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Naturally occurring and chemically engineered modifications are among the most powerful strategies explored for fine-tuning the conformational characteristics and intrinsic stability of nucleic acids topologies. Modifications at the 2′-position of the ribose or 2′-deoxyribose moieties differentiate nucleic acid structures and have a significant impact on their electronic properties and base-pairing interactions. 2′-O-Methylation, a common post-transcriptional modification of tRNA, is directly involved in modulating specific anticodon–codon base-pairing interactions. 2′-Fluorinated and arabino nucleosides possess novel and beneficial medicinal properties and find use as therapeutics for treating viral diseases and cancer. However, the potential to deploy 2′-modified cytidine chemistries for tuning i-motif stability is largely unknown. To address this knowledge gap, the effects of 2′-modifications including O-methylation, fluorination, and stereochemical inversion on the base-pairing interactions of protonated cytidine nucleoside analogue base pairs, the core stabilizing interactions of i-motif structures, are examined using complementary threshold collision-induced dissociation techniques and computational methods. The 2′-modified cytidine nucleoside analogues investigated here include 2′-O-methylcytidine, 2′-fluoro-2′-deoxycytidine, arabinofuranosylcytosine, 2′-fluoro-arabinofuranosylcytosine, and 2′,2′-difluoro-2′-deoxycytidine. All five 2′-modifications examined here are found to enhance the base-pairing interactions relative to the canonical DNA and RNA cytidine nucleosides with the greatest enhancements arising from 2′-O-methylation and 2′,2′-difluorination, suggesting that these modifications should well be tolerated in the narrow grooves of i-motif conformations. [ABSTRACT FROM AUTHOR]

DNA nanotechnology has been employed to develop devices based on i-motif structures. The protonated cytosine-cytosine base pairs that stabilize i-motif conformations are favored under slightly acidic conditions. This unique property has enabled development of the first DNA molecular motor driven by pH changes. The ability to alter the stability and pH transition range of such DNA molecular motors is desirable. Understanding how i-motif structures are influenced by modifications, and which modifications enhance stability and/or affect the pH characteristics, are therefore of great interest. Here, the influence of 5-halogenation of the cytosine nucleobases on the base pairing of protonated cytidine nucleoside analogue base pairs is examined using complementary threshold collision-induced dissociation techniques and computational methods. The nucleoside analogues examined here include the 5-halogenated forms of the canonical DNA and RNA cytidine nucleosides. Comparisons among these systems and to the analogous canonical base pairs previously examined enable the influence of 5-halogenation and the 2′-hydroxy substituent on the base pairing to be elucidated. 5-Halogenation of the cytosine nucleobases is found to enhance the strength of base pairing of DNA base pairs and generally weakens the base pairing for RNA base pairs. Trends in the strength of base pairing indicate that both inductive and polarizability effects influence the strength of base pairing. Overall, the present results suggest that 5‑halogenation, and in particular, 5-fluorination and 5-iodination, provide effective means of stabilizing DNA i-motif conformations for applications in nanotechnology, whereas only 5-iodination is effective for stabilizing RNA i-motif conformations but the enhancement in stability is less significant. [ABSTRACT FROM AUTHOR]

The gas-phase structures of protonated unsymmetrical 1,1-dimethylhydrazine (UDMH) and the proton-bound dimers of UDMH and hydrazine are examined by infrared multiple photon dissociation (IRMPD) action spectroscopy utilizing light generated by a free electron laser and an optical parametric oscillator laser system. To identify the structures present in the experimental studies, the measured IRMPD spectra are compared to spectra calculated at the B3LYP-GD3BJ/6-311+G(d,p) level of theory. These comparisons show that protonated UDMH binds the proton at the methylated nitrogen atom (α) with two low-lying α conformers probably being populated. For (UDMH)2H+, the proton is shared between the methylated nitrogen atoms with several low-lying α conformers likely to be populated. Higher-lying conformers of (UDMH)2H+ in which the proton is shared between α and β (unmethylated) nitrogen atoms cannot be ruled out on the basis of the IRPMD spectrum. For (N2H4)2H+, there are four low-lying conformers that all reproduce the IRMPD spectrum reasonably well. As hydrazine and UDMH see usage as fuels for rocket engines, such spectra are potentially useful as a means of remotely monitoring rocket launches, especially in cases of unsuccessful launches where environmental hazards need to be assessed. [ABSTRACT FROM AUTHOR]

Cisplatin, (NH3)2PtCl2, has been known as a successful metal-based anticancer drug for more than half a century. Its analogue, Argplatin, arginine-linked cisplatin, (Arg)PtCl2, is being investigated because it exhibits reactivity towards DNA and RNA that differs from that of cisplatin. In order to understand the basis for its altered reactivity, the deprotonated and sodium cationized forms of Argplatin, [(Arg-H)PtCl2]− and [(Arg)PtCl2 + Na]+, are examined by infrared multiple photon dissociation (IRMPD) action spectroscopy in the IR fingerprint and hydrogen-stretching regions. Complementary electronic structure calculations are performed using density functional theory approaches to characterize the stable structures of these complexes and to predict their infrared spectra. Comparison of the theoretical IR spectra predicted for various stable conformations of these Argplatin complexes to their measured IRMPD spectra enables determination of the binding mode(s) of Arg to the Pt metal center to be identified. Arginine is found to bind to Pt in a bidentate fashion to the backbone amino nitrogen and carboxylate oxygen atoms in both the [(Arg-H)PtCl2]− and [(Arg)PtCl2 + Na]+ complexes, the NO− binding mode. The neutral side chain of Arg also interacts with the Pt center to achieve additional stabilization in the [(Arg-H)PtCl2]− complex. In contrast, Na+ binds to both chlorido ligands in the [(Arg)PtCl2 + Na]+ complex and the protonated side chain of Arg is stabilized via hydrogen-bonding interactions with the carboxylate moiety. These findings are consistent with condensed-phase results, indicating that the NO− binding mode of arginine to Pt is preserved in the electrospray ionization process even under variable pH and ionic strength. [ABSTRACT FROM AUTHOR]

Ionic liquids (ILs) exhibit unique properties that have led to their development and widespread use for a variety of applications. Development efforts have generally focused on achieving desired macroscopic properties via tuning of the IL through variation of the cations and anions. Both the macroscopic and microscopic properties of an IL influence its tunability and thus feasibility of use for selected applications. Works geared toward a microscopic understanding of the nature and strength of the intrinsic cation--anion interactions of ILs have been limited to date. Specifically, the intrinsic strength of the cation--anion interactions in ILs is largely unknown. In previous work, we employed threshold collision-induced dissociation (TCID) approaches supported and enhanced by electronic structure calculations to determine the bond dissociation energies (BDEs) and characterize the nature of the cation--anion interactions in a series of four 2 : 1 clusters of 1-alkyl-3-methylimidazolium cations with the hexafluorophosphate anion, [2Cnmim:PF6]+. To examine the effects of the 1-alkyl chain on the structure and energetics of binding, the cation was varied over the series: 1-ethyl-3-methylimidazolium, [C2mim]+, 1-butyl-3-methylimidazolium, [C4mim]+, 1-hexyl-3-methylimidazolium, [C6mim]+, and 1-octyl- 3-methylimidazolium, [C8mim]+. The variation in the strength of binding among these [2Cnmim:PF6]+ clusters was found to be similar in magnitude to the average experimental uncertainty in the measurements. To definitively establish an absolute order of binding among these [2Cnmim:PF6]+ clusters, we extend this work again using TCID and electronic structure theory approaches to include competitive binding studies of three mixed 2 : 1 clusters of 1-alkyl-3-methylimidazolium cations and the hexafluorophosphate anion, [Cn-2mim:PF6:Cnmim]+ for n = 4, 6, and 8. The absolute BDEs of these mixed [Cn-2mim:PF6:Cnmim]+ clusters as well as the absolute difference in the strength of the intrinsic binding interactions as a function of the cation are determined with significantly improved precision. By combining the thermochemical results of the previous independent and present competitive measurements, the BDEs of the [2Cnmim:PF6]+ clusters are both more accurately and more precisely determined. Comparisons are made to results for the analogous [2Cnmim:BF4]+ and [Cn-2mim:BF4:Cnmim]+ clusters previously examined to elucidate the effects of the [PF6]- and [BF4]- anions on the binding. [ABSTRACT FROM AUTHOR]

Background: HDV antibody testing is recommended for universal screening and as the first line in an HDV double reflex testing strategy for effectively identifying patients with active infection for therapeutic treatments., Objective: The aim of this study is to evaluate the performance of a newly developed ARCHITECT HDV Total Ig (ARCHITECT HDV Ig) prototype assay., Study Design: Performance characteristics were determined for the ARCHITECT HDV Ig and a reference test, LIAISON XL Anti-HDV using a well-characterized specimen panel, comprising HDV RNA positive (n = 62) and negative (n = 70) samples, and healthy US blood donors., Results: Healthy US blood donors (n=200) showed 99.5% (199/200, 95%CI=97.65-99.98) specificity with ARCHITECT HDV Ig and 98.5 % (197/200, 95 %CI = 96.10-99.64) with LIAISON Anti-HDV. Among known HDV RNA positive samples, ARCHITECT HDV Ig detected 59/62 demonstrating 95.2 % sensitivity while LIAISON Anti-HDV sensitivity was 90.3 % (56/62). Among 101 HBV positive samples, 70 were reactive in the ARCHITECT test, 59 of which tested positive for HDV RNA for a positive predictive value (PPV) for the presence of HDV RNA was 84.3 %. For LIAISON Anti-HDV, 79 specimens were reactive and 56 contained HDV RNA: PPV for HDV RNA was 70.9 %. Among 70 HDV RNA negative samples, 39 were HBV positive. ARCHITECT HDV Ig negative predictive value (NPV) was 71.8 % and LIAISON Anti-HDV NPV was 41 % for the HBV positive group, respectively., Conclusion: When compared to the LIASON Anti-HDV test, the ARCHITECT HDV Ig assay demonstrated enhanced sensitivity and specificity and better NPV and PPV values for HDV RNA status. The ARCHITECT HDV Ig assay represents a promising tool for universal screening of all HBsAg-positive persons., Competing Interests: Declaration of competing interest X.Q., A.H., A.O., A.H., M.K., M.R. and G.C. are employees and shareholders of Abbott Laboratories stock., (Copyright © 2024. Published by Elsevier B.V.)

Background: Excessive dietary salt intake increases vascular stiffness in humans, especially in salt-sensitive populations. While we recently suggested that the endothelial sodium channel (EnNaC) contributes to salt-sensitivity related endothelial cell (EC) and arterial stiffening, mechanistic understanding remains incomplete. This study therefore aimed to explore the role of EC-serum and glucocorticoid regulated kinase 1 (SGK1), as a reported regulator of sodium channels, in EC and arterial stiffening., Methods and Results: A mouse model of salt sensitivity-associated vascular stiffening was produced by subcutaneous implantation of slow-release deoxycorticosterone acetate (DOCA) pellets, with salt (1 % NaCl, 0.2 % KCl) administered via drinking water. Preliminary data showed that global SGK1 deletion caused significantly decreased blood pressure (BP), EnNaC activity and aortic endothelium stiffness as compared to control mice following DOCA-salt treatment. To probe EC signaling pathways, selective deletion of EC-SGK1 was performed by cross-breeding cadherin 5-Cre mice with sgk1 flox/flox mice. DOCA-salt treated control mice had significantly increased BP, EC and aortic stiffness in vivo and ex vivo, which were attenuated by EC-SGK1 deficiency. To demonstrate relevance to humans, human aortic ECs were cultured in the absence or presence of aldosterone and high salt with or without the SGK1 inhibitor, EMD638683 (10uM or 25uM). Treatment with aldosterone and high salt increased intrinsic stiffness of ECs, which was prevented by SGK1 inhibition. Further, the SGK1 inhibitor prevented aldosterone and high salt induced actin polymerization, a key mechanism in cellular stiffening., Conclusion: EC-SGK1 contributes to salt-sensitivity related EC and aortic stiffening by mechanisms appearing to involve regulation of actin polymerization., Competing Interests: Declaration of competing interest The authors report no conflict of interest in regard to the material presented in this manuscript. JG (DK124329) and MAH (HL119290) receive support from the National Institutes of Health., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The 2022 outbreak of the clade IIb monkeypox virus and subsequent global spread lead to an urgent need for the development of high-throughput, sensitive, and reproducible diagnostic tests., Methods: We developed 3 assays to detect monkeypox virus, 2 (MPXV+ and MPXV) for m2000 RealTime and 1 (MPXV) for Alinity m platforms. Dual targets in E9L and B6R (MPXV+) and J2L and B7R (MPXV) increased mutation resistance. In silico prediction indicates MPXV+ cross-reactivity with orthopox viruses and specific monkeypox virus detection with MPXV., Results: m2000 RealTime MPXV+ and MPXV assay sensitivity was determined to be 3.2 plaque-forming units/mL using a reference virus culture diluted into universal transport medium (UTM). Alinity m MPXV lower limit of detection was 200 copies/mL using monkeypox virus plasmids in pooled UTM matrix. m2000 RealTime MPXV+ and MPXV assays were validated with lesion swabs in UTM and 1:1 saliva to UTM mixtures. Commercially available and remnant clinical lesion specimens in UTM were tested with RealTime MPXV+, RealTime MPXV and Alinity m MPXV assays and demonstrated high agreement to known mpox (MPX)-positive specimens., Conclusions: RealTime MPXV+, RealTime MPXV, and Alinity MPXV are high throughput and sensitive assays used for the detection of monkeypox virus. These assays maybe useful during MPX outbreaks., Competing Interests: Potential conflicts of interest. M. A., A. H., K. L., A. O., K. F., T. M., C. S., M. K, D. T., M. R., D. L., and G. C. are employees and shareholders of Abbott Laboratories. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Glioblastoma (GBM) is the most common primary malignant brain tumor. Currently, there are few effective treatment options for GBM beyond surgery and chemo-radiation, and even with these interventions, median patient survival remains poor. While immune checkpoint inhibitors (ICIs) have demonstrated therapeutic efficacy against non-central nervous system cancers, ICI trials for GBM have typically had poor outcomes. TIGIT is an immune checkpoint receptor that is expressed on activated T-cells and has a role in the suppression of T-cell and Natural Killer (NK) cell function. As TIGIT expression is reported as both prognostic and a biomarker for anti-TIGIT therapy, we constructed a molecular imaging agent, [ 89 Zr]Zr-DFO-anti-TIGIT ( 89 Zr-αTIGIT), to visualize TIGIT in preclinical GBM by immunoPET imaging. PET imaging and biodistribution analysis of 89 Zr-αTIGIT demonstrated uptake in the tumor microenvironment of GBM-bearing mice. Blocking antibody and irrelevant antibody tracer studies demonstrated specificity of 89 Zr-αTIGIT with significance at a late time point post-tracer injection. However, the magnitude of 89 Zr-αTIGIT uptake in tumor, relative to the IgG tracer was minimal. These findings highlight the features and limitations of using 89 Zr-αTIGIT to visualize TIGIT in the GBM microenvironment., (© 2024. The Author(s).)

Out-of-hospital cardiac arrest is a leading cause of death, accounting for ≈50% of all cardiovascular deaths. The prognosis of such individuals is poor, with <10% surviving to hospital discharge. Survival with a favorable neurologic outcome is highest among individuals who present with a witnessed shockable rhythm, received bystander cardiopulmonary resuscitation, achieve return of spontaneous circulation within 15 minutes of arrest, and have evidence of ST-segment elevation on initial ECG after return of spontaneous circulation. The cardiac catheterization laboratory plays an important role in the coordinated Chain of Survival for patients with out-of-hospital cardiac arrest. The catheterization laboratory can be used to provide diagnostic, therapeutic, and resuscitative support after sudden cardiac arrest from many different cardiac causes, but it has a unique importance in the treatment of cardiac arrest resulting from underlying coronary artery disease. Over the past few years, numerous trials have clarified the role of the cardiac catheterization laboratory in the management of resuscitated patients or those with ongoing cardiac arrest. This scientific statement provides an update on the contemporary approach to managing resuscitated patients or those with ongoing cardiac arrest.

Background: Effective rehabilitation after limb loss is necessary to maximize function and promote independence. Physical therapists (PT) are one of the primary drivers of the rehabilitation process. While general physical therapy knowledge and abilities have been shown to be important to the rehabilitation process, it is unclear what individuals with limb loss value in their PT's., Objective: The purpose of this study was to understand the elements that define an ideal PT from the perspective of individuals with limb loss., Methodology: Mixed-method design consisting of a 20-item web-based survey and semi-structured interviews that were administered to individuals 18 years or older, who spoke English, and had a history of lower limb loss., Findings: Individuals with limb loss describe an ideal PT as promoting a therapeutic alliance, having specialized knowledge, and collaborating with a prosthetist. Knowledge of the PT as it relates to limb loss was found to be both the greatest facilitator and barrier to the rehabilitation process., Conclusion: From the perspective of those with limb loss, an ideal PT promotes a strong therapeutic alliance through communication, has specialized knowledge when it comes to the limb loss rehabilitation process, and collaborates with the prosthetist to problem-solve throughout the rehabilitation process., Competing Interests: None., (Copyright (c) 2023 Lee DJ, Gambale A, Nisani M, Miller C, Leung E, Rodgers M, et al.)

Background: Due to the disadvantages of manual disinfection of patient rooms, mobile disinfection robots using ultraviolet C (UV-C) radiation are increasingly being used. Assessing their in situ effectiveness remains challenging., Aim: This study describes a new method to prove adequate in situ disinfection (≥5-log reduction in bacterial load), and uses this method to assess the efficacy of a mobile disinfection robot using UV-C radiation., Methods: Agar plates serving as proxies for smooth surfaces in patient rooms were inoculated with bacterial suspension and placed on various surfaces in a patient room. After irradiation by an automated mobile UV-C robot, reduction in colony growth was determined by comparing the irradiated plates to a reference series of non-irradiated plates, enabling the evaluation of whether an adequate reduction in colony-forming units (CFU's) of ≥5-log was reached on these irradiated surfaces., Findings: The new technique described here proved a successful method for demonstrating an in situ ≥5-log reduction in CFU's for five different bacterial pathogens. Of the 32 plates placed on UV-accessible surfaces, 31 showed an adequate reduction in CFU's of ≥5-log. One plate could not be assessed., Conclusion: Inoculated agar plates placed in patient rooms before irradiation and subsequently compared to a reference series can be used to assess in situ efficacy of mobile disinfection robots using UV-C radiation. Our findings support the idea that UV-C robots, used adjunctively to conventional manual washing and disinfection, may achieve adequate bacterial load reduction on UV-accessible smooth surfaces in patient rooms for a selected subset of pathogens., (© 2023 The Authors.)

Background/aim: As a fundamental staple of the Mediterranean diet, olive oil has long been recognized for its health benefits, including its ability to reduce cardiovascular and neurological disease. Oleuropein is the primary phenolic chemical found in all parts of the olive tree, especially in the leaves and fruit. Oleuropein exhibits anti-inflammatory and antioxidant properties, and has been associated with cancer inhibition in various animal and cell models. We investigated the effects of oleuropein on the MCF-7 human breast cancer cell line, and compared it to the non-cancerous MCF-10A breast epithelial line., Materials and Methods: Both cell lines were treated with two different concentrations of oleuropein for 48 and 72 hours. Cytotoxicity, apoptosis, and peroxiredoxin expression were measured., Results: Forty-eight hours of oleuropein treatment induced cytotoxicity in MCF-7 cells, whereas it had no effect on MCF-10A cells. Furthermore, oleuropein-induced cytotoxicity in MCF-7 cells involved a measurable increase in apoptosis. Oleuropein treatment of MCF-7 cells significantly and dramatically increased expression of all six peroxiredoxin mRNAs (Prdx1-Prdx6), whereas oleuropein treatment of MCF-10A cells resulted in only a small increase in Prdx1 and Prdx6 expression, with no change in the expression of the other peroxiredoxins. Together, these data demonstrate differential susceptibility to oleuropein-induced cell death between the two lines, and differential regulation of peroxiredoxins., Conclusion: Oleuropein-induced over-expression of peroxiredoxins in MCF-7 cells may either facilitate its cancer-specific cytotoxicity or, alternatively, is a consequence of an altered response of cancer cells., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Scoping reviews and evidence maps are forms of evidence synthesis that aim to map the available literature on a topic and are well-suited to visual presentation of results. A range of data visualisation methods and interactive data visualisation tools exist that may make scoping reviews more useful to knowledge users. The aim of this study was to explore the use of data visualisation in a sample of recent scoping reviews and evidence maps on health topics, with a particular focus on interactive data visualisation., Methods: Ovid MEDLINE ALL was searched for recent scoping reviews and evidence maps (June 2020-May 2021), and a sample of 300 papers that met basic selection criteria was taken. Data were extracted on the aim of each review and the use of data visualisation, including types of data visualisation used, variables presented and the use of interactivity. Descriptive data analysis was undertaken of the 238 reviews that aimed to map evidence., Results: Of the 238 scoping reviews or evidence maps in our analysis, around one-third (37.8%) included some form of data visualisation. Thirty-five different types of data visualisation were used across this sample, although most data visualisations identified were simple bar charts (standard, stacked or multi-set), pie charts or cross-tabulations (60.8%). Most data visualisations presented a single variable (64.4%) or two variables (26.1%). Almost a third of the reviews that used data visualisation did not use any colour (28.9%). Only two reviews presented interactive data visualisation, and few reported the software used to create visualisations., Conclusions: Data visualisation is currently underused by scoping review authors. In particular, there is potential for much greater use of more innovative forms of data visualisation and interactive data visualisation. Where more innovative data visualisation is used, scoping reviews have made use of a wide range of different methods. Increased use of these more engaging visualisations may make scoping reviews more useful for a range of stakeholders., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Commercial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody tests were developed before variants with spike protein mutations emerged, leading to concerns that these tests have reduced sensitivity for detecting antibody responses in individuals infected with Omicron subvariants. This study was performed to evaluate Abbott ARCHITECT serologic assays, AdviseDx SARS-CoV-2 IgG II, and SARS-CoV-2 IgG for the detection of spike (S) and nucleocapsid (N) IgG antibody increases in vaccinated healthcare workers infected with Omicron subvariants., Methods: During the BA.1/2 and BA.4/5 waves, 171 SARS-CoV-2-infected individuals (122 in the BA.1/2 wave, 49 in the BA.4/5 wave) were tested for S and N IgG post infection. Sequencing and SARS-CoV-2 variant confirmation were performed on nasal swab samples from individuals infected during the BA.1/2 wave., Results: Twenty-seven Omicron sequence confirmed individuals in the BA.1/2 wave and all 49 in the BA.4/5 wave had pre-infection antibody data. Compared to pre-infection levels, post-infection S IgG increased 6.6-fold from 1294 ± 302 BAU/ml (mean ± standard error measurement) to 9796 ± 1252 BAU/ml ( P < 0.001) during the BA.1/2 wave, and 3.6-fold from 1771 ± 351 BAU/ml to 8224 ± 943 BAU/ml ( P < 0.001) during the BA.4/5 wave. N IgG increased post infection 19.1-fold from 0.2 ± 0.1 to 3.7 ± 0.5 ( P < 0.001) during the BA.1/2 wave and 13.5-fold from 0.22 ± 0.1 to 3.2 ± 0.3 ( P < 0.001) during the BA.4/5 wave. Among 159 infection-naïve individuals, positive N IgG levels were detected with a sensitivity of 88% in the 87 individuals who were tested between 14 days and 60 days post infection., Conclusions: The large increases in post-infection S IgG along with the N IgG sensitivity that was comparable to previously reported N IgG sensitivity data in unvaccinated individuals after Omicron infection, support the use of Abbott SARS-CoV-2 assays for detecting increased S IgG and seroconversion of N IgG in vaccinated individuals post Omicron infection. Given that 68% of the United States population is fully vaccinated, these results are of current relevance., Competing Interests: The authors declare the following financial interests/personal relationships: MA, MR, AO, BH, MS, VH, AA, EG, TF, EA, and GC are employees and shareholders of Abbott Laboratories. This work was funded by Abbott Laboratories. AL is a consultant for Abbott Laboratories., (© 2023 The Author(s).)

Objectives: To evaluate pre-analytical challenges related to high-volume central laboratory SARS-CoV-2 antigen testing with a prototype qualitative SARS-CoV-2 antigen immunoassay run on the automated Abbott ARCHITECT instrument., Methods: Contrived positive and negative specimens and de-identified nasal and nasopharyngeal specimens in transport media were used to evaluate specimen and reagent on-board stability, assay analytical performance and interference, and clinical performance., Results: TCID50/mL values were similar for specimens in various transport media. Inactivated positive clinical specimens and viral lysate (USA-WA1/2020) were positive on the prototype immunoassay. Within-laboratory imprecision was ≤0.10 SD (<1.00 S/C) with a ≤10% CV (≥1.00 S/C). Assay reagents were stable on board the instrument for 14 days. No high-dose hook effect was observed with a SARS-CoV-2 stock of Ct 13.0 (RLU>1.0 × 10 6 ). No interference was observed from mucin, whole blood, 12 drugs, and more than 20 cross-reactants. While specimen stability was limited at room temperature for specimens with or without viral inactivation, a single freeze/thaw cycle or long-term storage (>30 days) at -20 °C did not adversely impact specimen stability or assay performance. Specificity of the prototype SARS-CoV-2 antigen immunoassay was ≥98.5% and sensitivity was ≥89.5% across two ARCHITECT instruments. Assay sensitivity was inversely correlated with Ct and was similar to that reported for the Roche Elecsys ® SARS-CoV-2 Ag immunoassay., Conclusions: The prototype SARS-CoV-2 antigen ARCHITECT immunoassay is sensitive and specific for detection of SARS-CoV-2 in nasal and nasopharyngeal specimens. Endogenous proteases in mucus may degrade the target antigen, which limits specimen storage and transport times and complicates assay workflow., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Small blood vessel diseases are often associated with impaired regulation of vascular tone. The current understanding of resistance arteries often focuses on how a level of vascular tone is achieved in the acute phase, while less emphasis is placed on mechanisms that maintain vascular tone. In this study, cannulated rat superior cerebellar arteries (SCA) developed spontaneous myogenic tone and showed a marked and sustained constriction in the presence of diluted serum (10%), a stimulus relevant to cerebrovascular disease. Both phosphorylated myosin light chain (MLC-p) and smooth muscle alpha actin (SM-α-actin) aligned with phalloidin-stained actin filaments in the vessel wall, while exhibiting a 'high to low' gradient across the layers of vascular smooth muscle cells (VSMC), peaking in the outer layer. The MLC-p distribution profile shifted towards the adventitia in serum treated vessels, while removal of the serum reversed it. Furthermore, a positive correlation between the MLC-p signal and vessel wall tension was also evident. The gradients of phosphorylated MLC and SM-α-actin are consistent with a spatial regulation of the myosin-actin apparatus in the vessel wall during the maintenance of vascular tone. Further, the changing profiles of MLC-p and SM-α-actin are consistent with SCA vasoconstriction being accompanied by VSMC cytoskeletal reorganization., (© 2023. The Author(s).)

Despite its success as an anticancer drug, cisplatin suffers from resistance and produces side effects. To overcome these limitations, amino-acid-linked cisplatin analogues have been investigated. Lysine-linked cisplatin, Lysplatin, (Lys)PtCl 2 , exhibited outstanding reactivity toward DNA and RNA that differs from that of cisplatin. To gain insight into its differing reactivity, the structure of Lysplatin is examined here using infrared multiple photon dissociation (IRMPD) action spectroscopy. To probe the influence of the local chemical environment on structure, the deprotonated and sodium-cationized Lysplatin complexes are examined. Electronic structure calculations are performed to explore possible modes of binding of Lys to Pt, their relative stabilities, and to predict their infrared spectra. Comparisons of the measured IRMPD and predicted IR spectra elucidate the structures contributing to the experimental spectra. Coexistence of two modes of binding of Lys to Pt is found where Lys binds via the backbone and side-chain amino nitrogen atoms, NN s , or to the backbone amino and carboxylate oxygen atoms, NO - . Glycine-linked cisplatin and arginine-linked cisplatin complexes have previously been found to bind only via the NO - binding mode. Present results suggest that the NN s binding conformers may be key to the outstanding reactivity of Lysplatin toward DNA and RNA.

Background: The economic and social costs of autism are significant. This study evaluates the cost-effectiveness of early intensive Applied Behaviour Analysis (ABA)-based interventions for autistic pre-school children in the UK., Methods: A de novo economic analysis was developed in Microsoft Excel comparing early intensive ABA-based interventions compared with treatment as usual (TAU). The analysis used 15.5-year time horizon, with costs and benefits discounted a 3.5%. The model structure was based on cohort structure to capture changes in adaptive behaviour and cognitive ability over time. The analysis was informed by an individual patient data (IPD) meta-analysis of available evidence., Results: Adopting a public sector perspective, early intensive ABA-based therapies were associated with greater incremental costs and greater benefits. When pessimistic assumptions were made regarding the long-term effects of treatment incremental costs were £46,103 and incremental quality-adjusted life years (QALYs) were 0.24, resulting in an incremental cost-effectiveness ratio (ICER) of £189,122 per quality-adjusted life year (QALY). When optimistic assumptions were made about long-term effects, incremental costs were £39,233 with incremental benefits of 0.84 QALYs. The resulting ICER was £46,768 per QALY. Scenario analyses emphasised the importance of assumptions made regarding adult outcomes and type of school attended, both of which significantly affect the results of the analysis., Conclusions: The results of this economic analysis suggest that early intensive ABA-based interventions are unlikely to represent value for money, based on a £20,000 to £30,000 per QALY threshold typically adopted to inform UK healthcare funding decisions. However, important gaps in the available evidence, limit the strength of the conclusions that can be drawn from the presented analysis. Further research, focusing on the trajectory of autistic children following intervention is likely to be highly beneficial to resolving some of these uncertainties., Competing Interests: The authors have declared that no competing interests exist.

Background: During the decades representing working-age adulthood, most people will experience one or several significant life events or transitions. These may present a challenge to mental health., Aim: The primary aim of this rapid systematic review of systematic reviews was to summarise available evidence on the effectiveness of interventions to promote and protect mental health relating to four key life events and transitions: pregnancy and early parenthood, bereavement, unemployment, and housing problems. This review was conducted to inform UK national policy on mental health support., Methods: We searched key databases for systematic reviews of interventions for working-age adults (19 to 64 years old) who had experienced or were at risk of experiencing one of four key life events. Titles and abstracts were screened by two reviewers in duplicate, as were full-text manuscripts of relevant records. We assessed the quality of included reviews and extracted data on the characteristics of each literature review. We prioritised high quality, recent systematic reviews for more detailed data extraction and synthesis., Results: The search and screening of 3997 titles/abstracts and 239 full-text papers resulted in 134 relevant studies, 68 of which were included in a narrative synthesis. Evidence was strongest and of the highest quality for interventions to support women during pregnancy and after childbirth. For example, we found benefits of physical activity and psychological therapy for outcomes relating to mental health after birth. There was high quality evidence of positive effects of online bereavement interventions and psychological interventions on symptoms of grief, post-traumatic stress, and depression. Evidence was inconclusive and of lower quality for a range of other bereavement interventions, unemployment support interventions, and housing interventions., Conclusions: Whilst evidence based mental health prevention and promotion is available during pregnancy and early parenthood and for bereavement, it is unclear how best to support adults experiencing job loss, unemployment, and housing problems.

Study Objectives: Characterize associations between sleep impairments and posttraumatic stress disorder (PTSD) symptoms, including anger, in service members seeking treatment for PTSD., Methods: Ninety-three US Army personnel recruited into a PTSD treatment study completed the baseline assessment. State-of-the-science sleep measurements included 1) retrospective, self-reported insomnia, 2) prospective sleep diaries assessing sleep patterns and nightmares, and 3) polysomnography measured sleep architecture and obstructive sleep apnea-hypopnea severity. Dependent variables included self-report measures of PTSD severity and anger severity. Pearson correlations and multiple linear regression analyses examined if sleep symptoms, not generally measured in PTSD populations, were associated with PTSD and anger severity., Results: All participants met PTSD, insomnia, and nightmare diagnostic criteria. Mean sleep efficiency = 70%, total sleep time = 5.5 hours, obstructive sleep apnea/hypopnea (obstructive sleep apnea-hypopnea index ≥ 5 events/h) = 53%, and clinically significant anger = 85%. PTSD severity was associated with insomnia severity (β = .58), nightmare severity (β = .24), nightmare frequency (β = .31), and time spent in Stage 1 sleep (β = .27, all P < .05). Anger severity was associated with insomnia severity (β = .37), nightmare severity (β = .28), and obstructive sleep apnea-hypopnea during rapid eye movement sleep (β = .31, all P < .05)., Conclusions: Insomnia and nightmares were related to PTSD and anger severity, and obstructive sleep apnea-hypopnea was related to anger. Better assessment and evidence-based treatment of these comorbid sleep impairments in service members with PTSD and significant anger should result in better PTSD, anger, and quality-of-life outcomes., Clinical Trials Registration: Registry: ClinicalTrials.gov; Name: Treatment of Comorbid Sleep Disorders and Post Traumatic Stress Disorder; Identifier: NCT02773693; URL: https://clinicaltrials.gov/ct2/show/NCT02773693., Citation: Miles SR, Pruiksma KE, Slavis D, et al. Sleep disorder symptoms are associated with greater posttraumatic stress and anger symptoms in US Army service members seeking treatment for posttraumatic stress disorder. J Clin Sleep Med . 2022;18(6):1617-1627., (© 2022 American Academy of Sleep Medicine.)

Background: Physical activity has been shown to be fundamental in the prevention of numerous diseases and disorders. Achieving and maintaining physical activity levels can be particularly challenging in those with impairments, such as those experiencing a lower limb amputation. To slow the spread of the virus, COVID-19 lockdown mandates imposed by the US state governments may have inadvertent consequences on physical activity levels of those dependent on specific forms of exercise. Understanding how physical activity levels may have affected persons with limb loss can inform intervention strategies for this vulnerable population., Objectives: Examine the effects of the COVID-19 pandemic on physical activity levels in persons with limb loss., Study Design: Mixed-method design., Methods: A 20-item logic web-based survey and semistructured interviews were administered to individuals who were 18 years or older, spoke English, and had a history of lower limb loss. Quantitative data were analyzed using SPSS v25, whereas qualitative data were analyzed using constant comparison to formulate themes., Results: There were a significant effect on the amount of physical activity minutes performed per day, a negative effect on the ability to exercise and participate in societal engagements, and a series of barriers to performing physical activity because of the pandemic., Conclusion: Physical activity was reduced significantly in persons with limb loss during the COVID-19 pandemic. A combination of health concerns, fitness center closures, and social distancing mandates were the primary drivers behind the decrease in activity., (Copyright © 2022 International Society for Prosthetics Orthotics.)

Detection and epidemiologic characterization of infectious disease outbreaks are key for early identification and response to potential pandemic threats. The rapid global spread of severe SARS-CoV-2 in 2020 highlighted the critical role of diagnostics in understanding the epidemiology of the virus early in the pandemic. As a natural extension of Abbott's work in diagnostics, virus discovery, and virus surveillance, the Abbott Pandemic Defense Coalition (APDC) was launched in early 2021. The APDC is a global multisector scientific and public health partnership whose primary objective is the early detection and mitigation of infectious disease threats of pandemic potential. As of January 2022, the APDC network has partners on 5 continents including academic institutions, governmental, and nongovernmental organizations. A novel element of the APDC is the capacity for early development and rapid deployment of scalable, quality diagnostics targeting newly identified pathogens of pandemic potential., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Associations between vaccine breakthrough cases and infection by different SARS coronavirus 2 (SARS-CoV-2) variants have remained largely unexplored. Here we analysed SARS-CoV-2 whole-genome sequences and viral loads from 1,373 persons with COVID-19 from the San Francisco Bay Area from 1 February to 30 June 2021, of which 125 (9.1%) were vaccine breakthrough infections. Vaccine breakthrough infections were more commonly associated with circulating antibody-resistant variants carrying ≥1 mutation associated with decreased antibody neutralization (L452R/Q, E484K/Q and/or F490S) than infections in unvaccinated individuals (78% versus 48%, P = 1.96 × 10 -8 ). Differences in viral loads were non-significant between unvaccinated and fully vaccinated cases overall (P = 0.99) and according to lineage (P = 0.09-0.78). Symptomatic vaccine breakthrough infections had comparable viral loads (P = 0.64), whereas asymptomatic breakthrough infections had decreased viral loads (P = 0.023) compared with infections in unvaccinated individuals. In 5 cases with serial samples available for serologic analyses, vaccine breakthrough infections were found to be associated with low or undetectable neutralizing antibody levels attributable to an immunocompromised state or infection by an antibody-resistant lineage. Taken together, our results show that vaccine breakthrough infections are overrepresented by antibody-resistant SARS-CoV-2 variants, and that symptomatic breakthrough infections may be as efficient in spreading COVID-19 as unvaccinated infections, regardless of the infecting lineage., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Breast amyloidosis is a rare condition which is mostly associated with hematological disorders or hereditary genetic disorders. Imaging findings of breast amyloidosis can mimic malignancy, which often leads to biopsy or excision of the lesion. Here, we presented a case of localized lactotransferrin-related breast amyloidosis in an elderly female patient. Histologic examination revealed extensive involvement of breast lobules by amorphous amyloid materials, with attenuation of lobular structures and prominent calcifications. Positive immunostains for myoepithelial cells helped to exclude the possibility of invasive carcinoma. The patient had no hematologic malignancy besides immunoglobulin G lambda monoclonal gammopathy of undetermined significance. Mass spectrometry of the breast amyloid identified lactotransferrin and no immunoglobulin or its light chain. On follow-up, the patient showed no recurrence of the breast lesion after local excision nor showed other systematic comorbidities, indicating the benign nature of the lesion. This first report of lactotransferrin-related amyloidosis may represent a special type of localized breast amyloidosis that has no correlation with systematic disorders.

High prevalence of risk behaviours may exacerbate existing poor health in disadvantaged groups. We aimed to identify and bring together systematic reviews with a focus on reducing risk behaviours in disadvantaged groups and highlight where evidence is lacking. We searched MEDLINE and Embase up to October 2020, with supplementary searching in Epistemonikos and Health Systems Evidence. We included systematic reviews that reported behavioural outcomes and targeted smoking, excessive alcohol use, unhealthy diet, or physical inactivity in groups with the following characteristics: low income or low socio-economic status (SES), unemployed people, homeless people, care leavers, prisoners, refugees or asylum seeker, Gypsies, Travellers, or Roma, people with learning disabilities and people living in disadvantaged areas. Reviews that included primary studies from any high-income country were eligible. Reviews were mapped based on the disadvantaged group(s) and behaviour(s) targeted. Ninety-two reviews were included, with the majority (n = 63) focusing on people with low income or low SES. We identified gaps in the evidence for care leavers; Gypsies, Travellers, and Roma and limited evidence for refugees and unemployed people. Few reviews targeted alcohol use. There was limited evidence on barriers and facilitators to behaviour change. This suggests there is insufficient evidence to inform policy and practice and new reviews or primary studies may be required., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine associations between COVID-19 media exposure and anxiety/perceived risk/severity and investigate their dependency on sex in middle-aged/older adults., Methods: Adults aged 50+ years completed online surveys: Coronavirus Anxiety Scale, COVID-19 media exposure, COVID-19 media dependency for health information, and COVID-19 perceived risk and severity. Multiple regressions examined independent and interactive (with sex) associations between COVID-19 media exposure/dependency and COVID-19 anxiety/perceived risk and severity. Analyses controlled for age, education, race, total medical conditions, and COVID-19 status., Results: Higher COVID-19 media exposure was associated with higher COVID-19 anxiety among men (not women) and higher perceived risk/severity in both sexes. Higher COVID-19 media dependency was associated with higher COVID-19 anxiety and perceived risk/severity in both sexes., Conclusion: In middle-aged/older adults, the use/dependency of media for COVID-19 information may be linked to negative psychological health and increased COVID-19 perceived risk and severity. Men may be at increased risk of anxiety related to media exposure.

Objective: As there is significant heterogeneity in the weight loss response to pharmacotherapy, one of the most important clinical questions in obesity medicine is how to predict an individual's response to pharmacotherapy. The present study examines patterns of weight loss among overweight and obese women who demonstrated early robust response to twice daily exenatide treatment compared to those treated with hypocaloric diet and matched placebo injections., Methods: We randomized 182 women (BMI 25-48 kg/m2) to treatment with exenatide alone or matched placebo injections plus hypocaloric diet. In both treatment groups, women who demonstrated ≥ 5% weight loss at 12 weeks were characterized as high responders and those who lost ≥10% of body weight were classified as super responders. Our primary outcome was long-term change in body weight among early high responders to either treatment. An exploratory metabolomic analysis was also performed., Results: We observed individual variability in weight loss with both exenatide and hypocaloric diet plus placebo injections. There was a trend toward a higher percentage of subjects who achieved ≥ 5% weight loss with exenatide compared to diet (56% of those treated with exenatide, 76% of those treated with diet, p = 0.05) but no significant difference in those who achieved ≥ 10% weight loss (23% of individuals treated with exenatide and 36% of those treated with diet, p = 0.55). In both treatment groups, higher weight loss at 3 months of treatment predicted super responder status (diet p=0.0098, exenatide p=0.0080). Both treatment groups also demonstrated similar peak weight loss during the study period. We observed lower cysteine concentrations in the exenatide responder group (0.81 vs 0.48 p < 0.0001) and a trend toward higher levels of serotonin, aminoisobutyric acid, anandamide, and sarcosine in the exenatide super responder group., Conclusion: In a population of early high responders, longer term weight loss with exenatide treatment is similar to that achieved with a hypocaloric diet., Clinical Trial Registration: www.clinicaltrialsgov, identifier NCT01590433., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rodgers, Migdal, Rodríguez, Chen, Nath, Gerszten, Kasid, Toschi, Tripaldi, Heineman, Phan, Ngo, Maratos-Flier and Dushay.)

Cisplatin, (NH 3 ) 2 PtCl 2 , has been known as a successful metal-based anticancer drug for more than half a century. Its analogue, Argplatin, arginine-linked cisplatin, (Arg)PtCl 2 , is being investigated because it exhibits reactivity towards DNA and RNA that differs from that of cisplatin. In order to understand the basis for its altered reactivity, the deprotonated and sodium cationized forms of Argplatin, [(Arg-H)PtCl 2 ] - and [(Arg)PtCl 2 + Na] + , are examined by infrared multiple photon dissociation (IRMPD) action spectroscopy in the IR fingerprint and hydrogen-stretching regions. Complementary electronic structure calculations are performed using density functional theory approaches to characterize the stable structures of these complexes and to predict their infrared spectra. Comparison of the theoretical IR spectra predicted for various stable conformations of these Argplatin complexes to their measured IRMPD spectra enables determination of the binding mode(s) of Arg to the Pt metal center to be identified. Arginine is found to bind to Pt in a bidentate fashion to the backbone amino nitrogen and carboxylate oxygen atoms in both the [(Arg-H)PtCl 2 ] - and [(Arg)PtCl 2 + Na] + complexes, the NO - binding mode. The neutral side chain of Arg also interacts with the Pt center to achieve additional stabilization in the [(Arg-H)PtCl 2 ] - complex. In contrast, Na + binds to both chlorido ligands in the [(Arg)PtCl 2 + Na] + complex and the protonated side chain of Arg is stabilized via hydrogen-bonding interactions with the carboxylate moiety. These findings are consistent with condensed-phase results, indicating that the NO - binding mode of arginine to Pt is preserved in the electrospray ionization process even under variable pH and ionic strength.

Background: Increasing use is now made of modalities other than surgery (including endoscopy and interventional radiology) in the care of patients with hepatopancreaticobiliary (HPB) diseases. However, the care of and responsibility for patients managed non-operatively continues to reside with surgical services. This investigation was undertaken to quantify the implications of non-operative patient related admissions our HPB unit over a 24 month period., Methods: Total admissions from Jan 2018-Dec 2019 in a tertiary HPB unit were analyzed to determine HPB-related non-operative admissions. Cost analysis was also undertaken., Results: There were 1528 admissions in 1029 patients for non-operative indications out of a total of 2576 admissions to the HPB unit. Of these, 707 were for diagnoses related to underlying HPB or upper gastrointestinal diagnoses. Patients were primarily treated with an interventional radiology procedure (n = 180), diagnostic or therapeutic endoscopy (n = 287), palliation (n = 57), symptomatic management (n = 152), other (n = 31). Patient age ≥80 (p < 0.05), acute admission (p < 0.01) and the presence of a stage 4 cancer diagnosis (p < 0.01) were associated with non-operative admission., Conclusion: Over half of patient admissions are for non-operative management. The contemporary HPB unit is responsible for providing surgical intervention as well as coordinating multidisciplinary care of patients with HPB disease., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)