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U-Pb age spectra of detrital zircons in samples from the Paleogene Colton Formation in the Uinta Basin of northeastern Utah and the Late Cretaceous McCoy Mountains Formation of southwestern Arizona (United States) are statistically indistinguishable. This finding refutes previous inferences that arkosic detritus of the Colton was derived from cratonic basement exposed by Laramide tectonism, and instead establishes the Cordilleran magmatic arc (which also provided sediment to the McCoy Mountains Formation) as the primary source. Given the existence of a north-south-trending drainage divide in eastern Nevada and the north-northeast direction of Laramide paleoflow throughout Arizona and southern Utah, we infer that a large river system headed in the arc of the Mojave region flowed northeast ~700 km to the Uinta Basin. Named after its source area, this Paleogene California River would have been equal in scale but opposite in direction to the modern Green River-Colorado River system, and the timing and causes of the subsequent drainage reversal are important constraints on the tectonic evolution of the Cordillera and the Colorado Plateau. © 2010 Geological Society of America.

Isotopic and elemental records of authigenic calcite from lacustrine deposits in the intraforeland basins of Utah were analyzed in an effort to reconstruct the regional paleoclimate, paleohydrology, and paleotopography of the early Cenozoic central North American Cordillera. Isotopic profiles for Paleogene Lakes Uinta, Flagstaff, and Claron show relatively large oxygen isotopic shifts that are diachronous among basins with an ∼7% decrease in δ18 Ocalcite values at ca. 45 Ma in Lake Flagstaff, an ∼5% decrease in δ18Ocalcite values between ca. 42 and 35 Ma in Lake Claron, and an ∼6% decrease in δ18Ocalcite values between ca. 44 and 43 Ma in Lake Uinta. We interpret these negative oxygen isotopic shifts to be the combined result of increased hypsometric mean elevation of basin catchments and related freshening associated with basin infilling. The basins studied also have undergone periods of intense evaporation during periods of hydrologic closure, which, for example, produced an ∼7% increase in δ18Ocalcite values in Lake Uinta beginning at ca. 51 Ma. Hydrologic closure in the Uinta Basin probably resulted from growth of local topography that diverted previously substantial inflows from low elevation regions within the foreland. This study adds to the growing body of evidence that suggests a pattern of along-strike variations in the timing of topographic development and dissection of the Cordilleran landscape during the early Cenozoic. We favor an interpretation that calls for the middle Eocene rearrangement of regional drainage patterns such that intraforeland basins that once received waters from far-flung foreland river systems became dominated by inflows of low δ18O waters from catchments with higher hypsometric mean elevations that drained the adjacent hinterland and/or basin-bounding uplifts. This drainage reorganization is analogous but subsequent to the large-scale integration of catchments in the northern Cordillera that has been recognized on the basis of isotopic and sedimentological evidence in Montana and Idaho at ca. 50-47 Ma, with rivers flowing southeast into Lake Gosiute at ca. 49 Ma and then for a time reaching Lake Uinta, causing a prominent highstand in that lake at 48.6 Ma. The negative oxygen isotopic shifts presented herein, which occurred between ca. 45 and ca. 35 Ma in the intraforeland basins of Utah, may reflect the north-to-south progression of drainage integration in the Cordillera as magmatism and related topography swept southward through the hinterland and increased the hypsometric mean of catchments that fed subjacent intraforeland basins. © 2008 Geological Society of America.

Using multiple isotope systems, we examine the complex effects of drainage reorganization in the Laramide Foreland in the context of stable isotope paleoaltimetry. Strontium, oxygen and carbon isotopic data from lacustrine carbonates formed in the southwestern Uinta Basin, Utah between the Late Cretaceous and late Middle Eocene reveal a two stage expansion in the drainage basin of Lake Uinta beginning at ~ 53 Ma culminating in the Mahogany highstand at 48.6 Ma. A marked increase in 87Sr/86Sr ratios of samples from the Main Body of the Green River Formation is interpreted as the result of water overflowing the Greater Green River Basin in Wyoming and entering Lake Uinta from the east via the Piceance Creek Basin of northwestern Colorado. This large new source of water caused a rapid expansion of Lake Uinta and was accompanied by a significant and rapid increase in the O isotope record of carbonate samples by ~ 6‰. The periodic overspilling of Lake Gosiute probably became continuous at ~ 49 Ma, when the lake captured low-δ18O water from the Challis and Absaroka Volcanic Fields to the north. However, evaporation in the Greater Green River and Piceance Creek Basins meant that the waters entering Lake Uinta were still enriched in 18O. By ~ 46 Ma, inflows from the Greater Green River Basin ceased, resulting in a lowstand of Lake Uinta and the deposition of bedded evaporites in the Saline Facies of the Green River Formation. We thus show that basin development and lake hydrology in the Laramide foreland were characterized by large-scale changes in Cordilleran drainage patterns, capable of confounding paleoaltimetry studies premised on too few isotopic systems, samples or localities. In the case of the North American Cordillera of the Paleogene, we further demonstrate the likelihood that (1) topographic evolution of distal source areas strongly influenced the isotopic records of intraforeland basins and (2) a pattern of drainage integration between the hinterland and foreland may correlate in space and time with the southward sweep of hinterland magmatism. © 2008 Elsevier B.V. All rights reserved.

Marine natural products (MNPs) continue to be tested primarily in cellular toxicity assays, both mammalian and microbial, despite most being inactive at concentrations relevant to drug discovery. These MNPs become missed opportunities and represent a wasteful use of precious bioresources. The use of cheminformatics aligned with published bioactivity data can provide insights to direct the choice of bioassays for the evaluation of new MNPs. Cheminformatics analysis of MNPs found in MarinLit ( n = 39,730) up to the end of 2023 highlighted indol-3-yl-glyoxylamides (IGAs, n = 24) as a group of MNPs with no reported bioactivities. However, a recent review of synthetic IGAs highlighted these scaffolds as privileged structures with several compounds under clinical evaluation. Herein, we report the synthesis of a library of 32 MNP-inspired brominated IGAs ( 25 - 56 ) using a simple one-pot, multistep method affording access to these diverse chemical scaffolds. Directed by a meta-analysis of the biological activities reported for marine indole alkaloids (MIAs) and synthetic IGAs, the brominated IGAs 25 - 56 were examined for their potential bioactivities against the Parkinson's Disease amyloid protein alpha synuclein (α-syn), antiplasmodial activities against chloroquine-resistant (3D7) and sensitive (Dd2) parasite strains of Plasmodium falciparum , and inhibition of mammalian (chymotrypsin and elastase) and viral (SARS-CoV-2 3CL pro ) proteases. All of the synthetic IGAs tested exhibited binding affinity to the amyloid protein α-syn, while some showed inhibitory activities against P. falciparum , and the proteases, SARS-CoV-2 3CL pro , and chymotrypsin. The cellular safety of the IGAs was examined against cancerous and non-cancerous human cell lines, with all of the compounds tested inactive, thereby validating cheminformatics and meta-analyses results. The findings presented herein expand our knowledge of marine IGA bioactive chemical space and advocate expanding the scope of biological assays routinely used to investigate NP bioactivities, specifically those more suitable for non-toxic compounds. By integrating cheminformatics tools and functional assays into NP biological testing workflows, we can aim to enhance the potential of NPs and their scaffolds for future drug discovery and development.

Background: Children with high-intensity neurologic impairment (HINI) have an increased risk of urinary tract infection (UTI) and prolonged intravenous (IV) antibiotic exposure., Objective: To determine the association between short (≤3 days) and long (>3 days) IV antibiotic courses and UTI treatment failure in hospitalized children with HINI., Methods: We performed a retrospective cohort study examining UTI hospitalizations at 49 hospitals in the Pediatric Health Information System from 2016 to 2021 for children (1-18 years) with HINI. The primary outcome was UTI readmission within 30 days. Our secondary outcome was the association of hospital-level variation in short IV antibiotic course use with readmission. Readmission rates were compared between short and long courses using multivariable regression., Results: Of 5612 hospitalizations, 3840 (68.4%) had short IV antibiotic courses. In our adjusted model, children with short IV courses were less likely than with long courses to have a 30-day UTI readmission (4.0%, 95% CI [3.6%, 4.5%] vs. 6.3%, 95% CI [5.1%, 7.8%]). Despite marked hospital-level variation in short IV course use (50.0%-87.5% of hospitalizations), there was no correlation with readmissions., Conclusions: Children with HINI hospitalized with UTI had low UTI readmission rates, but those who received long IV antibiotic courses were more likely to experience UTI readmission versus those receiving short courses. While residual confounding may influence our results, we did not find that short IV courses impacted readmission at the hospital level despite variation in use across institutions. Long IV antibiotic courses are associated with risks and may not confer benefit in this population., (© 2024 Society of Hospital Medicine.)

Synthetic efforts toward complex natural product (NP) scaffolds are useful ones, particularly those aimed at expanding their bioactive chemical space. Here, we utilised an orthogonal cheminformatics-based approach to predict the potential biological activities for a series of synthetic bis-indole alkaloids inspired by elusive sponge-derived NPs, echinosulfone A ( 1 ) and echinosulfonic acids A-D ( 2 - 5 ). Our work includes the first synthesis of desulfato-echinosulfonic acid C, an α-hydroxy bis(3'-indolyl) alkaloid ( 17 ), and its full NMR characterisation. This synthesis provides corroborating evidence for the structure revision of echinosulfonic acids A-C. Additionally, we demonstrate a robust synthetic strategy toward a diverse range of α-methine bis(3'-indolyl) acids and acetates ( 11 - 16 ) without the need for silica-based purification in either one or two steps. By integrating our synthetic library of bis-indoles with bioactivity data for 2048 marine indole alkaloids (reported up to the end of 2021), we analyzed their overlap with marine natural product chemical diversity. Notably, the C-6 dibrominated α-hydroxy bis(3'-indolyl) and α-methine bis(3'-indolyl) analogues ( 11 , 14 , and 17 ) were found to contain significant overlap with antibacterial C-6 dibrominated marine bis-indoles, guiding our biological evaluation. Validating the results of our cheminformatics analyses, the dibrominated α-methine bis(3'-indolyl) alkaloids ( 11 , 12 , 14 , and 15 ) were found to exhibit antibacterial activities against methicillin-sensitive and -resistant Staphylococcus aureus . Further, while investigating other synthetic approaches toward bis-indole alkaloids, 16 incorrectly assigned synthetic α-hydroxy bis(3'-indolyl) alkaloids were identified. After careful analysis of their reported NMR data, and comparison with those obtained for the synthetic bis-indoles reported herein, all of the structures have been revised to α-methine bis(3'-indolyl) alkaloids.

A bisphosphonate recently isolated from Tropaeolum tuberosum is almost certainly a contaminant and not a genuine natural product.

Covering: January to the end of December 2022This review covers the literature published in 2022 for marine natural products (MNPs), with 645 citations (633 for the period January to December 2022) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, the submerged parts of mangroves and other intertidal plants. The emphasis is on new compounds (1417 in 384 papers for 2022), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. An analysis of NP structure class diversity in relation to biota source and biome is discussed.

We examined associations between a validated, multidimensional measure of social determinants of health and population-based hospitalization rates among children <18 years across 18 states from the 2017 Healthcare Cost and Utilization Project State Inpatient Databases and the US Census. The exposure was ZIP code-level Child Opportunity Index (COI), a composite measure of neighborhood resources and conditions that matter for children's health. The cohort included 614,823 hospitalizations among a population of 29,244,065 children (21.02 hospitalizations per 1000). Adjusted hospitalization rates decreased significantly and in a stepwise fashion as COI increased (p < .001 for each), from 26.56 per 1000 (95% confidence interval [CI] 26.41-26.71) in very low COI areas to 14.76 per 1000 (95% CI 14.66-14.87) in very high COI areas (incidence rate ratio 1.8; 95% CI 1.78-1.81). Decreasing neighborhood opportunity was associated with increasing hospitalization rates among children in 18 US states. These data underscore the importance of social context and community-engaged solutions for health systems aiming to eliminate care inequities., (© 2023 Society of Hospital Medicine.)

NMR fingerprints are valuable tools for analyzing complex natural product mixtures and identifying incorrectly assigned structures in the literature. Our diagnostic NMR fingerprints for formyl phloroglucinol meroterpenoids revealed discrepancies in the structures reported for eucalyprobusal C ( 1a ) and eucalypcamal K ( 2a ). NMR fingerprinting PCA analyses identified 1a as an oxepine-diformyl phloroglucinol and 2a as an oxepine 3-acyl-1-formyl phloroglucinol, contrary to their initial assignments as pyrano-diformyl and pyrano 3-acyl-1-formyl phloroglucinols, respectively. Extensive reinterpretation of their reported one- and two-dimensional NMR data, coupled with GIAO DFT-calculated 1 H and 13 C NMR chemical shift and DP4+ analyses, supported the unequivocal reassignment of eucalyprobusal C to 1b and eucalypcamal K to 2b . The absolute configurations of the revised oxepine-containing phloroglucinol meroterpenoids were confirmed via the reinterpretation of their reported ROESY and NOESY NMR data, along with comparative TDDFT-calculated and experimental ECD spectra.

Importance: Inadequate communication between caregivers and clinicians at hospital discharge contributes to medication dosing errors in children. Health literacy-informed communication strategies during medication counseling can reduce dosing errors but have not been tested in the pediatric hospital setting., Objective: To test a health literacy-informed communication intervention to decrease liquid medication dosing errors compared with standard counseling in hospitalized children., Design, Setting, and Participants: This parallel, randomized clinical trial was performed from June 22, 2021, to August 20, 2022, at a tertiary care, US children's hospital. English- and Spanish-speaking caregivers of hospitalized children 6 years or younger prescribed a new, scheduled liquid medication at discharge were included in the analysis., Interventions: Permuted block (n = 4) randomization (1:1) to a health literacy-informed discharge medication communication bundle (n = 99) compared with standard counseling (n = 99). A study team member delivered the intervention consisting of a written, pictogram-based medication instruction sheet, teach back (caregivers state information taught), and demonstration of dosing with show back (caregivers show how they would draw the liquid medication in the syringe)., Main Outcome and Measures: Observed dosing errors, assessed using a caregiver-submitted photograph of their child's medication-filled syringe and expressed as the percentage difference from the prescribed dose. Secondary outcomes included caregiver-reported medication knowledge. Outcome measurements were blinded to participant group assignment., Results: Among 198 caregivers randomized (mean [SD] age, 31.4 [6.5] years; 186 women [93.9%]; 36 [18.2%] Hispanic or Latino and 158 [79.8%] White), the primary outcome was available for 151 (76.3%). The observed mean (SD) percentage dosing error was 1.0% (2.2 percentage points) among the intervention group and 3.3% (5.1 percentage points) among the standard counseling group (absolute difference, 2.3 [95% CI, 1.0-3.6] percentage points; P < .001). Twenty-four of 79 caregivers in the intervention group (30.4%) measured an incorrect dose compared with 39 of 72 (54.2%) in the standard counseling group (P = .003). The intervention enhanced caregiver-reported medication knowledge compared with the standard counseling group for medication dose (71 of 76 [93.4%] vs 55 of 69 [79.7%]; P = .03), duration of administration (65 of 76 [85.5%] vs 49 of 69 [71.0%]; P = .04), and correct reporting of 2 or more medication adverse effects (60 of 76 [78.9%] vs 13 of 69 [18.8%]; P < .001). There were no differences in knowledge of medication name, indication, frequency, or storage., Conclusions and Relevance: A health literacy-informed discharge medication communication bundle reduced home liquid medication administration errors and enhanced caregiver medication knowledge compared with standard counseling. Routine use of these standardized strategies can promote patient safety following hospital discharge., Trial Registration: ClinicalTrials.gov Identifier: NCT05143047.

Background and Objectives: Children hospitalized with a mental health crisis often receive pharmacologic restraint for management of acute agitation. We examined associations between pharmacologic restraint use and race and ethnicity among children admitted for mental health conditions to acute care nonpsychiatric children's hospitals., Methods: We performed a retrospective cohort study of children (aged 5-≤18 years) admitted for a primary mental health condition from 2018 to 2022 at 41 US children's hospitals. Pharmacologic restraint use was defined as parenteral administration of medications for acute agitation. The association of race and ethnicity and pharmacologic restraint was assessed using generalized linear multivariable mixed models adjusted for clinical and demographic factors. Stratified analyses were performed based on significant interaction analyses between covariates and race and ethnicity., Results: The cohort included 61 503 hospitalizations. Compared with non-Hispanic Black children, children of non-Hispanic White (adjusted odds ratio [aOR], 0.81; 95% confidence interval [CI], 0.72-0.92), Asian (aOR, 0.82; 95% CI, 0.68-0.99), or other race and ethnicity (aOR, 0.68; 95% CI, 0.57-0.82) were less likely to receive pharmacologic restraint. There was no significant difference with Hispanic children. When stratified by sex, racial/ethnic differences were magnified in males (aORs, 0.49-0.68), except for Hispanic males, and not found in females (aORs, 0.83-0.93). Sensitivity analysis revealed amplified disparities for all racial/ethnic groups, including Hispanic youth (aOR, 0.65; 95% CI, 0.47-0.91)., Conclusions: Non-Hispanic Black children were significantly more likely to receive pharmacologic restraint. More research is needed to understand reasons for these disparities, which may be secondary to implicit bias and systemic and interpersonal racism., (Copyright © 2024 by the American Academy of Pediatrics.)

Covering: marine indole alkaloids ( n = 2048) and their reported bioactivities up to the end of 2021Despite increasing numbers of marine natural products (MNPs) reported each year, most have only been examined for cytotoxic, antibacterial, and/or antifungal biological activities with the majority found to be inactive in these assays. In this context, why are natural products continuing to be examined in assays they are unlikely to show significant activity in, and what targets might be more useful for expanding knowledge of their biologically relevant chemical space? We have undertaken a meta-analysis of the biological activities for 2048 marine indole alkaloids (MIAs), a diverse sub-class of MNPs reported up to the end of 2021, and this has highlighted that the bioactivity potentials for up to 86% of published MIAs remains underexplored and/or undefined. Although most published MIAs are not cytotoxic or antimicrobial, there is a continued focus on using these assays to evaluate new structurally related analogues. Using cheminformatics analyses, the chemical diversity of the 2048 MIAs were clustered using fragment based fingerprints and their reported bioactivity potency towards specific disease targets was assessed for structure activity trends. These analyses showed that there are groups of MIAs that possess potent and diverse activities and that many analogues, previously tested only in cellular toxicity assays, could be better exploited to generate structure activity relationships associated with leads to treat emerging diseases. A collection of indole drug and drug-lead structures from non-natural sources were also incorporated into the dataset providing complementary bioactivity profiles that were further used to predict underexplored areas of potential new activity and to better direct future testing of MIAs. Our findings clearly suggest the biological evaluation of MIAs continues to be conducted on a narrow range of bioassays and disease targets, and that shifting the focus to non-toxic disease targets should provide expanded knowledge of biologically relevant chemical space aimed at maximising the potential of MIAs for drug discovery.

Six new thiazole-containing cyclic peptides, the cyclotheonellazoles D-I ( 1 - 6 ), were isolated from the Australian marine sponge Theonella sp. (2131) with their structures assigned by comprehensive 1D and 2D NMR spectroscopic and MS spectrometric analyses, Marfey's derivatization studies, and comparison with time-dependent density functional theory (TDDFT) calculated ECD data. The Type 2 azole-homologated peptides herein comprise up to five nonproteinogenic amino acids, including the protease transition state mimic α-keto-β-amino acid residue 3-amino-4-methyl-2-oxohexanoic acid (Amoha), while 1 - 3 also contain a terminal hydantoin residue not previously found in cyclotheonellazoles. The keramamides A ( 7 ) and L ( 8 ) were reisolated affording expanded exploration of their biological activities. The peptides were examined for protease inhibitory activities against two mammalian serine proteases (elastase and chymotrypsin) and SARS-CoV-2 3-chymotrypsin-like protease (3CL pro ), a validated antiviral therapeutic target for COVID-19. Peptides 1 - 6 and keramamide A ( 7 ) displayed potent nanomolar inhibition of elastase (IC 50 16.0 to 61.8 nM), while 7 also contained modest inhibition of chymotrypsin and SARS-CoV-2 3CL pro (IC 50 0.73 and 1.1 μM, respectively). The cyclotheonellazoles D-E ( 1 - 3 ) do not affect the viability of human breast, ovarian, and colon cancer cells (>100 μM), with the cytotoxicity previously reported for keramamide L ( 8 ) not replicated (inactive >20 μM).

Amyloid protein aggregates are linked to the progression of neurodegenerative conditions and may play a role in life stages of Plasmodium falciparum , the parasite responsible for malaria. We hypothesize that amyloid protein aggregation inhibitors may show antiplasmodial activity and vice versa. To test this hypothesis, we screened antiplasmodial active extracts from 25 Australian eucalypt flowers using a binding affinity mass spectrometry assay to identify molecules that bind to the Parkinson's disease-implicated protein α-syn. Myrtucommulone P ( 1 ) from a flower extract of Eucalyptus cloeziana was shown to have α-syn affinity and antiplasmodial activity and to inhibit α-syn aggregation. 1 exists as a mixture of four interconverting rotamers. Assignment of the NMR resonances of all four rotamers allowed us to define the relative configuration, conformations, and ratios of rotamers in solution. Four additional new compounds, cloeziones A-C ( 2 - 4 ) and cloeperoxide ( 5 ), along with three known compounds were also isolated from E. cloeziana . The structures of all compounds were elucidated using HRMS and NMR analysis, and the absolute configurations for 2 - 4 were determined by comparison of TDDFT-calculated and experimental ECD data. Compounds 1 - 3 displayed antiplasmodial activities between IC 50 6.6 and 16 μM. The α-syn inhibitory and antiplasmodial activity of myrtucommulone P ( 1 ) supports the hypothesized link between antiamyloidogenic and antiplasmodial activity.

Three new bis-formyl phloroglucinol-meroterpenoids ( 1 - 3 ), three new euglobal type formyl phloroglucinol-meroterpenoids ( 4 - 6 ), and one new dimeric formyl phloroglucinol ( 7 ) were isolated from the leaves of Eucalyptus camaldulensis . Camaldulensal A ( 1 ) is the first bis-isovaleryl-formyl-phloroglucinol-sesquiterpenoid. It features a novel 6/6/10/3/6/6 fused ring system and contains six stereogenic centers. Camaldulensals B ( 2 ) and C ( 3 ) are the first bis-isovaleryl-formyl-phloroglucinols, each conjugated to a monoterpene. Formyl phloroglucinol compounds (FPCs) containing two spatially separated formyl phloroglucinols conjugated to a terpene core such as 1 - 3 have not been reported previously. The structures of these compounds were elucidated by spectroscopic methods and computational analysis. Camaldulensals B ( 2 ) and C ( 3 ) exhibited significant antibacterial activity against methicillin-susceptible and methicillin-resistant Staphylococcus aureus . Structure activity relationships are discussed in relation to previously reported antibacterial activities of other molecules from the FPC structure class.

The early Eocene Climatic Optimum (EECO) represents the peak of Earth's last sustained greenhouse climate interval. To investigate hydroclimate variability in western North America during the EECO, we developed an orbitally resolved leaf wax δ 2 H record from one of the most well-dated terrestrial paleoclimate archives, the Green River Formation. Our δ 2 H wax results show ∼60‰ variation and evidence for eccentricity and precession forcing. iCESM simulations indicate that changes in the Earth's orbit drive large seasonal variations in precipitation and δ 2 H of precipitation at our study site, primarily during the summer season. Our findings suggest that the astronomical response in δ 2 H wax is attributable to an asymmetrical climate response to the seasonal cycle, a "clipping" of precession forcing, and asymmetric carbon cycle dynamics, which further enhance the influence of eccentricity modulation on the hydrological cycle during the EECO. More broadly, our study provides an explanation for how and why eccentricity emerges as a dominant frequency in climate records from ice-free greenhouse worlds.

NMR fingerprints provide powerful tools to identify natural products in complex mixtures. Principal component analysis and machine learning using 1 H and 13 C NMR data, alongside structural information from 180 published formyl phloroglucinols, have generated diagnostic NMR fingerprints to categorize subclasses within this group. This resulted in the reassignment of 167 NMR chemical shifts ascribed to 44 compounds. Three pyrano-diformyl phloroglucinols, euglobal In-1 and psiguadiols E and G, contained 1 H and 13 C NMR data inconsistent with their predicted phloroglucinol subclass. Subsequent reinterpretation of their 2D NMR data combined with DFT 13 C NMR chemical shift and ECD calculations led to their structure revisions. Direct covariance processing of HMBC data permitted 1 H resonances for individual compounds in mixtures to be associated, and analysis of their 1 H/ 13 C HMBC correlations using the fingerprint tool further classified components into phloroglucinol subclasses. NMR fingerprinting HMBC data obtained for six eucalypt flower extracts identified three subclasses of pyrano-acyl-formyl phloroglucinols from Eucalyptus gittinsii subsp. gittinsii . New, eucalteretial F and (+)-eucalteretial B, and known, (-)-euglobal VII and eucalrobusone C, compounds, each belonging to predicted subclasses, were isolated and characterized. Staphylococcus aureus and Plasmodium falciparum screening revealed eucalrobusone C as the most potent antiplasmodial formyl phloroglucinol to date.

Objectives: Children are at increased risk for medication errors and the transition from hospital-to-home is a vulnerable time for errors to occur. This study aimed to explore the perspectives of multidisciplinary clinicians and caregivers regarding discharge medication counseling and to develop a conceptual model to inform intervention efforts to reduce discharge medication dosing errors., Methods: We conducted semistructured interviews with clinicians and caregivers of children <4 years old discharged from the hospital on a liquid medication. A hierarchical coding system was developed using the interview guide and several transcripts. Qualitative analysis employed an iterative inductive-deductive approach to identify domains and subthemes and inform a conceptual framework., Results: We conducted focus groups and individual interviews with 17 caregivers and 16 clinicians. Using the Donabedian structure-process-outcomes model of quality evaluation, domains and subthemes included: (1) infrastructure of healthcare delivery, including supplies for counseling, content and organization of discharge instructions, clinician training and education, roles and responsibilities of team members, and hospital pharmacy delivery and counseling program; (2) processes of healthcare delivery, including medication reconciliation, counseling content, counseling techniques, and language barriers and health literacy; and (3) measurable outcomes, including medication dosing accuracy and caregiver understanding and adherence to discharge instructions., Conclusions: The conceptual model resulting from this analysis can be applied to the development and evaluation of interventions to reduce discharge medication dosing errors following a hospitalization. Interventions should use a health literacy universal precautions approach-written materials with plain language and pictures and verbal counseling with teach-back and show-back., (Copyright © 2023 by the American Academy of Pediatrics.)

Background: Penicillin (PCN) allergy labels are widely recognized to be highly inaccurate. Little is known about parental perceptions of the PCN allergy evaluation and removal process, especially in the hospital setting., Methods: Focus groups were held with parents of children and adolescents with a PCN allergy label discharged from a large academic children's hospital between January 1, 2019, and April 15, 2020. The open-ended, semistructured moderator guide included questions about PCN allergy testing and evaluation, accuracy of the PCN allergy diagnosis, amoxicillin oral challenges, delabeling process, and preferred setting for PCN allergy delabeling evaluation (outpatient clinic, hospital, etc). Study investigators coded the transcripts and identified underlying themes using inductive and deductive thematic analysis., Results: A total of 21 parents and 2 adolescents participated across 4 focus groups. We developed a theoretical framework depicting key elements of parents' and adolescents' experiences with PCN allergies, consisting of 4 major interconnected themes: (1) family context; (2) the invitation to delabel; (3) decision context; and (4) the PCN delabeling outcome. PCN allergies remained a concern for families even if their children passed an oral challenge. Some parents preferred testing to be performed in the hospital and felt this was a safer location for the procedure., Conclusions: Parents are amenable to hospital based PCN allergy evaluation and delabeling. Further studies should incorporate parental and patient preferences to implement safe and effective PCN allergy delabeling processes in the hospital setting., (Copyright © 2023 by the American Academy of Pediatrics.)

The aggregation of the neuronal protein α-synuclein (α-syn) is intrinsically linked to the development and progression of Parkinson's disease (PD). Recently we screened the MeOH extracts from 283 marine invertebrates for α-syn binding activity using an affinity mass spectrometry (MS) binding assay and found that the extract of the ascidian Polycarpa procera displayed activity. A subsequent bioassay-guided purification led to the isolation of one new α-syn aggregation inhibitory butenolide procerolide E ( 3 ) and one new α-syn aggregation inhibitory diphenylbutyrate methyl procerolate A ( 5 ). Herein we report the structure elucidation of procerolide E ( 3 ) and methylprocerolate A ( 5 ) and α-syn aggregation inhibitory activity of procerolides C-E ( 1 - 3 ), methyl procerolate A ( 5 ) and procerone A ( 4 ). We also report the α-syn binding activity of 3-bromo-4-methoxyphenylacetamide ( 6 ) and a synthetic butenolide library, which has allowed us to determine α-syn aggregation inhibitory structure-activity relationships for this class of compounds.

Bioassay-guided investigation of the sponge Aaptos lobata resulted in the isolation and identification of two new amphiphilic polyamines, aaptolobamines A ( 1 ) and B ( 2 ). Their structures were determined through analysis of NMR and MS data. MS analysis also indicated that A. lobata contained a complex mixture of aaptolobamine homologues. Both aaptolobamines A ( 1 ) and B ( 2 ) show broad bioactivity, including cytotoxicity against cancer cell lines, moderate antimicrobial activity against a methicillin-resistant strain of Staphylococcus aureus , and weak activity against a Pseudomonas aeruginosa strain. The mixtures of aaptolobamine homologues were shown to contain compounds that bind to the Parkinson's disease associated amyloid protein α-synuclein and inhibit its aggregation.

Covering: January to December 2021This review covers the literature published in 2021 for marine natural products (MNPs), with 736 citations (724 for the period January to December 2021) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1425 in 416 papers for 2021), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. An analysis of the number of authors, their affiliations, domestic and international collection locations, focus of MNP studies, citation metrics and journal choices is discussed.

Background: Children in mental health crises are increasingly admitted to children's hospitals awaiting inpatient psychiatric placement. During hospitalization, patients may exhibit acute agitation prompting pharmacologic restraint use., Objective: To determine hospital-level incidence and variation of pharmacologic restraint use among children admitted for mental health conditions in children's hospitals., Design, Setting, and Participants: We examined data for children (5 to ≤18 years) admitted to children's hospitals with a primary mental health condition from 2018 to 2020 using the Pediatric Health Information System database. Hospital rates of parenteral pharmacologic restraint use per 1000 mental health bed days were determined and compared after adjusting for patient-level and demographic factors. Cluster analysis (k-means) was used to group hospitals based on overall restraint use (rate quartiles) and drug class. Hospital-level factors for pharmacologic restraint use were compared., Results: Of 29,834 included encounters, 3747 (12.6%) had pharmacologic restraint use. Adjusted hospital rates ranged from 35 to 389 pharmacologic restraint use days per 1000 mental health bed days with a mean of 175 (standard deviation: 72). Cluster analysis revealed three hospitals were high utilizers of all drug classes. No significant differences in pharmacologic restraint use were found in the hospital-level analysis., Conclusions: Children's hospitals demonstrate wide variation in pharmacologic restraint rates for mental health hospitalizations, with a 10-fold difference in adjusted rates between highest and lowest utilizers, and high overall utilizers order medications across all drug classes., (© 2022 Society of Hospital Medicine.)

Given their threatened status, there is considerable interest in establishing monitoring techniques that can be used to evaluate the health of sea turtles in the wild. The present study represents a methodological contribution towards field-scale metabolomic assessment of sea turtles, by exploring differences in blood biochemistry associated with site characteristics and capture technique. We compared the metabolome of blood from animals at three locations (two coastal and one reefal), collected from turtles that were either resting or active, and sampled across multiple seasons at one location. Our results show clear differences in the metabolome of turtles from the three locations, some of which are likely attributable to differences in diet or forage quality and others which may reflect differences in other factors (e.g., occurrence of land-based contaminants or other biotic and/or abiotic stressors) between coastal and reefal sites. Our analysis also revealed the influence of capture technique on metabolite profiles, with numerous markers of physical exertion in animals captured while active that were absent in turtles sampled while resting. We observed a modest potential for temporal differences in the metabolome, but controlling for sampling time did not change the overall conclusions of our study. This suggests that temporal differences in the metabolome warrant consideration when designing studies to evaluate the status of sea turtles in the wild, but that site characteristics and capture technique are bigger drivers. However, sample size for this comparison was relatively small and further investigation of seasonal differences in the metabolome are warranted. Research exploring each of these factors more closely will further contribute towards achieving robust metabolomics analysis of sea turtles across large spatial and temporal scales., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A new aryl dihydronaphthalene lignan, echiumin E ( 1 ), and four known compounds, echiumin A, globoidnan A, (-)-rabdosiin, and rosmarinic acid ( 2 - 5 ), were isolated from the Australian invasive plant Echium plantagineum (Paterson's curse) for the first time. Echiumin E ( 1 ) was characterized by 1D/2D NMR spectroscopy and MS spectrometry, with its absolute configuration assigned through comparison of experimental and TDDFT-calculated ECD data. Echiumin E ( 1 ) along with compounds 3 - 5 were screened in vitro against three cancer cell lines (SH-SY5Y, HeLa, and PC-3) and a prostate stromal (normal) cell line (WPMY-1) using a resazurin reduction assay. Echiumin E ( 1 ) was found to be active toward HeLa cells (IC 50 0.21 μM).

Successful publication of quality improvement (QI) work is predicated on the use of established QI frameworks and rigorous analytical methods that allow teams to understand the impact of interventions over time. This article is meant to help QI teams disseminate their work more broadly through publication by providing tangible methods that many journals desire in QI articles with specific examples of published works referenced throughout the article. We introduce improvement frameworks that teams should identify early and use as a foundation throughout their projects. We review vital aspects of QI projects, such as team formation, creation of a succinct and clear aim statement, defining primary, process, and balancing measures, as well as QI tools like key driver diagrams, Ishikawa (fishbone) diagrams, and Pareto charts. Finally, we highlight the importance of analyzing data over time to understand the impacts of plan-do-study-act cycles on data. Annotated run charts or, more preferably, annotated statistical process control (or Shewhart) charts are both statistically sound methods to identify significant changes over time. Deliberate planning and execution of QI projects using these concepts will lead to improved chances of QI teams finding success in their project and eventual article acceptance., (Copyright © 2022 by the American Academy of Pediatrics.)

The concentration of coloured terrestrial dissolved organic matter (tDOM) from vegetation appears to be increasing in lakes in some regions of the world, leading to the term brownification. The light attenuating effect of coloured tDOM on phytoplankton growth has been a major focus of attention, but the phytotoxic effects of tDOM, particularly on cyanobacterial blooms, are less well understood. This mesocosm study tested whether coloured tDOM, leached from the leaves of a Eucalyptus tree species, inhibited a naturally occurring bloom of the toxic cyanobacterium, Raphidiopsis raciborskii, in a reservoir over a 10 day period. The study found that tDOM leachate, measured as dissolved organic carbon (DOC), inhibited photosynthesis and growth of both R. raciborskii, as well as species present at lower densities, i.e. other cyanobacteria and diatoms. However, the effect was greater at higher tDOM input loads. The photosynthetic yield (Fv/Fm) of cyanobacteria decreased rapidly in treatments with 5.9 and 25 mg L -1 DOC addition, compared to the control (reservoir water with background DOC concentration of 6.85 ± 1.09 mg L -1 ). tDOM had no measurable effect in the 2 and 3.3 mg L -1 DOC addition treatments. By day 5, cell densities of cyanobacteria, including R. raciborskii, and diatoms, in treatments with 5.9 and 25 mg L -1 DOC addition were significantly lower than the control with no tDOM addition, and this effect continued throughout the experiment. This is despite the leachate addition increasing phosphate concentrations which counteracted the low background concentrations of phosphate. Light attenuation and dissolved oxygen (DO) levels were also affected by the tDOM addition, but were only significantly lower in the 25 mg L -1 DOC treatment compared with the control. DOC, dissolved organic nitrogen (DON) and dissolved organic phosphorus (DOP) concentrations all decreased in the tDOM addition treatments over the first 3 days, as the microbial cell densities increased. The components of the tDOM that decreased over time were determined by 1 H NMR spectroscopy in the 25 mg L -1 DOC treatment. After 5 d, the relative concentrations of fatty acids, sugars and gallic acid decreased by around 60%, while concentrations of flavonoids and myo-inositol decreased by 45 and 35% respectively. This study suggests that phytotoxic compounds in tDOM can suppress cyanobacterial blooms, despite the increased nutrient inputs. This has implications for predicting the future likelihood of cyanobacterial blooms in lakes and reservoirs with climate-change driven changes in flow events, and other changes in the amount and types of vegetation cover. Revegetation of riparian zones, resulting in increased tDOM into waterways, may also be beneficial in reducing cyanobacterial blooms., (Copyright © 2022. Published by Elsevier B.V.)

Covering: 2020This review covers the literature published in 2020 for marine natural products (MNPs), with 757 citations (747 for the period January to December 2020) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1407 in 420 papers for 2020), together with the relevant biological activities, source organisms and country of origin. Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included. A meta analysis of bioactivity data relating to new MNPs reported over the last five years is also presented.

Preventing the aggregation of certain amyloid proteins has the potential to slow down the progression of diseases like Alzheimer's, Parkinson's, and type 2 diabetes mellitus. During a high-throughput screen of 300 Australian marine invertebrate extracts, the extract of the marine sponge Thorectandra sp. 4408 displayed binding activity to the Parkinson's disease-associated protein, α-synuclein. Isolation of the active component led to its identification as the known plant growth promoter asterubine (1). This molecule shares distinct structural similarities with potent amyloid beta aggregation inhibitors tramiprosate (homotaurine) and ALZ-801. Herein we report the isolation, NMR data acquired in DMSO and α-synuclein binding activity of asterubine (1)., (Copyright © 2022 Elsevier Ltd. All rights reserved.)