease. Aberrations in the Trx and TrxR systems could be a promising drug target to prevent and treat neurodegenerative, neuro-inflammatory, neuro-oxidative stress processes, and related brain disorders., Competing Interests: The authors declare no conflict of interest.

Reactions of 2-benzoylpyridine, (py)(ph)CO, with InX 3 (X = Cl, Br) in EtOH at room temperature have been studied. The InCl 3 /(py)(ph)CO system has provided access to complex [InCl 3 {(py)(ph)CO}(EtOH)]·{(py)(ph)CO} (1) and the byproduct {(pyH)(ph)CO}Cl (2). The reaction of InBr 3 with (py)(ph)CO has led to a mixture of (L)[InBr 4 {(py)(ph)CO}] (3) and [In 2 Br 4 {(py)(ph)CH(O)} 2 (EtOH) 2 ] (4), where L + is the 9-oxo-indolo[1,2- a ]pyridinium cation and (py)(ph)CH(O) - is the anion of (pyridin-2-yl)methanol. Based on solubility and crystallisation time differences between the two components of the mixture, complex 4 was isolated in pure form, i.e. free from 3. The formations of the counterion L + and the coordinated (py)(ph)CH(O) - anion represent clearly InBr 3 -promoted/assisted transformations. Reaction mechanisms have been proposed for the formation of 2, 3 and 4. Complex 4 could also be isolated by the reaction of InBr 3 and pre-formed (py)(ph)CH(OH) in EtOH. The solid-state structures of 1, 3 and 4 were determined by single-crystal X-ray crystallography, while the identity of the salt 2 was confirmed by microanalyses and a variety of spectroscopic techniques, including ESI-MS spectra. In the indium(III) complexes, the metal ions are 6-coordinate with a distorted octahedral geometry. The halogeno groups (Cl - , Br - ) in the three complexes are terminal. The (py)(ph)CO molecule behaves as a N,O-bidentate (1.11) ligand in 1 and 3. A terminal EtOH ligand completes the coordination sphere of In III in 1. The alkoxo oxygen atoms of the two 2.21 (py)(ph)CH(O) - ligands doubly bridge the In III centers in 4 creating a {InIII2(μ-OR) 2 } 4+ core; a nitrogen atom of one reduced organic ligand, two bromo ions and one terminal EtOH molecule complete the 6-coordination at each metal centre. Complexes 1, 3 and 4 were characterised by IR and Raman spectroscopies, and the data were discussed in terms of their known solid-state structures. Molar conductivity data and 1 H NMR spectra were used in an attempt to probe the behaviour of the complexes in DMSO. The to-date observed metal ion-assisted/promoted transformations of (py)(ph)CO are also discussed.

Real-world data suggest that protection against COVID-19 declines a few months after vaccination, particularly in the elderly and immunocompromised individuals. Our study aimed to analyze the humoral response induced by a third supplemental dose of BNT162b2 vaccine in a mixed group of immunocompromised individuals by determining anti-spike (anti-S) IgG antibody titers at baseline (pre-third vaccine dose) and 4 weeks after the dose. Serum samples were obtained from a total group of 85 immunocompromised individuals (history of cancer: n = 20, lymphoma: n = 4, leukemia: n = 3, transplant recipients: n = 4, autoimmune disease: n = 42, inflammatory disease: n = 6, autoimmune diabetes type 1: n = 6) all of whom had previously received a two-dose schedule of the vaccine. The average number of days between second and third dose was 139.6145 (±41.39071). The overall IgG GMCs 4 weeks postvaccination were increased by more than 35 times (fold change = 35.30, p < 0.001). Fold changes were not significantly correlated with underlying condition, age, sex nor with days between second and third dose. Considering the predominance of omicron variants in the current period and the results of studies showing a decrease in the effectiveness of the third dose after 10 weeks we highly recommend a fourth dose to this vulnerable population group., (© 2022 Wiley Periodicals LLC.)

Introduction: Postprandial hypoglycaemia after gastric bypass surgery (also known as postbariatric hypoglycaemia or PBH) is an increasingly encountered clinical problem. PBH is characterised by meal-induced rapid spikes and consequent falls in glycaemia, resulting in both hypoglycaemia burden and high glycaemic variability. Despite its frequency, there is currently no approved pharmacotherapy. The purpose of this investigation is to evaluate efficacy and safety of empagliflozin 25 mg, a sodium-glucose cotransporter 2-inhibitor, to reduce glucose excursions and hypoglycaemia burden in patients with PBH after gastric bypass surgery., Methods and Analysis: In a prospective, single-centre, randomised, double-blind, placebo-controlled, crossover trial, we plan to enrol 22 adults (≥18 years) with PBH after Roux-en-Y gastric bypass surgery (plasma or sensor glucose <3.0 mmol/L). Eligible patients will be randomised to receive empagliflozin 25 mg and placebo once daily, each for 20 days, in random order. Study periods will be separated by a 2-6 weeks wash-out period. The primary efficacy outcome will be the amplitude of plasma glucose excursion (peak to nadir) during a mixed meal tolerance test. Results will be presented as paired-differences±SD plus 95% CIs with p values and hypothesis testing for primary and secondary outcomes according to intention-to-treat. Secondary outcomes include continuous glucose monitoring-based outcomes, further metabolic measures and safety., Ethics and Dissemination: The DEEP-EMPA trial (original protocol title: Randomized, double-blind, placebo-controlled crossover trialassessing the impact of the SGLT2 inhibitor empagliflozin onpostprandial hypoglycaemia after gastric bypass) was approved by the Bern Ethics Committee (ID 2021-01187) and Swissmedic (Ref. Number: 102663190) in October and November 2021, respectively. First results are expected in the first quarter of 2023 and will be disseminated via peer-reviewed publications and presented at national and international conferences. The acronym DEEP was derived from an overarching project title (DEciphering the Enigma of Postprandial Hyperinsulinaemic Hypoglycaemia after Bariatric Surgery), the term EMPA stands for the drug empagliflozin., Trial Registration Number: NCT05057819., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Perioperative management of glucose levels remains challenging. We aimed to assess whether fully closed-loop subcutaneous insulin delivery would improve glycemic control compared with standard insulin therapy in insulin-requiring patients undergoing elective surgery., Research Design and Methods: We performed a single-center, open-label, randomized controlled trial. Patients with diabetes (other than type 1) undergoing elective surgery were recruited from various surgical units and randomly assigned using a minimization schedule (stratified by HbA1c and daily insulin dose) to fully closed-loop insulin delivery with fast-acting insulin aspart (closed-loop group) or standard insulin therapy according to local clinical practice (control group). Study treatment was administered from hospital admission to discharge (for a maximum of 20 days). The primary end point was the proportion of time with sensor glucose in the target range (5.6-10.0 mmol/L)., Results: Forty-five patients were enrolled and assigned to the closed-loop (n = 23) or the control (n = 22) group. One patient (closed-loop group) withdrew from the study before surgery and was not analyzed. Participants underwent abdominal (57%), vascular (23%), orthopedic (9%), neuro (9%), or thoracic (2%) surgery. The mean proportion of time that sensor glucose was in the target range was 76.7 ± 10.1% in the closed-loop and 54.7 ± 20.8% in the control group (mean difference 22.0 percentage points [95% CI 11.9; 32.0%]; P < 0.001). No episodes of severe hypoglycemia (<3.0 mmol/L) or hyperglycemia with ketonemia or any study-related adverse events occurred in either group., Conclusions: In the context of mixed elective surgery, the use of fully closed-loop subcutaneous insulin delivery improves glucose control without a higher risk of hypoglycemia., (© 2022 by the American Diabetes Association.)