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Methanol is one of the most abundant interstellar Complex Organic Molecules (iCOMs) and represents a major building block for the synthesis of increasingly complex oxygen-containing molecules. The reaction between protonated methanol and its neutral counterpart, giving protonated dimethyl ether, $ \require{mhchem} \ce{(CH3)2OH+} $ (CH 3 ) 2 OH + , along with the ejection of a water molecule, has been proposed as a key reaction in the synthesis of dimethyl ether in space. Here, gas phase vibrational spectra of the $ \ce{(CH3)2OH+} $ (CH 3 ) 2 OH + reaction product and the $ \ce{[C2H9O2]+} $ [ C 2 H 9 O 2 ] + intermediate complex(es), formed under different pressure and temperature conditions, are presented. The widely tunable free electron laser for infrared experiments, FELIX, was employed to record these vibrational fingerprint spectra using different types of infrared action spectroscopy in the 600-1700 cm $ ^{-1} $ − 1 frequency range, complemented with measurements using an OPO/OPA system to cover the $ \ce{O-H} $ O − H stretching region $ 3400-3700\,{\rm cm}^{-1} $ 3400 − 3700 c m − 1 . The formation of protonated dimethyl ether as a product of the reaction is spectroscopically confirmed, providing the first gas-phase vibrational spectrum of this potentially relevant astrochemical ion. [ABSTRACT FROM AUTHOR]

Interest in the observation and characterization of organic isomers in astronomical environments has grown rapidly with an increase in the sensitivity of detection techniques. Accurate modeling and interpretation of these environments require experimental isomer-specific reactivity and spectroscopic measurements. Given the abundance of formaldehyde (H 2 CO) in various astrophysical objects, the properties and reactivities of its cation isomers H 2 CO •+ and HCOH •+ are of significant interest. However, for the hydroxymethylene radical cation HCOH •+ (and its isotopologue DCOH •+ ), detailed reactivity studies have been limited by the lack of suitable experimental methods to generate this isomer with high purity. Here, potential approaches to the isomer-selective generation of HCOH •+ and DCOH •+ are characterized through differential reactivity measurements. While the dissociative photoionization of cyclopropanol (c-CH 2 CH 2 CHOH) is determined to be unsuitable, the dissociation of methanol- d 3 (CD 3 OH) allows for the formation of DCOH •+ with a fractional abundance of >99% at photon energies below 14.8 eV. These results will allow future spectroscopic and reactivity measurements of HCOH •+ /DCOH •+ to be conducted, laying the groundwork for future detection and incorporation into models of the interstellar medium.

The coordination chemistry and electrochemistry of novel N -acridine thiosemicarbazones (NATs) were investigated along with their redox activity, antiproliferative efficacy, transmetalation, and dissociation properties. The ability of NAT Fe(III) complexes to inhibit detrimental oxy-myoglobin (oxy-Mb) oxidation was also examined. The NATs act as tridentate ligands with a 2:1 L/Zn(II) complex crystal structure, revealing a distorted octahedral geometry, where both ligands bind Zn(II) in a meridional conformation. The NAT Fe(III) complexes exhibited fully reversible one-electron Fe III/II couples with more positive potentials than the Fe(III) complexes of a related clinically trialed thiosemicarbazone (e.g., [Fe(DpC) 2 ] + ) due to the electron-donating capacity of acridine. Surprisingly, the NAT-Zn(II) complexes showed generally greater or similar antiproliferative activity than their ligands, Cu(II), or Fe(III) complexes. This may be explained by ( 1 ) formation of a highly lipophilic Zn(II) complex that acts as a chaperone to promote cellular uptake and ( 2 ) the capacity of the Zn(II) complex to dissociate or undergo transmetalation to the redox-active Cu(II) complex. Of the NAT-Fe(III) complexes, [Fe(AOBP) 2 ] + demonstrated a significant ( p < 0.0001) improvement in preventing oxy-Mb oxidation than the Fe(III) complex of the clinically trialed thiosemicarbazone, DpC. This article advances our understanding of NAT coordination chemistry, electrochemistry, and the intriguing biological activity of their complexes.

Background: Current acute healthcare service metrics are not meaningful for older people living with frailty. Healthcare knowledge, situational security, and physical and psychosocial function are important outcomes typically not collected. The use of patient-reported outcome measures (PROMs) could support these assessments. Existing instruments are not comprehensive as they typically consider function, while older people with frailty also value enablement (self-determination and security in health and healthcare). This study field-tested and validated a PROM for older people with frailty receiving acute care (PROM-OPAC) to measure enablement., Methods: People aged 65+ with Clinical Frailty Scale 5-8 were recruited within seventy-two hours of an emergency attendance. Iterations of the novel instrument were administered over three stages: (1) preliminary field-testing for reliability (response distribution and internal consistency) and structure (exploratory factor analysis, EFA); (2) intermediate field-testing of an improved instrument for reliability and structure; (3) final draft validation assessing reliability, structure (confirmatory factor analysis, CFA), and construct validity based on a priori hypotheses. Feasibility was appraised throughout using data completeness and response rates and times., Results: 241 people participated. Three items of a preliminary seven-item measure had poor response distribution or loading and were accordingly improved. The intermediate instrument had interpretability issues and three items required further improvement. The final eight-item draft had acceptable reliability (Cronbach's alpha: 0.71), structure (two factors for self-determination and security; RMSEA: 0.065; TLI: 0.917; CFI: 0.944), and construct validity (lower scores from respondents waiting longer and requiring admission). Feasibility was promising (response rate 39%; 98% responses complete; median completion time 11 (IQR: 12) minutes)., Conclusions: Administration of the PROM-OPAC appeared feasible and the instrument had acceptable psychometric properties. Further evaluation is required to assess generalisability., (© 2024. The Author(s).)

The gas phase reactivity of the radical cation isomers H 2 CNH˙ + (methanimine) and HCNH 2 ˙ + (aminomethylene) with propene (CH 3 CHCH 2 ) has been investigated by measuring absolute reactive cross sections and product branching ratios, under single collision conditions, as a function of collision energy (in the range ∼0.07-11.80 eV) using guided ion beam mass spectrometry coupled with VUV photoionization for selective isomer generation. Experimental results have been merged with theoretical calculations to elucidate reaction pathways and structures of products. The H 2 CNH˙ + isomer is over a factor two more reactive than HCNH 2 ˙ + . A major channel from both isomers is production of protonated methanimine CH 2 NH 2 + via hydrogen-atom transfer reaction but, while H 2 CNH˙ + additionally gives charge and proton transfer products, the HCNH 2 ˙ + isomer leads instead to protonated vinylimine CH 2 CHCHNH 2 + , produced alongside CH 3 ˙ radicals. The reactions have astrochemical implications in the build up of chemical complexity in both the interstellar medium and the hydrocarbon-rich atmospheres of planets and satellites.

Objectives: We explored the perspectives of older veterans in Gerofit, a Department of Veteran Affairs (VA) supervised clinical exercise program, to understand the factors associated with participation and how the program supported personal health goals., Methods: Twenty semistructured interviews were conducted with active and inactive Gerofit participants. We used a hybrid inductive and deductive approach to thematic analysis of transcripts, with the latter informed by the Health Action Process Approach model of behavior change., Results: Active and inactive participants differed in their perspectives about how Gerofit impacted their progress toward meeting personal health goals. Active participants noted program features (e.g., schedule, staffing) as facilitators and suggested greater self-efficacy about program participation compared to inactive participants. Both groups perceived the camaraderie with other veterans as a facilitator., Conclusions: Exercise program features, including camaraderie, are important factors that affect the ability of older veterans to participate in exercise and achieve personal health goals., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Parents exposed to psychosocial adversities often experience challenges which, combined with the needs of a new-born infant, can be difficult to manage and increase the risk of poor outcomes for both parents and infants. Psychosocial adversity can disrupt the development of parental-foetal attachment to the baby during pregnancy, which can have a negative effect on parental care and quality of interaction during the postnatal period. This intervention is based on the proposition that enhanced parental capacity to mentalise and emotionally connect to unborn children during pregnancy, and better understanding about how to manage distressing infant behaviour (i.e., persistent crying and sleep problems) will: (i) promote the development of secure parent-infant attachment; (ii) improve antenatal bonding and postnatal parenting; and, (ii) reduce parental distress., Method: This protocol is for a pilot randomised control trial evaluating a new intervention, which makes use of innovative technologies to support parents experiencing moderate psychosocial adversity (Australian New Zealand Clinical Trials Registry: ACTRN12622000287730). The New Technology for New Parents (NTNP) intervention provides support using antenatal ultrasound scans and 'virtual home visits' during the perinatal period. Quantitative outcomes include mentalising capacity, parental-foetal/infant attachment, and parental competence., Conclusion: To the best of our knowledge, no study has evaluated the combined effectiveness of two novel technologies (3D/4D ultrasound scans and virtual home visits) to support parents across the antenatal and postnatal periods. This protocol, which includes the rationale for this innovative intervention, addresses a gap in services for parents experiencing moderate psychosocial adversity.

Innovative N -acridine thiosemicarbazones (NATs) were designed along with their iron(iii), copper(ii), and zinc(ii) complexes. Lysosomal targeting was promoted by specifically incorporating the lysosomotropic Pgp substrate, acridine, into the thiosemicarbazone scaffold to maintain the tridentate N, N, S-donor system. The acridine moiety enables a significant advance in thiosemicarbazone design, since: (1) it enables tracking of the drugs by confocal microscopy using its inherent fluorescence; (2) it is lysosomotropic enabling lysosomal targeting; and (3) as acridine is a P-glycoprotein (Pgp) substrate, it facilitates lysosomal targeting, resulting in the drug overcoming Pgp-mediated resistance. These new N -acridine analogues are novel, and this is the first time that acridine has been specifically added to the thiosemicarbazone framework to achieve the three important properties above. These new agents displayed markedly greater anti-proliferative activity against resistant Pgp-expressing cells than very low Pgp-expressing cells. The anti-proliferative activity of NATs against multiple Pgp-positive cancer cell-types (colon, lung, and cervical carcinoma) was abrogated by the third generation Pgp inhibitor, Elacridar, and also Pgp siRNA that down-regulated Pgp. Confocal microscopy demonstrated that low Pgp in KB31 (-Pgp) cells resulted in acridine's proclivity for DNA intercalation promoting NAT nuclear-targeting. In contrast, high Pgp in KBV1 (+Pgp) cells led to NAT lysosomal sequestration, preventing its nuclear localisation. High Pgp expression in KBV1 (+Pgp) cells resulted in co-localization of NATs with the lysosomal marker, LysoTracker™, that was significantly ( p < 0.001) greater than the positive control, the di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) Zn(ii) complex, [Zn(DpC) 2 ]. Incorporation of acridine into the thiosemicarbazone scaffold led to Pgp-mediated transport into lysosomes to overcome Pgp-resistance., Competing Interests: The authors declare no competing conflict of interest., (This journal is © The Royal Society of Chemistry.)

We implemented isosteric replacement of sulfur to selenium in a novel thiosemicarbazone (PPTP4c4mT) to create a selenosemicarbazone (PPTP4c4mSe) that demonstrates potentiated anticancer efficacy and selectivity. Their design specifically incorporated cyclohexyl and styryl moieties to sterically inhibit the approach of their Fe(III) complexes to the oxy-myoglobin heme plane. Importantly, in contrast to the Fe(III) complexes of the clinically trialed thiosemicarbazones Triapine, COTI-2, and DpC, the Fe(III) complexes of PPTP4c4mT and PPTP4c4mSe did not induce detrimental oxy-myoglobin oxidation. Furthermore, PPTP4c4mSe demonstrated more potent antiproliferative activity than the homologous thiosemicarbazone, PPTP4c4mT, with their selectivity being superior or similar, respectively, to the clinically trialed thiosemicarbazone, COTI-2. An advantageous property of the selenosemicarbazone Zn(II) complexes relative to their thiosemicarbazone analogues was their greater transmetalation to Cu(II) complexes in lysosomes. This latter effect probably promoted their antiproliferative activity. Both ligands down-regulated multiple key receptors that display inter-receptor cooperation that leads to aggressive and resistant breast cancer.

The metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), inhibits pro-oncogenic signaling in pancreatic cancer (PC). This investigation dissected a novel mechanism induced by NDRG1 on WNT/β-catenin signaling in multiple PC cell types. NDRG1 overexpression decreased β-catenin and downregulated glycogen synthase kinase-3β (GSK-3β) protein levels and its activation. However, β-catenin phosphorylation at Ser33, Ser37, and Thr41 are classically induced by GSK-3β was significantly increased after NDRG1 overexpression, suggesting a GSK-3β-independent mechanism. Intriguingly, NDRG1 overexpression upregulated protein kinase Cα (PKCα), with PKCα silencing preventing β-catenin phosphorylation at Ser33, Ser37, and Thr41, and decreasing β-catenin expression. Further, NDRG1 and PKCα were demonstrated to associate, with PKCα stabilization occurring after NDRG1 overexpression. PKCα half-life increased from 1.5 ± 0.8 h (3) in control cells to 11.0 ± 2.5 h (3) after NDRG1 overexpression. Thus, NDRG1 overexpression leads to the association of NDRG1 with PKCα and PKCα stabilization, resulting in β-catenin phosphorylation at Ser33, Ser37, and Thr41. The association between PKCα, NDRG1, and β-catenin was identified, with the formation of a potential metabolon that promotes the latter β-catenin phosphorylation. This anti-oncogenic activity of NDRG1 was multi-modal, with the above mechanism accompanied by the downregulation of the nucleo-cytoplasmic shuttling protein, p21-activated kinase 4 (PAK4), which is involved in β-catenin nuclear translocation, inhibition of AKT phosphorylation (Ser473), and decreased β-catenin phosphorylation at Ser552 that suppresses its transcriptional activity. These mechanisms of NDRG1 activity are important to dissect to understand the marked anti-cancer efficacy of NDRG1-inducing thiosemicarbazones that upregulate PKCα and inhibit WNT signaling., Competing Interests: Conflict of 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.)

Background: For psoriatic patients who need to receive nonlive or live vaccines, evidence-based recommendations are needed regarding whether to pause or continue systemic therapies for psoriasis and/or psoriatic arthritis., Objective: To evaluate literature regarding vaccine efficacy and safety and to generate consensus-based recommendations for adults receiving systemic therapies for psoriasis and/or psoriatic arthritis receiving nonlive or live vaccines., Methods: Using a modified Delphi process, 22 consensus statements were developed by the National Psoriasis Foundation Medical Board and COVID-19 Task Force, and infectious disease experts., Results: Key recommendations include continuing most oral and biologic therapies without modification for patients receiving nonlive vaccines; consider interruption of methotrexate for nonlive vaccines. For patients receiving live vaccines, discontinue most oral and biologic medications before and after administration of live vaccine. Specific recommendations include discontinuing most biologic therapies, except for abatacept, for 2-3 half-lives before live vaccine administration and deferring next dose 2-4 weeks after live vaccination., Limitations: Studies regarding infection rates after vaccination are lacking., Conclusion: Interruption of antipsoriatic oral and biologic therapies is generally not necessary for patients receiving nonlive vaccines. Temporary interruption of oral and biologic therapies before and after administration of live vaccines is recommended in most cases., Competing Interests: Conflicts of interest Dr Chat, Dr Ellebrecht, Ms. Kingston, and Dr Cordoro have no conflicts of interest to declare. Dr Bell is an employee of the National Psoriasis Foundation. Author Gondo is an employee of the National Psoriasis Foundation. Dr Desai has served as a research investigator, consultant, speaker, and/or advisor for AbbVie, Galderma, Foundation for Research & Education of Dermatology, Almirall, Dermavant, Ferndale Laboratories, Inc, Incyte Corporation, Gore Range Capital, AOBiome, LLC, Bristol Myers Squibb, Verrica Pharmaceuticals, UCB, Ortho Dermatologics, Scientis, EPI Health, Avita, Pfizer, Lilly, LEO, Incyte Corporation, L'Oreal USA, Inc, Beiersdorf, Inc, and Johnson and Johnson; is a board member of the National Psoriasis Foundation and Women's Derm Society; and is a stockholder for Gore Range Capital. Dr Duffin has been a consultant, advisor, or served as an investigator for AbbVie, AnaptysBio, Amgen, Bristol-Myers Squib, Celgene, CorEvitas/Corrona, Boehringer-Ingelheim, Janssen, Lilly, Novartis, Ortho Dermatologica, Pfizer, Regeneron, Sienna, Stiefel, and UCB. Dr Feldman has received research, speaking and/or consulting support from Eli Lilly and Company, GlaxoSmithKline/Stiefel, AbbVie, Janssen, Alovtech, vTv Therapeutics, Bristol-Myers Squibb, Samsung, Pfizer, Boehringer Ingelheim, Amgen Inc, Dermavant, Arcutis, Novartis, Novan, UCB, Helsinn, SunPharma, Almirall, Galderma, Leo Pharma, Mylan, Celgene, Valeant, Menlo, Merck & Co, Qurient Forte, Arena, Biocon, Accordant, Argenx, Sanofi, Regeneron, the National Biological Corporation, Caremark, Advance Medical, Suncare Research, Informa, UpToDate and the National Psoriasis Foundation; is the founder and majority owner of www.DrScore.com; is a founder and part owner of Causa Research; and has stock in Sensal Health. Dr Garg is an advisor for AbbVie, Aclaris Therapeutics, Anaptys Bio, Aristea Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Incyte, InflaRx, Insmed, Janssen, Novartis, Pfizer, UCB, and Viela Biosciences; receives honoraria; and receives research grants from AbbVie, UCB and National Psoriasis Foundation. Dr Gelfand served as a consultant for Abbvie, BMS, Boehringer Ingelheim, Celldex (DSMB), FIDE (which is sponsored by multiple pharmaceutical companies) GSK, Happify, Lilly (DMC), Leo, Janssen Biologics, Neumentum, Novartis Corp, Pfizer, UCB (DSMB), Neuroderm (DSMB), Regeneron, Trevi, and Mindera Dx., receiving honoraria; receives research grants (to the Trustees of the University of Pennsylvania) from Boehringer Ingelheim, and Pfizer Inc; and received payment for continuing medical education work related to psoriasis that was supported indirectly pharmaceutical sponsors. Dr Gelfand is a co-patent holder of resiquimod for treatment of cutaneous T cell lymphoma. Dr Gelfand is a Deputy Editor for the Journal of Investigative Dermatology receiving honoraria from the Society for Investigative Dermatology, is Chief Medical Editor for Healio Psoriatic Disease (receiving honoraria) and is a member of the Board of Directors for the International Psoriasis Council, receiving no honoraria. Dr Gladman has served as a consultant for AbbVie, Amgen, BMS, Eli Lily, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB; and has received grants from AbbVie, Amgen, Eli Lily, Janssen, Novartis, Pfizer, and UCB. Dr Green is a research investigator, speaker, and/or consultant for AbbVie, Amgen, Arcutis, BMS, Dermavant, Lilly, MC2, SunPharma, and UCB. Dr Gudjonsson has served as an advisor for Novartis, Janssen, Almirall, Eli Lilly, Sanofi, and Boehringer Ingelheim; and has received research support from Almirall, Eli Lilly, Prometheus, BMS, and Janssen. Dr Han has served as a research investigator, consultant, and/or speaker for AbbVie, Amgen, Boehringer Ingelheim, BMS, Dermavant, Janssen, Lilly, UCB, Novartis, Leo Pharma, Regeneron, Sanofi Genzyme, Ortho Dermatologics, Bond Avillion, Pellepharm, MC2, Athenex, Celgene, Sun Pharma, and Pfizer. Dr Hawkes is an advisor and/or consultant for AbbVie, Arcutis, Boehringer Ingelheim, Janssen, LearnSkin, LEO, Lilly, Novartis, Pfizer, Regeneron-Sanofi Genzyme, and UCB; is a board member of the National Psoriasis Foundation; and has stock ownership/equity of Regeneron Pharmaceuticals. Dr Kircik is a research investigator, speaker, advisor, and/or consultant for Abbott Laboratories, Allergan, Almirall, Amgen, Arcutis, Biogen-Idec, BMS, Boehringer-Ingleheim, Breckinridge Pharma, Celgene, Centocor, Inc, Cellceutix, Cipher, Combinatrix, Connetics Corporation, Coria, Dermavant, Dermira, Dow Pharmaceutical Sciences, Inc, Dr Reddy's Lab, Eli Lilly, Galderma, Genentech, Inc, GlaxoSmithKline, PLC, Idera, Leo, Maruho, Merck, Medicis Pharmaceutical Corp., Novartis AG, Promius, PharmaDerm, Pfizer, Serono, Stiefel Laboratories, Inc, Sun Pharma, Taro, UCB, Valeant Pharmaceuticals Intl, and XenoPort. Dr Koo is a speaker and/or advisor for AbbVie, Amgen, Lilly, UCB, Ortho Dermatologics, LEO, Sun Pharma, Janssen, and Epi Pharm. Dr Langley has been an investigator, served on the scientific advisory board, and/or has provided a lecture for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Leo, Lilly, Merck, Novartis, Pfizer, and UCB. Dr Lebwohl is an employee of Mount Sinai; receives research funds from AbbVie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Cara Therapeutics, Dermavant Sciences, Eli Lilly, Incyte, Janssen Research & Development, LLC, Ortho Dermatologics, Regeneron, and UCB, Inc; and is a consultant for Aditum Bio, Almirall, AltruBio Inc, AnaptysBio, Arcutis, Inc, Arena Pharmaceuticals, Aristea Therapeutics, Arrive Technologies, Avotres Therapeutics, BiomX, Brickell Biotech, Boehringer-Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, Corevitas, Dermavant Sciences, Dr Reddy's Laboratories, Evelo Biosciences, Evommune, Inc, Facilitatation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Helsinn Therapeutics, Hexima Ltd., LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica. Dr Lewitt has received speaking and/or consulting support from AbbVie, Lilly, Janssen, Ortho Dermatologics, UCB, Galderma, Pfizer; received honoraria; and served as an advisor for AbbVie, Janssen, and Dermavant. Dr Liao has received research/grant support from AbbVie, Amgen, Janssen, Leo, Novartis, Trex Bio, Pfizer, and Regeneron. Dr Martin has served as an advisor for Bristol Meyers Squibb, DUSA/SUN, AbbVie, Ortho/Bausch Health, Galderma, Pfizer, LEO, Janssen, Horizon, UCB, Trevi, Almirall, Dermavent, Incyte, and Lilly; has served as a consultant for Bristol Meyers Squibb, DUSA/SUN, AbbVie, Ortho/Bausch Health, Galderma, Pfizer, LEO, UCB, Trevi, Almirall, Lilly, Arcutis, and Dermavant; and has received speaking support from UCB, Almirall, LEO, Incyte, Dermavant, and Bristol Meyers Squibb. Dr Orbai is a consultant and/or advisor for Janssen, Novartis, and UCB; and receives research support from AbbVie, Amgen, and Celgene. Dr Reddy has served as a consultant for Novartis, AbbVie, Janssen, and UCB; and has received grant support from Pfizer. Ms Richardson has served as an advisor for and received honoraria from Boehringer Engelheim and Lilly. Dr Ritchlin is a consultant and/or speaker for Novartis, Lilly, AbbVie, Janssen, UCB, and Pfizer. Dr Schwartzman has received speaking support from AbbVie, Janssen, Lilly, Pfizer, Novartis, and UCB; served as a consultant for Abbvie, Janssen, Lilly, Myriad, Novartis, Regeneron, Sanofi, UCB, Stelexis, Jubilant, and Teijin; is a board member of the National Psoriasis Foundation; and served as an advisor for Myriad. Dr Siegel has served as an advisor, speaker, and/or consultant for Abbvie, UCB, Lilly, Horizon, and BMS. Dr Van Voorhees has served as a research investigator and/or scientific advisor for Lilly, AbbVie, UCB, Bristol Meyers Squibb, Amgen, Boehringer Ingelheim, Novartis, and Merck. Dr Wallace serves as an investigator for Pfizer and Target RWE. Dr Weinberg is a research investigator, consultant, and/or speaker for Novartis, Lilly, Amgen, AbbVie, Sun, Janssen, and BMS. Dr Winthrop is a consultant for Pfizer, AbbVie, Union Chimique Belge (UCB), Eli Lilly & Company, Galapagos, GlaxoSmithKline (GSK), Roche, Gilead, Bristol Myers Squibb (BMS), Regeneron, Sanofi, AstraZeneca, and Novartis; and receives research funding from BMS and Pfizer. Dr Yamauchi serves as a research investigator, consultant, and speaker for Abbvie, Amgen, BMS, Janssen, Lilly, Novartis, Pfizer, Sun Pharma, UCB. Dr Armstrong has served as a research investigator, scientific advisor, and/or speaker to AbbVie, Almirall, Arcutis, ASLAN, Beiersdorf, BI, BMS, EPI, Incyte, Leo, UCB, Janssen, Lilly, Mindera, Nimbus, Novartis, Ortho Dermatologics, Sun, Dermavant, Dermira, Sanofi, Regeneron, and Pfizer., (Copyright © 2024. Published by Elsevier Inc.)

As part of the Integrated Atmospheric Deposition Network, precipitation ( n = 207) and air ( n = 60) from five sites and water samples ( n = 87) from all five Great Lakes were collected in 2021-2023 and analyzed for 41 per- and polyfluoroalkyl substances (PFAS). These measurements were combined with other available data to estimate the mass budget for four representative compounds, PFBA, PFBS, PFOS, and PFOA for the basin. The median Σ 41 PFAS concentrations in precipitation across the five sites ranged between 2.4 and 4.5 ng/L. The median Σ 41 PFAS concentration in lake water was highest in Lake Ontario (11 ng/L) and lowest in Lake Superior (1.3 ng/L). The median Σ 41 PFAS concentration in air samples was highest in Cleveland at 410 pg/m 3 and lowest at Sleeping Bear Dunes at 146 pg/m 3 . The net mass transfer flows were generally negative for Lakes Superior, Michigan, and Huron and positive for Lakes Erie and Ontario, indicating that the three most northern lakes are accumulating PFAS and the other two are eliminating PFAS. Atmospheric deposition is an important source of PFAS, particularly for Lake Superior.

Coulomb crystals have proven to be powerful and versatile tools for the study of ion-molecule reactions under cold and controlled conditions. Reactions in Coulomb crystals are typically monitored through a combination of in situ fluorescence imaging of the laser-cooled ions and destructive time-of-flight mass spectrometry measurements of the ejected ions. However, neither of these techniques is able to provide direct structural information on the positions of nonfluorescing "dark" ions within the crystal. In this work, structural information is obtained using a phosphor screen and a microchannel plate detector in conjunction with a Timepix3 camera. The Timepix3 camera simultaneously records the spatial and temporal distribution of all ions that strike the phosphor screen detector following crystal ejection at a selected reaction time. A direct comparison can be made between the observed Timepix3 ion distributions and the distributions established from SIMION simulations of the ion trajectories through the apparatus and onto the detector. Quantitative agreement is found between the measured Timepix3 signal and the properties of Coulomb crystals assigned using fluorescence imaging─independently confirming that the positions and numbers of nonfluorescing ions within Coulomb crystals can be accurately determined using molecular dynamics simulations. It is anticipated that the combination of high-resolution spatial and temporal data will facilitate new measurements of the ion properties within Coulomb crystals.

The gas-phase reaction between the ethyl cation (C 2 H 5 + ) and ethyne (C 2 H 2 ) is re-investigated by measuring absolute reactive cross sections (CSs) and branching ratios (BRs) as a function of collision energy, in the thermal and hyperthermal energy range, via tandem-guided ion beam mass spectrometry under single collision conditions. Dissociative photoionization of C 2 H 5 Br using tuneable VUV radiation in the range 10.5-14.0 eV is employed to generate C 2 H 5 + , which has also allowed us to explore the impact of increasing (vibrational) excitation on the reactivity. Reactivity experiments are complemented by theoretical calculations, at the G4 level of theory, of the relative energies and structures of the most relevant stationary points on the reactive potential energy hypersurface (PES) and by mass-analyzed ion kinetic energy (MIKE) spectrometry experiments to probe the metastable decomposition from the [C 4 H 7 ] + PES and elucidate the underlying reaction mechanisms. Two main product channels have been identified at a centre-of-mass collision energy of ∼0.1 eV: (a) C 3 H 3 + +CH 4 , with BR = 0.76±0.05 and (b) C 4 H 5 + +H 2 , with BR = 0.22±0.02. A third channel giving C 2 H 3 + in association with C 2 H 4 is shown to emerge at both high internal excitation of C 2 H 5 + and high collision energies. From CS measurements, energy-dependent total rate constants in the range 4.3×10-11-5.2×10-10 cm3·molecule-1·s-1 have been obtained. Theoretical calculations indicate that both channels stem from a common covalently bound intermediate, CH 3 CH 2 CHCH + , from which barrierless and exothermic pathways exist for the production of both cyclic c-C 3 H 3 + and linear H 2 CCCH + isomers of the main product channel. For the minor C 4 H 5 + product, two isomers are energetically accessible: the three-member cyclic isomer c-C 3 H 2 (CH 3 ) + and the higher energy linear structure CH 2 CHCCH 2 + , but their formation requires multiple isomerization steps and passages via transition states lying only 0.11 eV below the reagents' energy, thus explaining the smaller BR. Results have implications for the modeling of hydrocarbon chemistry in the interstellar medium and the atmospheres of planets and satellites as well as in laboratory plasmas (e.g., plasma-enhanced chemical vapor deposition of carbon nanotubes and diamond-like carbon films).

The di-2-pyridylthiosemicarbazone (DpT) analogs demonstrate potent and selective anti-proliferative activity against human tumors. The current investigation reports the synthesis and chemical and biological characterization of the Fe(iii), Co(iii), Ni(ii), Cu(ii), Zn(ii), Ga(iii), and Pd(ii) complexes of the promising second generation DpT analog, di-2-pyridylketone-4-ethyl-4-methyl-3-thiosemicarbazone (Dp4e4mT). These studies demonstrate that the Dp4e4mT Co(iii), Ni(ii), and Pd(ii) complexes display distinct biological activity versus those with Cu(ii), Zn(ii), and Ga(iii) regarding anti-proliferative efficacy against cancer cells and a detrimental off-target effect involving oxidation of oxy-myoglobin (oxy-Mb) and oxy-hemoglobin (oxy-Hb). With regards to anti-proliferative activity, the Zn(ii) and Ga(iii) Dp4e4mT complexes demonstrate facile transmetallation with Cu(ii), resulting in efficacy against tumor cells that is strikingly similar to the Dp4e4mT Cu(ii) complex (IC 50 : 0.003-0.006 μM and 72 h). Relative to the Zn(ii) and Ga(iii) Dp4e4mT complexes, the Dp4e4mT Ni(ii) complex demonstrates kinetically slow transmetallation with Cu(ii) and intermediate anti-proliferative effects (IC 50 : 0.018-0.076 μM after 72 h). In contrast, the Co(iii) and Pd(ii) complexes demonstrate poor anti-proliferative activity (IC 50 : 0.262-1.570 μM after 72 h), probably due to a lack of transmetallation with Cu(ii). The poor efficacy of the Dp4e4mT Co(iii), Ni(ii), and Pd(ii) complexes to transmetallate with Fe(iii) markedly suppresses the oxidation of oxy-Mb and oxy-Hb. In contrast, the 2 : 1 Dp4e4mT: Cu(ii), Zn(ii), and Ga(iii) complexes demonstrate facile reactions with Fe(iii), leading to the redox active Dp4e4mT Fe(iii) complex and oxy-Mb and oxy-Hb oxidation. This study demonstrates the key role of differential transmetallation of Dp4e4mT complexes that has therapeutic ramifications for their use as anti-cancer agents., Competing Interests: No financial conflict of interest exists., (This journal is © The Royal Society of Chemistry.)

Background: Mammalian gonadal sex is determined by the presence or absence of a Y chromosome and the subsequent production of sex hormones contributes to secondary sexual differentiation. However, sex chromosome-linked genes encoding dosage-sensitive transcription and epigenetic factors are expressed well before gonad formation and have the potential to establish sex-biased expression that persists beyond the appearance of gonadal hormones. Here, we apply a comparative bioinformatics analysis on a pair of published single-cell datasets from mouse and human during very early embryogenesis-from two-cell to pre-implantation stages-to characterize sex-specific signals and to assess the degree of conservation among early acting sex-specific genes and pathways., Results: Clustering and regression analyses of gene expression across samples reveal that sex initially plays a significant role in overall gene expression patterns at the earliest stages of embryogenesis which potentially may be the byproduct of signals from male and female gametes during fertilization. Although these transcriptional sex effects rapidly diminish, sex-biased genes appear to form sex-specific protein-protein interaction networks across pre-implantation stages in both mammals providing evidence that sex-biased expression of epigenetic enzymes may establish sex-specific patterns that persist beyond pre-implantation. Non-negative matrix factorization (NMF) on male and female transcriptomes generated clusters of genes with similar expression patterns across sex and developmental stages, including post-fertilization, epigenetic, and pre-implantation ontologies conserved between mouse and human. While the fraction of sex-differentially expressed genes (sexDEGs) in early embryonic stages is similar and functional ontologies are conserved, the genes involved are generally different in mouse and human., Conclusions: This comparative study uncovers much earlier than expected sex-specific signals in mouse and human embryos that pre-date hormonal signaling from the gonads. These early signals are diverged with respect to orthologs yet conserved in terms of function with important implications in the use of genetic models for sex-specific disease., (© 2023. The Author(s).)

Background: Blood transfusions can serve as a life-saving treatment, but inappropriate blood product transfusions can result in patient harm and excess costs for health systems. Despite published evidence supporting restricted packed red blood cell (pRBC) usage, many providers transfuse outside of guidelines. Here, we report a novel prospective, randomized control trial to increase guideline-concordant pRBC transfusions comparing three variations of clinical decision support (CDS) in the electronic health record (EHR)., Methods: All inpatient providers at University of Colorado Hospital (UCH) who order blood transfusions were randomized in a 1:1:1 fashion to the three arms of the study: (1) general order set improvements, (2) general order set improvements plus non-interruptive in-line help text alert, and (3) general order set improvements plus interruptive alert. Transfusing providers received the same randomized order set changes for 18 months. The primary outcome of this study is the guideline-concordant rate of pRBC transfusions. The primary objective of this study is to compare the group using the new interface (arm 1) versus the two groups using the new interface with interruptive or non-interruptive alerts (arms 2 and 3, combined). The secondary objectives compare guideline-concordant transfusion rates between arm 2 and arm 3 as well as comparing all of arms of the study in aggregate to historical controls. This trial concluded after 12 months on April 5, 2022., Discussion: CDS tools can increase guideline-concordant behavior. This trial will examine three different CDS tools to determine which type is most effective at increasing guideline-concordant blood transfusions., Trial Registration: Registered on ClinicalTrials.gov 3/20/21, NCT04823273 . Approved by University of Colorado Institutional Review Board (19-0918), protocol version 1 4/19/2019, approved 4/30/2019., (© 2023. The Author(s).)

Background: Sudden Infant Death Syndrome (SIDS) constitutes one of the main causes of mortality in children under one year of age in developed countries; it's frequency to varies geographically. In Mexico the real incidence of SIDS is not known., Methods: National databases of deaths in children under one year of age, from 2005 to 2020, were analyzed, due to Sudden Unexpected Infant Death (SUID) [SIDS (R95), accidental suffocation in a sleeping environment (W75), and other ill-defined and unspecified causes of mortality (R99), according to the International Classification of Diseases, tenth revision (ICD 10)]. Mortality rates per year of occurrence due to SUID and their subcategories were calculated. Simple frequencies of SIDS were obtained per year and month of occurrence, state of residence, age, place of death, and access to social security services., Results: In the study period 473,545 infant deaths occurred; 7,714 (1.62%) deaths were due to SUID; of these, 6,489 (84%) were due to SIDS, which is among the 10 leading causes of infant death in Mexico. The average mortality rate for SUID was 22.4/100,000 live births, for SIDS was 18.8/100,000 live births. Mortality rates within the states were variable, ranging from 2.4/100,000 to 105.1/100,000 live births. In 81% of SIDS records there was no autopsy; 38% of deaths due to SIDS occurred in infants under one month of age, up to 87% of deaths occurred in families without social security services or it was unknown, and 76.2% of deaths occurred at home. Deaths were more frequent during the last months of autumn and during winter., Conclusion: In Mexico there is an underregistry of SIDS as cause of death, along with other SUID categories. Health workers need to be trained to improve diagnosis and data registration, including the practice of autopsies; additionally, it is necessary to implement a public health campaign., 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., (© 2022 Martínez-Valdez, Richardson, Bautista-Márquez and Hernández-Ávila.)

Endothelial function (brachial artery flow-mediated dilation [FMD]) is reduced in estrogen-deficient postmenopausal women, mediated, in part, by reduced nitric oxide (NO) bioavailability, secondary to tetrahydrobiopterin (BH 4 ) deficiency and oxidative stress. FMD is increased, but not fully restored, in postmenopausal women after acute intravenous vitamin C (VITC; superoxide scavenger) or oral BH 4 supplementation. In vitro studies demonstrate that coadministration of VITC with BH 4 prevents endothelial nitric oxide synthase (eNOS) uncoupling and reductions in NO by peroxynitrite. To investigate mechanisms of endothelial dysfunction in women, we assessed the separate and combined effects of VITC and BH 4 to determine whether coadministration of VITC + BH 4 improves FMD in healthy postmenopausal women ( n = 19, 58 ± 5 yr) to premenopausal ( n = 14, 36 ± 9 yr) levels, with exploratory testing in perimenopausal women ( n = 8, 51 ± 3 yr). FMD was measured during acute intravenous infusions of saline (control) and VITC (∼2-3 g) ∼3 h after a single dose of oral BH 4 (KUVAN, 10 mg/kg body wt) or placebo (randomized crossover, separated by ∼1 mo). Under the placebo condition, FMD was reduced in postmenopausal compared with premenopausal women during the saline infusion (5.6 ± 0.7 vs. 11.6 ± 0.9%, P < 0.001) and increased in postmenopausal women during VITC (+3.5 [1.4, 5.6]%, P = 0.001) and acute BH 4 (+1.8 [0.37, 3.2]%, P = 0.01) alone. Coadministration of VITC + BH 4 increased FMD in postmenopausal women (+3.0 [1.7, 4.3]%, P < 0.001), but FMD remained reduced compared with premenopausal women ( P = 0.02). Exploratory analyses revealed that VITC + BH 4 did not restore FMD in perimenopausal women to premenopausal levels ( P = 0.045). Coadministration of VITC + BH 4 does not restore FMD in menopausal women, suggesting that additional mechanisms may be involved. NEW & NOTEWORTHY Endothelial function is reduced across the menopausal stages related to increased oxidative stress associated with estrogen deficiency. In vitro studies demonstrate that coadministration of VITC with BH 4 prevents endothelial nitric oxide synthase (eNOS) uncoupling and reductions in NO by peroxynitrite; however, this remains untested in humans. We demonstrate that the coadministration of BH 4 + VITC does not restore endothelial function in perimenopausal and postmenopausal women to the level of premenopausal women, suggesting that other mechanisms contribute.

Methanol is a key species in astrochemistry as its presence and reactivity provides a primary route to the synthesis of more complex interstellar organic molecules (iCOMs) that may eventually be incorporated in newly formed planetary systems. In the interstellar medium, methanol is formed by hydrogenation of CO ices on grains, and its fate upon collisions with interstellar ions should be accounted for to correctly model iCOM abundances in objects at various stages of stellar evolution. The absolute cross sections (CSs) and branching ratios (BRs) for the collisions of He˙ + ions with CH 3 OH are measured, as a function of the collision energy, using a Guided Ion Beam Mass Spectrometer (GIB-MS). Insights into the dissociative electron (charge) exchange mechanism have been obtained by computing the entrance and exit multidimensional Potential Energy Surfaces (PESs) and by modelling the non-adiabatic transitions using an improved Landau-Zener-Stückelberg approach. Notably, the dynamical treatment reproducing the experimental findings includes a strong orientation effect of the system formed by the small He˙ + ion and the highly polar CH 3 OH molecule, in the electric field gradient associated to the strongly anisotropic intermolecular interaction. This is a stereodynamical effect that plays a fundamental role in collision events occurring under a variety of conditions, with kinetic energy confined within intervals ranging from the sub-thermal to the hyper-thermal regime.

Background: The di-2-pyridylketone thiosemicarbazones, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), demonstrate potent and selective anti-tumor activity. In fact, DpC entered Phase I clinical trials for advanced and resistant tumors., Methods: This investigation examined the activity of these thiosemicarbazones in five tumor cell-types compared to nine clinically used chemotherapeutics and also in combination with these drugs., Results: Dp44mT and especially DpC demonstrated potent anti-proliferative activity that was significantly greater than a range of standard anti-cancer therapeutics. As most anti-cancer drugs are given in combination, further studies were performed to examine the synergistic activity of DpC or Dp44mT with these chemotherapeutics. Combination experiments revealed broad synergy between Dp44mT or DpC upon addition of these drugs, with a sequential protocol of treating first with standard chemotherapies followed by incubation with the thiosemicarbazones being optimal. However, combining DpC and Dp44mT resulted in a pronounced antagonistic drug interaction. To dissect the mechanism of this latter effect, custom-prepared 14 C-DpC was implemented and examined for its uptake by cells. The avid uptake of 14 C-DpC by tumor cells observed at 37 °C was suppressed at 4 °C and by the metabolic inhibitor, sodium fluoride, suggesting a temperature- and energy-dependent mechanism. Furthermore, competition studies using an excess of unlabeled Dp44mT or DpC inhibited 14 C-DpC or 14 C-Dp44mT uptake, respectively, suggesting these ligands utilize the same carrier/receptor, antagonizing the internalization of each other., Conclusions and General Significance: These studies demonstrate the potent and broad anti-proliferative activity of Dp44mT and particularly DpC, and are important for establishing optimized combinations with standard chemotherapies., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: The current service metrics used to evaluate quality in emergency care do not account for specific healthcare outcome goals for older people living with frailty. These have previously been classified under themes of 'Autonomy' and 'Functioning'. There is no person-reported outcome measure (PROM) for older people with frailty and emergency care needs. This study aimed to identify and co-produce recommendations for instruments potentially suitable for use in this population., Methods: In this systematic review, we searched six databases for PROMs used between 2010 and 2021 by older people living with frailty receiving acute hospital care. Studies were reviewed against predefined eligibility criteria and appraised for quality using the COSMIN Risk of Bias checklist. Data were extracted to map instrument constructs against an existing framework of acute healthcare outcome goals. Instrument face and content validity were assessed by lay collaborators. Recommendations for instruments with potential emergency care suitability were formed through co-production., Results: Of 9392 unique citations screened, we appraised the full texts of 158 studies. Nine studies were identified, evaluating nine PROMs. Quality of included studies ranged from 'doubtful' to 'very good'. Most instruments had strong evidence for measurement properties. PROMs mainly assessed 'Functioning' constructs, with limited coverage of 'Autonomy'. Five instruments were considered too burdensome for the emergency care setting or too specific for older people living with frailty., Conclusions: Four PROMs were recommended as potentially suitable for further validation with older people with frailty and emergency care needs: COOP/WONCA charts, EuroQol, McGill Quality of Life (Expanded), and Palliative care Outcome Scale., (© 2022. The Author(s).)