Peripheral Sites Research Articles

Peripheral site modification in a family of dinuclear [Dy2(hynad)2-6(NO3)0-6(sol)0-2]0/2- single-molecule magnets bearing a {Dy2(μ-OR)2}4+ diamond-shaped core and exhibiting dissimilar magnetic dynamics.

The first use of the organic chelate N-hydroxy-1,8-naphthalimide (hynadH) in DyIII chemistry has unveiled access to a synthetic 'playground' composed of four new dinuclear complexes, all of which possess the same planar {Dy2(μ-OR)2}4+ diamond-shaped core, resulting from the bridging and chelating capacity of the hynad- groups. The structural stability of the central {Dy2} core has allowed for the modulation of the peripheral coordination sites of the metal ions, and specifically the NO3-/hynad- ratio of capping groups, thus affording the compounds [Dy2(hynad)2(NO3)4(DMF)2] (1), (Me4N)2[Dy2(hynad)2(NO3)6] (2), [Dy2(hynad)4(NO3)2(H2O)2] (3), and [Dy2(hynad)6(H2O)2] (4). Because of the chemical and structural modifications in the series 1-4, the DyIII coordination polyhedra are also dissimilar, comprising the muffin (1 and 3), tetradecahedral (2), and spherical tricapped trigonal prismatic (4) geometries. Complexes 1, 2, and 4 exhibit a ferromagnetic response at low temperatures, while 3 is antiferromagnetically coupled. All compounds exhibit out-of-phase (χ''M) ac signals as a function of ac frequency and temperature, thus behaving as single-molecule magnets (SMMs), in the absence or presence of applied dc fields. Interestingly, the hynad--rich and nitrato-free complex 4, demonstrates the largest energy barrier (Ueff = 69.62(1) K) for the magnetization reversal which is attributed to the presence of the two axial triangular faces of the spherical tricapped trigonal prism by the negatively charged O-atoms of the hynad- ligands.

Evaluation of In Vitro and In Silico Anti-Alzheimer Potential of Nonpolar Extracts and Essential Oil from Mentha piperita

The anticholinesterase and antioxidant activities with chemical composition and molecular docking of essential oil and nonpolar extracts of Mentha piperita were evaluated using enzymatic and chemical methods. Molecular docking tools were used to explain the interaction of the major chemical constituents with the enzymes. GC/MS analyses revealed that the main compounds in M. piperita essential oil were l-menthone (43.601%) followed by pulegone (21.610%), linolenic acid (25.628%), and l-menthone (10.957%), representing the major compounds of the petroleum ether extract. Imidazoquinoline (7.767%) and 17-N-acetyl-oroidine (5.363%) were the major constituents of the chloroform extract. Linolenic acid (19.397%) and l-menthone (6.336%) were the most abundant compounds in the hexane extract. The M. piperita essential oil and nonpolar extracts showed moderate antioxidant activity. The essential oil showed the most promising anticholinesterase activity with IC50 = 10.66 ± 0.12 µg/mL and IC50 = 16.33 ± 0.03 µg/mL against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively, close to galantamine in AChE and more active in BChE, followed by the interesting activity in the petroleum ether extract with IC50 = 23.42 ± 3.06 µg/mL in AChE and IC50 = 62.00 ± 3.22 µg/mL in BChE. The docking experiments showed that among the seven major identified compounds, N-acetyl-17-oroidine showed the highest binding score (63.01 in AChE and 63.68 in BChE). This compound was found to bind the catalytic and peripheral sites, resulting in more potent inhibitory activity than galantamine, which only binds to the catalytic site. These findings suggested the possible use of M. piperita essential oil and nonpolar extracts as a potential source of alternative natural anti-Alzheimer compounds.

Treating peripheral nerve injury-induced spinal cord degeneration and neuropathic pain with peripherally administrated stem cells.

Treating peripheral nerve injury-induced spinal cord degeneration and neuropathic pain with peripherally administrated stem cells.

Production Centers of Cooking Pots in Iron Age Judah

This article will discuss a recent, multifaceted study of the production of cooking pots during the Iron Age II (ca. 1,000–586 BCE) in Judah (modern Israel). In particular, the article will present the compositional analysis of 541 cooking vessels from 11 sites in Iron Age Judah. The study employs petrographic and chemical (NAA) analysis and examines forming techniques. The results of this research provide new information about production centers and the mobility of cooking pots in Iron Age II Judah. The vast majority of the cooking pots sampled from most types appear to have been made of a similar type of clay, related to terra rossa soil. This is also true of sites in the northern Negev and Judean Desert, where this type of soil was not available in the region of the sites. Furthermore, many of the cooking pots distributed throughout Judah were made in Jerusalem, according to a well-located chemical profile (JleB). Other groups may represent Judean Shephelah production centers, such as the Lachish area, or production centers in southern Israel or ancient Edom. The study will conclude with a general discussion of the implications of importation patterns of cooking pots near peripheral Judean sites.

ダビガトラン過量服薬に対するイダルシズマブの静脈内投与：血漿中ダビガトラン濃度と血液凝固能の関連性(Intravenous idarucizumab for dabigatran overdose: association between plasma dabigatran concentration and coagulation profile)

要旨ダビガトランは直接トロンビンを阻害することで抗凝固作用を示す経口抗凝固薬であり，近年処方機会が急増している。過量内服症例における，血漿中ダビガトラン濃度および血液凝固能の推移に関するデータは不足している。腎機能障害のない，非弁膜症性心房細動をもつ71歳邦人女性が近医より処方されていたダビガトランを合計7,480mg自殺目的に過量内服し，当院に搬送された。過量内服4時間後の血漿中ダビガトラン濃度は4,217ng/mL（治療域濃度100～400ng/mL）であり，APTTは160.3秒，PT–INRは9.46であった。イダルシズマブ5g経静脈投与後，血漿中ダビガトラン濃度は経時的に低下し，それに伴いAPTTとPT–INRも正常化した。血漿中ダビガトラン濃度とAPTT（R2=0.9898），およびPT–INR（R2=0.9998）との間には強固な関連性が認められた。本症例は第9病日に後遺症なく独歩退院した。治療域の40倍の血漿中濃度を示すダビガトラン大量内服症例において，イダルシズマブは血漿中ダビガトラン濃度を安全に，かつ効果的に低下させた。また，血液凝固能は，血漿中ダビガトラン濃度を強固に反映した。本症例により，一般的な血液凝固能検査を用いることで，ダビガトランの血中薬物動態を推定できる可能性が示された。

Analgesic Action of Acetaminophen via Kv7 Channels

The mechanism of acetaminophen (APAP) analgesia is at least partially unknown. Previously, we showed that the APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) activated Kv7 channels in neurons in vitro, and this activation of Kv7 channels dampened neuronal firing. Here, the effect of the Kv7 channel blocker XE991 on APAP-induced analgesia was investigated in vivo. APAP had no effect on naive animals. Induction of inflammation with λ-carrageenan lowered mechanical and thermal thresholds. Systemic treatment with APAP reduced mechanical hyperalgesia, and co-application of XE991 reduced APAP's analgesic effect on mechanical pain. In a second experiment, the analgesic effect of systemic APAP was not antagonized by intrathecal XE991 application. Analysis of liver samples revealed APAP and glutathione-coupled APAP indicative of metabolization. However, there were no relevant levels of these metabolites in cerebrospinal fluid, suggesting no relevant APAP metabolite formation in the CNS. In summary, the results support an analgesic action of APAP by activating Kv7 channels at a peripheral site through formation of the metabolite NAPQI.

Association of Pressure Wave Reflections With Left Ventricular Mass: a Systematic Review and Meta-Analysis.

Pressure wave reflections (PWRs) within the circulation are assessed at various arterial sites by various noninvasive methods. We aimed at reviewing the conflicting data regarding the hypothesis that higher PWRs are associated with higher left ventricular mass and tested whether this association stands for all available indices of PWRs, all (proximal or distal to the heart) sites of assessment, and is modified by sex, age and heart rate. Based on a predefined protocol applying the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines, we identified eligible for meta-analysis data regarding: augmentation index, augmentation pressure, backward pressure (Pb), reflection index, and their association with left ventricular mass index (19 studies, total population n=8686). We found statistically significant associations, independent from blood pressure level, for all indices of PWRs at all arterial sites (carotid augmentation index; odds ratio; standardized beta coefficient [β]: 0.14 [95% CI, 0.07% to 0.21%], per SD increase), radial augmentation index (β: 0.21; 0.11 to 0.31), central augmentation pressure (β: 0.15; 0.03 to 0.27), central Pb (β: 0.23; 0.05 to 0.42), and central reflection index (β: 0.14; 0.06 to 0.22), except for aortic augmentation index as estimated by generalized transfer functions. Meta-regression analysis showed that the association between carotid augmentation index and left ventricular mass was higher among populations with higher heart rate (P=0.036, beta: 0.017 [95% CI, 0.001 to 0.033]) and tended to be higher in middle-aged (P=0.07, beta: -0.001; -0.021 to 0.001). A clinically meaningful association between PWRs and left ventricular mass, assessed at either central or peripheral arterial sites by most available methods was shown, suggesting that PWR reduction strategies might be useful. Based on the present evidence, such trials should target middle-aged populations with high normal heart rate.

De novo cholesterol biosynthesis: an additional therapeutic target for the treatment of postmenopausal breast cancer with excessive adipose tissue.

The onset and development of breast cancer in postmenopausal women are associated with closely related individual-dependent factors, including weight gain and high levels of circulating androgens. Adipose tissue is the most peripheral site of aromatase enzyme synthesis; therefore, the excessive accumulation of visceral fat results in increased androgens aromatization and estradiol production that provides the microenvironment favorable to tumorigenesis in mammary epithelial cells expressing estrogen receptors (ERs). Moreover, to meet the increased requirement of cholesterol for cell membrane assembly and the production of steroid hormones to sustain their proliferation, ER-positive cells activate de novo cholesterol biosynthesis and subsequent steroidogenesis. Several approaches have been followed to neutralize the de novo cholesterol synthesis, including specific enzyme inhibitors, statins, and, more recently, metformin. Cumulating evidence indicated that inhibiting cholesterol biosynthesis by statins and metformin may be a promising therapeutic strategy to block breast cancer progression. Unlike antiestrogens and aromatase inhibitors (AIs) which compete for binding to ER and inhibit androgens aromatization, respectively, statins block the production of mevalonic acid by inhibiting the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and metformin hampers the activation of the sterol regulatory element-binding protein 2 (SREBP2) transcription factor, thus inhibiting the synthesis of several enzymes involved in cholesterol biosynthesis. Noteworthy, statins and metformin not only improve the prognosis of overweight patients with ER-positive cancer but also improve the prognosis of patients with triple-negative breast cancer, the aggressive tumor subtype that lacks, at present, specific therapy.

Two new dilactonized glycerol glycosides of the dual anticholinesterase active extract from Ocotea daphnifolia using bioguided fractionation and molecular docking studies.

The dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) is considered as an important strategy for the treatment of Alzheimer's disease. In this study, we applied the bioguided fractionations of Ocotea daphinifolia ethyl acetate active extract to furnish a fraction with high inhibitory activity for AChE and BuChE (82% and 92%, respectively). High-performance liquid chromatography semipreparative purification of this fraction provided two new natural products: 1-β-D-galactopyranosyl-glycerol-2,3-heptanedionate, (1) whose complete chemical structural elucidation was made with spectrometric analysis (MS, 1D, and 2D NMR) and its minor derivative 1-β-D-gulopyranosyl-glycerol-2,3-heptanedionate; (2) which could be characterized by 2D 1 H-13 C heteronuclear single-quantum correlation spectra analysis. Investigation of the intermolecular interactions with cholinesterases was carried out by molecular docking studies, and results suggested that both compounds are capable to interact with the catalytic site of both enzymes. Compounds 1 and 2 interact with residues of catalytic domains and the peripheral anionic binding site of AChE and BuChE. The results are comparable to those achieved with rivastigmine and galantamine. Thus, this study provides evidence for consideration of the glycosylglycerol from O. daphnifolia as new valuable dual cholinesterases inhibitor.

Aggregated alpha-synuclein transcriptionally activates pro-inflammatory canonical and non-canonical NF-κB signaling pathways in peripheral monocytic cells

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by chronic neuroinflammation, loss of dopaminergic neurons in the substantia nigra, and in several cases accumulation of alpha-synuclein fibril (α-syn) containing Lewy-bodies (LBs). Peripheral inflammation may play a causal role in inducing and perpetuating neuroinflammation in PD and accumulation of fibrillar α-syn has been reported at several peripheral sites including the gut and liver. Peripheral fibrillar α-syn may induce activation of monocytes via recognition by toll-like receptors (TLRs) and stimulation of downstream NF-κB signaling; however, the specific mechanism by which this occurs is not defined. In this study we utilized the THP-1 monocytic cell line to model the peripheral transcriptional response to preformed fibrillar (PFF) α-syn. Compared to monomeric α-syn, PFF α-syn displays overt inflammatory gene upregulation and pathway activation including broad pan-TLR signaling pathway activation and increases in TNF and IL1B gene expression. Notably, the non-canonical NF-κB signaling pathway gene and PD genome wide association study (GWAS) candidate NFKB2 was upregulated. Additionally, non-canonical NF-κB activation-associated RANK and CD40 pathways were also upregulated. Transcriptional-phenotype analysis suggests PFFs induce transcriptional programs associated with differentiation of monocytes towards macrophages and osteoclasts via non-canonical NF-κB signaling as a potential mechanism in which myeloid/monocyte cells may contribute to peripheral inflammation and pathogenesis in PD.

Cross-sectional area and echo intensity values of peripheral nerves: Ultrasonographic and cadaveric correlation.

Ultrasonography allows high-resolution visualisation of the peripheral nerves for quantitative and qualitative analyses. We report cross-sectional area values (quantitative measure) and echo intensity values (qualitative measure) for 46 peripheral nerve sites in upper and lower extremities in cadaveric specimens. To determine cross-sectional area values and echo intensity values of peripheral nerves of upper and lower extremities at 46 nerve sites. Nerve measurements were obtained using electronic callipers and ultrasonography for linear dimension and cross-sectional area measurements, respectively, in six cadaveric specimens for 46 peripheral nerve sites. Ultrasound images were further analysed to estimate echo intensity percentage values for 46 nerves. We present normal cross-sectional area values of various nerves of upper and lower extremities with their respective echo intensity values. Calculated cross-sectional area values from linear dimensions did not match the measured cross-sectional area values via trace method. Cross-sectional area values (quantitative measure) and echo intensity values (qualitative measure) for 46 peripheral nerve sites in upper and lower extremities in cadaveric specimens are presented. The estimation of cross-sectional area via linear measurement is not a good approximation of the cross-sectional area (cross-sectional area measured by trace method on ultrasound image).

Design, synthesis, anti-acetylcholinesterase evaluation and molecular modelling studies of novel coumarin-chalcone hybrids

The major enzyme responsible for the hydrolytic breakdown of the neurotransmitter acetylcholine (ACh) is acetylcholinesterase (AChE). Acetylcholinesterase inhibitors (AChEIs) are the most prescribed class of medications for the treatment of Alzheimer’s disease (AD) and dementia. The limitations of available therapy, like side effects, drug tolerance, and inefficacy in halting disease progression, drive the need for better, more efficacious, and safer drugs. In this study, a series of fourteen novel chalcone-coumarin derivatives (8a-n) were designed, synthesized and characterized by spectral techniques like FT-IR, NMR, and HR-MS. Subsequently, the synthesized compounds were tested for their ability to inhibit acetylcholinesterase (AChE) activity by Ellman’s method. All tested compounds showed AChE inhibition with IC50 value ranging from 0.201 ± 0.008 to 1.047 ± 0.043 μM. Hybrid 8d having chloro substitution on ring-B of the chalcone scaffold showed relatively better potency, with IC50 value of 0.201 ± 0.008 μM compared to other members of the series. The reference drug, galantamine, exhibited an IC50 at 1.142 ± 0.027 μM. Computational studies revealed that designed compounds bind to the peripheral anionic site (PAS), the catalytic active site (CAS), and the mid-gorge site of AChE. Putative binding modes, ligand-enzyme interactions, and stability of the best active compound are studied using molecular docking, followed by molecular dynamics (MD) simulations. The cytotoxicity of the synthesised derivatives was determined using the MTT test at three concentrations (100 g/mL, 500 g/mL, and 1 mg/mL). None of the chemicals had a significant effect on the body at the highest dose of 1 mg/mL. Communicated by Ramaswamy H. Sarma

A series of 1,2,3-triazole compounds: Synthesis, characterization, and investigation of the cholinesterase inhibitory properties via in vitro and in silico studies

A series of 1,2,3-triazole compounds derived from a salicylaldehyde moiety were synthesized in high yields using copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. The structures of the newly synthesized 1,2,3-triazole compounds were characterized by FT-IR, NMR, and HRMS analyses. The inhibitory activities of all the target compounds were investigated against electric eel acetylcholinesterase (eeAChE) and equine serum butyrylcholinesterase (eqBChE) enzymes. The activity results were compared with galantamine used as a reference compound. The in vitro biological assays showed that most of the target compounds had quite good inhibition activities for eeAChE, while weaker towards eqBChE. Among them, compound 23f exhibited better activity than both other target compounds and galantamine against both eeAChE (IC50: 0.458 µM) and eqBChE (IC50:1.721 µM). Molecular docking studies of all target compounds were performed on the 3D crystallographic structures of eeAChE, Homo sapiens AChE, and BChE enzymes. The binding energies appear to be consistent with the activity results. Moreover, it was determined that 23f interacted with crucial residues of the catalytic active site (CAS) and peripheral anionic site (PAS) of both AChE and BChE due to its dual binding feature. Finally, in silico ADME and toxicity properties of the compounds were investigated using the Swiss ADME and ProTox-II websites. The compounds have appropriate drug-likeness scores, Additionally, it has been estimated that 23f, the most active compound, and 23c are within the best limits in terms of oral bioavailability and exhibit low levels of toxicity. Consequently, the target compounds, especially 23f, can be considered promising inhibitors for the cholinesterase enzymes.

Species richness of Antbirds (Thamnophilidae) in more central and peripheral sites of terra firme forest in the eastern edge of the Amazonia

Antbirds (Thamnophilidae) comprise many insectivorous, mostly understory birds present in all Neotropical biomas. Many species occur specifically in the Amazonia, so a decline in species richness is expected from central Amazonian sites, to peripheral ones; this pattern is due primarily to the evolutionary history of the taxon. Rapid surveys to state the antbird species richness were performed in six sites of terra firme forest in the Belém Center of Endemism, the Easternmost and one of the most threatened regions in the Amazonia. These sites followed a series from more central to more peripheral areas, the latter being located in the edge of the Amazonia. The antbird species richness of every site was stated by presence-absence criteria. Two surveys were made in each site, by walking three transects in each of two trails in every survey. This species richness progressively fell from 19 species in the most central site (Gurupi Biological Reserve) to only two in the most peripheral one (São Luís). Probably, the gradient in the species richness is primarily associated to the evolutionary history of this group, however new studies using methods appropriated to assess the effects of environmental degradation in the regional richness of Thamnophilidae and other forest bird species should be encouraged.

Inhibitory Action of Omega-3 and Omega-6 Fatty Acids Alpha-Linolenic, Arachidonic and Linoleic acid on Human Erythrocyte Acetylcholinesterase.

Acetylcholinesterase (AChE, E.C. 3.1.1.7) termed as the true cholinesterase functions to end cholinergic transmission at synapses. Due to its diverse expression in non-neural tissues such as erythrocytes and bones along with its various molecular forms, researchers seek a non-classical role for this protein. Here, the inhibitory action of unsaturated 18 carbon fatty acids linoleic acid and alpha-linolenic acid and 20 carbon fatty acid arachidonic acid on AChE were investigated. Enzyme activity was measured in kinetic assay method according to Ellman assay utilizing acetylthiocholine. Analysis of the activity data revealed that among the fatty acids examined the IC50 values differed according to the length of the fatty acid and the number of the double bonds. Arachidonic acid, a 20-carbon fatty acid with 4 unsaturated bonds (20:4 n-6, cis 5,8,11,14) displayed an IC50 value of 2.78 µM and Ki value of 396.35 µM. Linoleic acid, an essential 18-carbon fatty acid (18:2 n-6, cis 9,12) had an IC50 value of 7.95 µM and Ki value of 8027.55 µM. The IC50 value of alpha-linolenic acid, 18-carbon fatty acid (18:3 n-3, cis-9,12,15) was found as 179.11 µM. Analysis of the data fit the inhibition mechanism for linoleic, alpha-linolenic and arachidonic acid as mixed-type; non-competitive. Molecular docking complied with these results yielding the best score for arachidonic acid. The alkenyl chain of the fatty acids predictably reached to the catalytic site while the carboxylate strongly interacted with the peripheric anionic site.

HCMV carriage in the elderly diminishes anti-viral functionality of the adaptive immune response resulting in virus replication at peripheral sites.

Human cytomegalovirus (HCMV) infection and periodic reactivation is, generally, well controlled by adaptative immune responses in the healthy. In older people, overt HCMV disease is rarely seen despite the association of HCMV with increased risk of mortality; evidence from studies of unwell aged populations suggest that HCMV seropositivity is an important co-morbidity factor. HCMV genomes have been detected in urine from older donors, suggesting that the immune response prevents systemic disease but possibly immunomodulation due to lifelong viral carriage may alter its efficacy at peripheral tissue sites. Previously we have demonstrated that there were no age-related expansions of T cell responses to HCMV or increase in latent viral carriage with age and these T cells produced anti-viral cytokines and viremia was very rarely detected. To investigate the efficacy of anti-HCMV responses with increasing age, we used an in vitro Viral Dissemination Assay (VDA) using autologous dermal fibroblasts to determine the anti-viral effector capacity of total PBMC, as well as important subsets (T cells, NK cells). In parallel we assessed components of the humoral response (antibody neutralization) and combined this with qPCR detection of HCMV in blood, saliva and urine in a cohort of young and old donors. Consistent with previous studies, we again show HCMV specific cIL-10, IFNγ and TNFα T cell responses to peptides did not show an age-related defect. However, assessment of direct anti-viral cellular and antibody-mediated adaptive immune responses using the VDA shows that older donors are significantly less able to control viral dissemination in an in vitro assay compared to young donors. Corroborating this observation, we detected viral genomes in saliva samples only from older donors, these donors had a defect in cellular control of viral spread in our in vitro assay. Phenotyping of fibroblasts used in this study shows expression of a number of checkpoint inhibitor ligands which may contribute to the defects observed. The potential to therapeutically intervene in checkpoint inhibitor pathways to prevent HCMV reactivation in the unwell aged is an exciting avenue to explore.

535. Evaluation of the BioFire Blood Culture Identification (BCID2) panel for transplant recipients with a bloodstream infection

Abstract Background In patients with bloodstream infections (BSI), the BioFire blood culture identification (BCID2) multiplex PCR panel is associated with decreased time to organism identification and antimicrobial susceptibility results needed to guide optimal therapy. While the performance of BCID2 has been evaluated in the general population, data for transplant recipients are limited. We sought to identify the utility of the BCID2 panel in transplant recipients. Methods A retrospective chart review was conducted to identify all solid organ recipients (SOTR) and bone marrow transplant recipients (BMTR) within 2 years of transplantation with BSI for whom BCID2 was performed from 06/2021 to 01/2022. Demographic and microbiological data were collected. Positive blood cultures for the same patient and same organism(s) occurring within 14 days of the initial test were considered a single BSI event. Descriptive statistics were performed. Results A total of 29 transplant recipients with 45 positive blood cultures underwent BCID2 testing. Mean age was 54 years, 69% were BMTR and 53% of cultures were from peripheral sites. A total of 51 organisms were recovered from 45 blood cultures. Organisms identified by blood cultures included Enterobacterales (45%), Enterococcus spp (20%), Candida spp (8%), non-Enterobacterales gram negative rods (14%), Streptococcus spp (8%), and other gram positives (5%). No anaerobic organisms were isolated. BCID2 did not detect 7/51 (14%) organisms identified by blood cultures including monomicrobial (n=6/39) and polymicrobial (n=1/6) cultures. All 7 organisms not identified by BCID2 were not in the BCID2 database. All occurred in BMTR; 4 were considered pathogenic and treated with antimicrobials vs. 3 contaminants (Table 1). BCID2 detected CTX-M or Van A/B in all 15 samples with ceftriaxone (n=9) or vancomycin resistance(n=6). Conclusion In transplant recipients, BCID2 detected 86% of organisms and 100% of resistance markers identified by conventional testing. All 7 (14%) missed cases involved off-target organisms, of which 4 were considered pathogenic. BCID2 is a useful tool for BSI detection in transplant recipients, but providers should consider the possibility of off-target pathogens when clinically appropriate. Disclosures David Peaper, MD, Tangen Biosciences: Stocks/Bonds Maricar F. Malinis, MD, Aicuris: Primary Investigator of Clinical Trial at Yale Site|Takeda: Primary investigator of clinical trial at Yale Site Maricar F. Malinis, MD, Aicuris: Primary Investigator of Clinical Trial at Yale Site|Takeda: Primary investigator of clinical trial at Yale Site.

1253: EFFECT OF PERIPHERALLY INFUSED NOREPINEPHRINE ON REDUCING CENTRAL VENOUS CATHETER UTILIZATION

Introduction: Vasoactive agents like norepinephrine have been historically administered via central venous catheters (CVCs) due to the perceived risk of local tissue injury with peripheral infusion. While infusion-related complications may be reduced with CVC administration, the higher rates of bacteremia, pneumothorax, and air embolism must be weighed, along with delays in administration and achievement of hemodynamic stability. This study is designed to add to the available safety data of peripheral norepinephrine administration while also investigating the direct cost savings associated with CVC avoidance. Methods: This is a retrospective analysis of adult patients who received norepinephrine between January 1 and September 1, 2021. A hospital guideline allows peripheral infusion of norepinephrine via dedicated, 16 – 20 gauge, mid-to-upper arm IV catheters for up to 24 hours. The primary outcome was the need for central venous access in patients initially started on peripherally infused norepinephrine. Safety outcomes included local tissue injury attributed to norepinephrine infusion. Results: Ninety-eight of 124 total patients initially received peripheral norepinephrine infusions, most of which required vasopressors for distributive or mixed shock. Thirty-six patients (37%) avoided the need for central line placement. The median duration of vasopressors was 6 hours [IQR 3.3 – 11.3] at a median maximum rate of 0.08 mcg/kg/min [IQR 0.05 – 0.15]. In the remaining 62 patients who progressed from peripheral to central line placement, the median duration was 15.5 hours [IQR 6 – 38.5] at a median maximum rate of 0.15 mcg/kg/min [IQR 0.06 – 0.25]. Eighty of the 98 patients (82%) who started peripherally infused norepinephrine required therapy for ≤12 hours. No extravasation or local complications were observed regardless of site of infusion. Avoiding progression to a CVC in 37 of every 100 peripheral lines resulted in an estimated direct supply cost savings of $8,900. Conclusions: Initial administration of norepinephrine via a dedicated peripheral IV site was safe and led to a reduction in the need for subsequent CVC access. To minimize cost while achieving timely resuscitation goals and maintaining patient safety, initial peripheral administration should be considered for all patients.

Rapid southeastern Laurentide Ice Sheet thinning during the last deglaciation revealed by elevation profiles of in situ cosmogenic 10Be

Accurate reconstruction of Laurentide Ice Sheet volume changes following the Last Glacial Maximum is critical for understanding ice sheet contribution to sea-level rise, the resulting influence of meltwater on oceanic circulation, and the spatial and temporal patterns of deglaciation. Here, we provide empirical constraints on Laurentide Ice Sheet thinning during the last deglaciation by measuring in situ cosmogenic 10Be in 81 samples collected along vertical transects of nine mountains in the northeastern United States. In conjunction with 107 exposure age samples over five vertical transects from previous studies, we reconstruct ice sheet thinning history. At peripheral sites (within 200 km of the terminal moraine), we find evidence for ∼600 m of thinning between 19.5 ka and 17.5 ka, which is coincident with the slow initial margin retreat indicated by varve records. At locations >400 km north of the terminal moraine, exposure ages above and below 1200 m a.s.l. exhibit different patterns. Ages above this elevation are variable and older, while lower elevation ages are indistinguishable over 800−1000 m elevation ranges, a pattern that suggests a subglacial thermal boundary at ∼1200 m a.s.l. separating erosive, warm-based ice below and polythermal, minimally erosive ice above. Low-elevation ages from up-ice mountains are between 15 ka and 13 ka, which suggests rapid thinning of ∼1000 m coincident with Bølling-Allerød warming. These rates of rapid paleo-ice thinning are comparable to those of other vertical exposure age transects around the world and may have been faster than modern basin-wide thinning rates in Antarctica and Greenland, which suggests that the southeastern Laurentide Ice Sheet was highly sensitive to a warming climate.

Design, Synthesis, Biological Evaluation and Molecular Dynamics Simulations Study of Genistein‐O‐1,3,5‐Triazine Derivatives as Multifunctional Anti‐Alzheimer Agents

AbstractTwenty‐four genistein‐O‐1,3,5‐triazine derivatives were designed, synthesized and evaluated as multi‐functional anti‐Alzheimer agents. These compounds were confirmed by IR, NMR and HRMS and single‐crystal X‐ray diffraction studies. Most target compounds showed good inhibition and selectivity to acetylcholinesterase. Among these compounds, compound 4 e (7‐((4‐chloro‐6‐(diisobutylamino)‐1,3,5‐triazin‐2‐yl)oxy)‐5‐hydroxy‐3‐(4‐hydroxyphenyl)‐4H‐chromen‐4‐one) exhibited the strongest inhibition to acetylcholinesterase with IC50 of 0.034 μM, which was comparable with that of donepezil (IC50=0.037 μM). The enzyme kinetics studies showed that this compound was a kind of mixed type inhibitor. Molecular docking and molecular dynamics simulations study of this compound indicated that it could interact with the crucial amino acids present at the catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase and bind to acetylcholinesterase stably. Furthermore, this compound also showed terrific metal chelating abilities. ADMET characteristics implied that these compounds could possess the properties to become drug candidates. Thus, this compound may become a latent multifunctional anti‐Alzheimer agent.