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Background: The incidence of cerebral white matter damage reported to the Australian and New Zealand Neonatal Network (ANZNN) varies between neonatal intensive care units (NICUs). Hypothesis: Differences in the capture, storage, and interpretation of the cerebral ultrasound scans could account for some of this variation. Methods: A total of 255 infants of birth weight <1500 g and gestation <32 weeks born between 1997 and 2002 and drawn equally from each of the six NICUs in New Zealand were randomly selected from the ANZNN database. Half had early cerebral ultrasound scans previously reported to ANZNN as normal, and half had scans reported as abnormal. The original scans were copied, anonymised, and independently read by a panel of three experts using a standardised method of reviewing and reporting. Results: There was considerable variation between NICUs in methods of image capture, quality, and completeness of the scans. There was only moderate agreement between the reviewers' reports and the original reports to the ANZNN (kappa 0.45-0.51) and between the reviewers (kappa 0.54-0.64). The reviewers reported three to six times more white matter damage than had been reported to the ANZNN. Conclusion: Some of the reported variation in white matter damage between NICUs may be due to differences in capture and interpretation of cerebral ultrasound scans. [ABSTRACT FROM AUTHOR]

Background: We evaluated the effect of weight loss (WL) or aerobic exercise (AEX) on pulmonary function in middle-aged and older (46-80 years) obese, sedentary men to determine the effect of reductions in body weight and increases in cardiorespiratory fitness on pulmonary function.Methods: Subjects were randomly assigned to WL (n = 73), AEX (n = 71), or control (n = 26) groups. Maximal oxygen uptake (VO2max), body composition and anthropometrics, pulmonary function, and arterial blood gases were measured at baseline and after interventions.Results: The 35 subjects who completed WL decreased weight by 11%, body fat percentage by 21% (p < .001), waist circumference by 8%, waist-hip ratio by 2%, and fat-free mass by 3% (p < .05). This resulted in a 3% increase in forced vital capacity (FVC) (4.08 +/- 0.71 L vs 4.21 +/- 0.76 L), a 5% increase in total lung capacity (6.62 +/- 0.99 L vs 6.94 +/- 0.99 L), an 18% increase in functional residual capacity (3.09 +/- 0.58 L vs 3.66 +/- 0.79 L), and an 8% increase in residual volume (2.20 +/- 0.44 L vs 2.37 +/- 0.52 L), with no change in forced expiratory volume in one second (FEV1), FEV1/FVC ratio, or carbon monoxide diffusing capacity. The change in FVC correlated with change in body weight (r = -.34, p < .05). The 38 subjects who completed AEX increased VO2max by 14%, with no change in pulmonary function. There were no changes in 8 control subjects.Conclusions: WL changes static lung volumes, not dynamic pulmonary function, in middle-aged and older, moderately obese, sedentary men. Some of the alterations in static lung function associated with aging may be due to the development of obesity and are modifiable by WL. [ABSTRACT FROM AUTHOR]

Objective: The Glucose in Well Babies (GLOW) Study showed that there are two phases of low glucose concentrations in healthy newborn infants: an initial phase in which plasma concentrations of ketones are low; and a second phase in which low glucose concentrations are accompanied by elevated concentrations of ketones. The implications of these two phases for the brain differ depending on whether ketones are available as alternative substrate for brain metabolism. The purpose of this study was to estimate the duration of these two phases of neonatal low glucose concentrations in 66 healthy breastfed newborns from the GLOW Study during the first 5 days of life., Methods: The sum of glucose and beta-hydroxybutyrate (BOHB) was used as a proxy for the total concentrations of insulin-dependent fuels for the brain; a threshold value below 4 mmol/L was taken to indicate the presence of relative hyperinsulinism and a BOHB concentration above 0.5 mmol/L to indicate ketonaemia., Results: The first phase of low glucose concentrations lasted a median of 40 hours and in 15% of infants, this persisted beyond 60 hours. Fifty (76%) of the 66 infants subsequently had ketonaemia, which resolved at a median age of 76 hours (range 41->120 hours)., Conclusions: These data suggest that monitoring BOHB concentrations may be useful for interpreting glucose concentrations in newborns and screening for persistent hyperinsulinism., Competing Interests: Competing interests: DDDL has received consulting fees from Zealand Pharma, Crinetics Pharmaceuticals, Hanmi Pharmaceuticals, Eiger Pharma, Twist Biosciences and Rhythm Pharmaceuticals; has received research funding from Zealand Pharma, Rezolute, Crinetics Pharmaceuticals, Hanmi Pharmaceuticals, Twist Biosciences, Eiger Pharma and Ultragenyx for studies not discussed in this manuscript. CAS serves on the Data and Safety Monitoring Board for Zealand Pharma clinical trials in hyperinsulinism. DDDL and CAS serve on the Scientific Advisory Board for Congenital Hyperinsulinism International., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Benzalkonium chloride (BAK) is a commonly used preservative to maintain sterility for multiuse eye drops such as latanoprost. One option to minimize the deleterious effects of BAK in eye drops may be to reduce the volume administered. The aim of this study was to assess the response of cells from the ocular surface to latanoprost+BAK administered by the Optejet technology, which dispenses a microdose (∼8 µL) ophthalmical spray. Methods: Cultured human conjunctival epithelial cells were exposed to the following treatments: (1) no treatment, (2) drop form of latanoprost without BAK (∼35 µL), (3) drop form of latanoprost with 0.01% BAK (∼35 µL), (4) ophthalmical spray form of latanoprost with 0.01% BAK delivered by the Optejet technology (∼8 µL). After 5 h, cells were assessed for changes in cytotoxicity, morphology, and inflammatory marker expression. Results: Latanoprost+BAK delivered by a drop induced cytotoxicity, cytoplasmic shrinkage, and loss of cell-cell contact, and expression of chemokine (C-C motif) ligand 2 and interleukin-6. In contrast, latanoprost+BAK delivered by the Optejet technology was both well tolerated and similar to no treatment controls and BAK-free latanoprost treatment. Conclusions: A microdose of latanoprost+BAK ophthalmical spray administered with the Optejet technology prevented the cytotoxicity associated with larger volumes found in eye drops. Precision dosing by the Optejet technology has the potential to decrease ocular surface disorder typically associated with eye drops containing preservatives.

The Fusarium head blight (FHB) pathogen Fusarium graminearum produces the trichothecene mycotoxin deoxynivalenol and reduces wheat yield and grain quality. Spring wheat ( Triticum aestivum ) genotype CB037 was transformed with constitutive expression (CE) constructs containing sorghum ( Sorghum bicolor ) genes encoding monolignol biosynthetic enzymes caffeoyl coenzyme A (CoA) 3- O -methyltransferase ( SbCCoAOMT ), 4-coumarate-CoA ligase ( Sb4CL ), or coumaroyl shikimate 3-hydroxylase ( SbC3'H ) or monolignol pathway transcriptional activator SbMyb60 . Spring wheats were screened for type I (resistance to initial infection, using spray inoculations) and type II (resistance to spread within the spike, using single-floret inoculations) resistances in the field (spray) and greenhouse (spray and single floret). Following field inoculations, disease index, percentage of Fusarium -damaged kernels (FDK), and deoxynivalenol measurements of CE plants were similar to or greater than those of CB037. For greenhouse inoculations, the area under the disease progress curve (AUDPC) and FDK were determined. Following screens, focus was placed on two each of SbC3'H and SbCCoAOMT CE lines because of trends toward a decreased AUDPC and FDK observed following single-floret inoculations. These four lines were as susceptible as CB037 following spray inoculations. However, single-floret inoculations showed that these CE lines had a significantly reduced AUDPC ( P < 0.01) and FDK ( P ≤ 0.02) compared with CB037, indicating improved type II resistance. None of these CE lines had increased acid detergent lignin compared with CB037, indicating that lignin concentration may not be a major factor in FHB resistance. The SbC3'H and SbCCoAOMT CE lines are valuable for investigating phenylpropanoid-based resistance to FHB., Competing Interests: The author(s) declare no conflict of interest.

Introduction: We sought to investigate if the availability of cerebral fuels soon after birth in healthy term babies was associated with developmental progress at 3 years of age., Methods: Healthy term babies had plasma glucose, lactate, and beta-hydroxybutyrate concentrations measured over the first 5 days. At 3 years, parents completed Ages and Stages (ASQ-3) questionnaires between December 2018 and August 2022. Developmental progress, analysed using structural equation modelling, was compared between children whose median fuel concentrations were above and below the mean neonatal concentrations of glucose (3.3 mmol/L) and total ATP-equivalents (140 mmol/L) in the first 48 h and over the first 5 days., Results: Sixty-four (96%) families returned completed questionnaires. We found no differences between developmental progress in children who had median neonatal plasma glucose concentrations &lt;3.3 or ≥3.3 mmol/L in the first 48 h (estimated mean difference in ASQ scores -1.0, 95% confidence interval: -5.8, 3.7, p = 0.66) or 120 h (-3.7, -12.0, 4.6, p = 0.39]). There were also no differences for any other measures of cerebral fuels including total ATP above and below the median over 48 and 120 h, any plasma or interstitial glucose concentration &lt;2.6 mmol/L, or cumulative duration of interstitial glucose concentration &lt;2.6 mmol/L., Conclusions: There was no detectable relationship between plasma concentrations of glucose, lactate, and beta-hydroxybutyrate soon after birth in healthy term babies and developmental progress at 3 years of age., (© 2024 S. Karger AG, Basel.)

Introduction: The U. S. Environmental Protection Agency's Endocrine Disruptor Screening Program (EDSP) Tier 1 assays are used to screen for potential endocrine system-disrupting chemicals. A model integrating data from 16 high-throughput screening assays to predict estrogen receptor (ER) agonism has been proposed as an alternative to some low-throughput Tier 1 assays. Later work demonstrated that as few as four assays could replicate the ER agonism predictions from the full model with 98% sensitivity and 92% specificity. The current study utilized chemical clustering to illustrate the coverage of the EDSP Universe of Chemicals (UoC) tested in the existing ER pathway models and to investigate the utility of chemical clustering to evaluate the screening approach using an existing 4-assay model as a test case. Although the full original assay battery is no longer available, the demonstrated contribution of chemical clustering is broadly applicable to assay sets, chemical inventories, and models, and the data analysis used can also be applied to future evaluation of minimal assay models for consideration in screening., Methods: Chemical structures were collected for 6,947 substances via the CompTox Chemicals Dashboard from the over 10,000 UoC and grouped based on structural similarity, generating 826 chemical clusters. Of the 1,812 substances run in the original ER model, 1,730 substances had a single, clearly defined structure. The ER model chemicals with a clearly defined structure that were not present in the EDSP UoC were assigned to chemical clusters using a k-nearest neighbors approach, resulting in 557 EDSP UoC clusters containing at least one ER model chemical., Results and Discussion: Performance of an existing 4-assay model in comparison with the existing full ER agonist model was analyzed as related to chemical clustering. This was a case study, and a similar analysis can be performed with any subset model in which the same chemicals (or subset of chemicals) are screened. Of the 365 clusters containing >1 ER model chemical, 321 did not have any chemicals predicted to be agonists by the full ER agonist model. The best 4-assay subset ER agonist model disagreed with the full ER agonist model by predicting agonist activity for 122 chemicals from 91 of the 321 clusters. There were 44 clusters with at least two chemicals and at least one agonist based upon the full ER agonist model, which allowed accuracy predictions on a per-cluster basis. The accuracy of the best 4-assay subset ER agonist model ranged from 50% to 100% across these 44 clusters, with 32 clusters having accuracy ≥90%. Overall, the best 4-assay subset ER agonist model resulted in 122 false-positive and only 2 false-negative predictions compared with the full ER agonist model. Most false positives (89) were active in only two of the four assays, whereas all but 11 true positive chemicals were active in at least three assays. False positive chemicals also tended to have lower area under the curve (AUC) values, with 110 out of 122 false positives having an AUC value below 0.214, which is lower than 75% of the positives as predicted by the full ER agonist model. Many false positives demonstrated borderline activity. The median AUC value for the 122 false positives from the best 4-assay subset ER agonist model was 0.138, whereas the threshold for an active prediction is 0.1., Conclusion: Our results show that the existing 4-assay model performs well across a range of structurally diverse chemicals. Although this is a descriptive analysis of previous results, several concepts can be applied to any screening model used in the future. First, the clustering of the chemicals provides a means of ensuring that future screening evaluations consider the broad chemical space represented by the EDSP UoC. The clusters can also assist in prioritizing future chemicals for screening in specific clusters based on the activity of known chemicals in those clusters. The clustering approach can be useful in providing a framework to evaluate which portions of the EDSP UoC chemical space are reliably covered by in silico and in vitro approaches and where predictions from either method alone or both methods combined are most reliable. The lessons learned from this case study can be easily applied to future evaluations of model applicability and screening to evaluate future datasets., Competing Interests: Authors MN, DH, DW, ReB, and SE were employed by RTI International. Authors TA, CR, GC and SB were employed by ToxStrategies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nelms, Antonijevic, Ring, Harris, Bever, Lynn, Williams, Chappell, Boyles, Borghoff, Edwards and Markey.)

The development of synthetic agonists for the orphan receptor GPR88 has recently attracted significant interest, given the promise of GPR88 as a novel drug target for psychiatric and neurodegenerative disorders. Examination of structure-activity relationships of two known agonist scaffolds 2-PCCA and 2-AMPP, as well as the recently resolved cryo-EM structure of 2-PCCA-bound GPR88, led to the design of a new scaffold based on the "reversed amide" strategy of 2-AMPP. A series of novel (4-substituted-phenyl)acetamides were synthesized and assessed in cAMP accumulation assays as GPR88 agonists, which led to the discovery of several compounds with better or comparable potencies to 2-AMPP. Computational docking studies suggest that these novel GPR88 agonists bind to the same allosteric site of GPR88 that 2-PCCA occupies. Collectively, our findings provide structural insight and SAR requirement at the allosteric site of GPR88 and a new scaffold for further development of GPR88 allosteric agonists.

Sweet sorghum ( Sorghum bicolor ) lines M81-E and Colman were previously shown to differ in responses to Fusarium thapsinum and Macrophomina phaseolina , stalk rot pathogens that can reduce the yields and quality of biomass and extracted sugars. Inoculated tissues were compared for transcriptomic, phenolic metabolite, and enzymatic activity during disease development 3 and 13 days after inoculation (DAI). At 13 DAI, M81-E had shorter mean lesion lengths than Colman when inoculated with either pathogen. Transcripts encoding monolignol biosynthetic and modification enzymes were associated with transcriptional wound (control) responses of both lines at 3 DAI. Monolignol biosynthetic genes were differentially coexpressed with transcriptional activator SbMyb76 in all Colman inoculations, but only following M. phaseolina inoculation in M81-E, suggesting that SbMyb76 is associated with lignin biosynthesis during pathogen responses. In control inoculations, defense-related genes were expressed at higher levels in M81-E than Colman. Line, treatment, and timepoint differences observed in phenolic metabolite and enzyme activities did not account for observed differences in lesions. However, generalized additive models were able to relate metabolites, but not enzyme activities, to lesion length for quantitatively modeling disease progression: in M81-E, but not Colman, sinapic acid levels positively predicted lesion length at 3 DAI when cell wall-bound syringic acid was low, soluble caffeic acid was high, and lactic acid was high, suggesting that sinapic acid may contribute to responses at 3 DAI. These results provide potential gene targets for development of sweet sorghum varieties with increased stalk rot resistance to ensure biomass and sugar quality., Competing Interests: The author(s) declare no conflict of interest.

Introduction: Neuropathic pain arises as a result of peripheral nerve injury or altered pain processing within the central nervous system. When this phenomenon affects the cornea, it is referred to as neuropathic corneal pain (NCP), resulting in pain, hyperalgesia, burning, and photoallodynia, severely affecting patients' quality of life. To date there is no suitable animal model for the study of NCP. Herein, we developed an NCP model by constriction of the long ciliary nerves innervating the eye., Methods: Mice underwent ciliary nerve constriction (CNC) or sham procedures. Safety was determined by corneal fluorescein staining to assess ocular surface damage, whereas Cochet-Bonnet esthesiometry and confocal microscopy assessed the function and structure of corneal nerves, respectively. Efficacy was assessed by paw wipe responses within 30 seconds of applying hyperosmolar (5M) saline at Days 3, 7, 10, and 14 post-constriction. Additionally, behavior was assessed in an open field test (OFT) at Days 7, 14, and 21., Results: CNC resulted in significantly increased response to hyperosmolar saline between groups ( p < 0.0001), demonstrating hyperalgesia and induction of neuropathic pain. Further, animals that underwent CNC had increased anxiety-like behavior in an open field test compared to controls at the 14- and 21-Day time-points ( p < 0.05). In contrast, CNC did not result in increased corneal fluorescein staining or decreased sensation as compared to sham controls ( p > 0.05). Additionally, confocal microscopy of corneal whole-mounts revealed that constriction resulted in only a slight reduction in corneal nerve density ( p < 0.05), compared to naïve and sham groups., Discussion: The CNC model induces a pure NCP phenotype and may be a useful model for the study of NCP, recapitulating features of NCP, including hyperalgesia in the absence of ocular surface damage, and anxiety-like behavior., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Seyed-Razavi, Kenyon, Qiu, Harris and Hamrah.)

The drought-resilient crop sorghum ( Sorghum bicolor [L.] Moench) is grown worldwide for multiple uses, including forage or potential lignocellulosic bioenergy feedstock. A major impediment to biomass yield and quality are the pathogens Fusarium thapsinum and Macrophomina phaseolina , which cause Fusarium stalk rot and charcoal rot, respectively. These fungi are more virulent with abiotic stresses such as drought. Monolignol biosynthesis plays a critical role in plant defense. The genes Brown midrib ( Bmr ) 6 , Bmr12 , and Bmr2 encode the monolignol biosynthesis enzymes cinnamyl alcohol dehydrogenase, caffeic acid O -methyltransferase, and 4-coumarate:CoA ligase, respectively. Plant stalks from lines overexpressing these genes and containing bmr mutations were screened for pathogen responses with controlled adequate or deficit watering. Additionally, near-isogenic bmr12 and wild-type lines in five backgrounds were screened for response to F. thapsinum with adequate and deficit watering. All mutant and overexpression lines were no more susceptible than corresponding wild-type under both watering conditions. The bmr2 and bmr12 lines, near-isogenic to wild-type, had significantly shorter mean lesion lengths (were more resistant) than RTx430 wild-type when inoculated with F. thapsinum under water deficit. Additionally, bmr2 plants grown under water deficit had significantly smaller mean lesions when inoculated with M. phaseolina than under adequate-water conditions. When well-watered, bmr12 in cultivar Wheatland and one of two Bmr2 overexpression lines in RTx430 had shorter mean lesion lengths than corresponding wild-type lines. This research demonstrates that modifying monolignol biosynthesis for increased usability may not impair plant defenses but can even enhance resistance to stalk pathogens under drought conditions., Competing Interests: The author(s) declare no conflict of interest.

Obesity and the metabolic syndrome are complex disorders resulting from multiple factors including genetics, diet, activity, inflammation, and gut microbes. Animal studies have identified roles for each of these, however the contribution(s) specifically attributed to the gut microbiota remain unclear, as studies have used combinations of genetically altered mice, high fat diet, and/or colonization of germ-free mice, which have an underdeveloped immune system. We investigated the role(s) of the gut microbiota driving obesity and inflammation independent of manipulations in diet and genetics in mice with fully developed immune systems. We demonstrate that the human obese gut microbiota alone was sufficient to drive weight gain, systemic, adipose tissue, and intestinal inflammation, but did not promote intestinal barrier leak. The obese microbiota induced gene expression promoting caloric uptake/harvest but was less effective at inducing genes associated with mucosal immune responses. Thus, the obese gut microbiota is sufficient to induce weight gain and inflammation.

In sorghum [Sorghum bicolor (L.) Moench] the Maturity (Ma1, Ma2, Ma3, Ma4, Ma5, Ma6) and Dwarf (Dw1, Dw2, Dw3, Dw4) loci, encode genes controlling flowering time and plant height, respectively, which are critical for designing sorghum ideotypes for a maturity timeframe and a harvest method. Publicly available whole-genome resequencing data from 860 sorghum accessions was analyzed in silico to identify genomic variants at 8 of these loci (Ma1, Ma2, Ma3, Ma5, Ma6, Dw1, Dw2, Dw3) to identify novel loss of function alleles and previously characterized ones in sorghum germplasm. From ~ 33 million SNPs and ~ 4.4 million InDels, 1445 gene variants were identified within these 8 genes then evaluated for predicted effect on the corresponding encoded proteins, which included newly identified mutations (4 nonsense, 15 frameshift, 28 missense). Likewise, most accessions analyzed contained predicted loss of function alleles (425 ma1, 22 ma2, 40 ma3, 74 ma5, 414 ma6, 289 dw1, 268 dw2 and 45 dw3) at multiple loci, but 146 and 463 accessions had no predicted ma or dw mutant alleles, respectively. The ma and dw alleles within these sorghum accessions represent a valuable source for manipulating flowering time and plant height to develop the full range of sorghum types: grain, sweet and forage/biomass., (© 2023. Springer Nature Limited.)

G protein-coupled receptor 3 (GPR3) is an orphan receptor potentially involved in many important physiological processes such as drug abuse, neuropathic pain, and anxiety and depression related disorders. Pharmacological studies of GPR3 have been limited due to the restricted number of known agonists and inverse agonists for this constitutively active receptor. In this medicinal chemistry study, we report the discovery of GPR3 agonists based off the diphenyleneiodonium (DPI) scaffold. The most potent full agonist was the 3-trifluoromethoxy analog (32) with an EC 50 of 260 nM and 90% efficacy compared to DPI. Investigation of a homology model of GPR3 from multiple sequence alignment resulted in the finding of a binding site rich in potential π-π and π-cation interactions stabilizing DPI-scaffold agonists. MMGBSA free energy analysis showed a good correlation with trends in observed EC 50 s. DPI analogs retained the same high receptor selectivity for GPR3 over GPR6 and GPR12 as observed with DPI. Collectively, the DPI analog series shows that order of magnitude improvements in potency with the scaffold were attainable; however, attempts to replace the iodonium ion to make the scaffold more druggable failed., 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 © 2023 Elsevier Ltd. All rights reserved.)

Background: Programmed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab., Methods: In this trial, participants with metastatic CSCC received cosibelimab 800 mg intravenously every 2 weeks. Primary endpoint was objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, V.1.1. Secondary endpoints included duration of response (DOR) and safety., Results: Objective response was observed in 37 of 78 participants (47.4% (95% CI: 36.0% to 59.1%)), with median follow-up of 15.4 months (range: 0.4 to 40.5) as of data cut-off. Median DOR was not reached (range: 1.4+ to 34.1+ months), with response ongoing in 73.0% of participants. Common treatment-emergent AEs (≥15%) were fatigue (26.9%), rash (16.7%), and anemia (15.4%). Eighteen participants (23.1%) experienced immune-related AEs (grade 3: n=2 (2.6%); no grade 4/5). No treatment-related deaths were reported., Conclusions: Cosibelimab demonstrated clinically meaningful ORR and DOR and was associated with a manageable safety profile., Trial Registration Number: NCT03212404., Competing Interests: Competing interests: PC has nothing to disclose. RL has received honoraria from AstraZeneca/MedImmune, Bristol Myers Squibb Foundation, MSD, and Sanofi; has served as a consultant and/or scientific advisor for AstraZeneca/MedImmune and Roche; and has received compensation for travel, accommodations, and other expenses from MSD. DB has nothing to disclose. DLH has served as a consultant and/or scientific advisor for Checkpoint Therapeutics. MM has nothing to disclose. SA has nothing to disclose. JC has nothing to disclose. SF has nothing to disclose. AK has nothing to disclose. DRM has nothing to disclose. AM has nothing to disclose. VSh has served as a speaker for Elekta. HS has nothing to disclose. AT has nothing to disclose. M-AB-G has served as a consultant and/or scientific advisor for BMS, Eisai, MSD, Novartis, and Pierre Fabre and has received research funding from Novartis. CC has received grant/research support from AstraZeneca, Novartis, and Roche. SD has received institutional research grants from BMS and MSD; has served as a consultant and/or scientific advisor for BMS, MSD, and Pierre Fabre; and has received compensation for congress attendance from BMS and MSD. AD has nothing to disclose. OD has nothing to disclose. PK has nothing to disclose. IL has financial or non-financial interests in Agenus, BMS, Janssen, MacroGenics, MSD, Pfizer, and Roche. HM has received honoraria from BMS, Merck Serono, MSD, Novartis, and Pierre Fabre; has received institutional support from BMS, Canceropole PACA, and Société Française de Dermatologie; has served as a consultant for BMS, Merck Serono, MSD, Novartis, and Pierre Fabre; has served on a data safety monitoring board/advisory board for Novartis and Pierre Fabre; and has received travel grants from Novartis and Pierre Fabre. EM-C has served as a consultant and/or scientific advisor for MBS, MSD, Novartis, Pierre Fabre, and Sanofi; has received honoraria from MBS, MSD, Novartis, Pierre Fabre, and Sanofi; and has received compensation for travel, accommodations, and other expenses from MSD. VSr has nothing to disclose. JO is an employee of Checkpoint Therapeutics and holds stocks and other ownership interests in the company; has served in leadership roles at Checkpoint Therapeutics; and has received compensation for travel, accommodations, and other expenses from Checkpoint Therapeutics. JD has served as a consultant and/or scientific advisor for Amgen, Bayer, BeiGene, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Merck KGaA, Novartis, Novotech, Pfizer, Pierre Fabre, and Roche/Genentech; has served on a data safety monitoring board/advisory board for Boehringer Ingelheim and Pfizer; has served as a board director for Cancer Trials Australia and ANZSA; and has received institutional grant/research support from AstraZeneca/MedImmune, BeiGene, BMS, GlaxoSmithKline, Lilly, Novartis, and Roche., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In Mycobacterium tuberculosis , proline dehydrogenase (PruB) and ∆ 1 -pyrroline-5-carboxylate (P5C) dehydrogenase (PruA) are monofunctional enzymes that catalyze proline oxidation to glutamate via the intermediates P5C and L-glutamate-γ-semialdehyde. Both enzymes are essential for the replication of pathogenic M. tuberculosis . Highly active enzymes were expressed and purified using a Mycobacterium smegmatis expression system. The purified enzymes were characterized using natural substrates and chemically synthesized analogs. The structural requirements of the quinone electron acceptor were examined. PruB displayed activity with all tested lipoquinone analogs (naphthoquinone or benzoquinone). In PruB assays utilizing analogs of the native naphthoquinone [MK-9 (II-H 2 )] specificity constants K cat /K m were an order of magnitude greater for the menaquinone analogs than the benzoquinone analogs. In addition, mycobacterial PruA was enzymatically characterized for the first time using exogenous chemically synthesized P5C. A K m value of 120 ± 0.015 µM was determined for P5C, while the K m value for NAD + was shown to be 33 ± 4.3 µM. Furthermore, proline competitively inhibited PruA activity and coupled enzyme assays, suggesting that the recombinant purified monofunctional PruB and PruA enzymes of M. tuberculosis channel substrate likely increase metabolic flux and protect the bacterium from methylglyoxal toxicity.

Over 25 years ago, the World Health Organization (WHO) acknowledged the importance of effective prevention, detection and treatment of neonatal hypoglycaemia, and declared it to be a global priority. Neonatal hypoglycaemia is common, linked to poor neurosensory outcomes and, if untreated, can cause seizures and death. Neonatal mortality in low and lower-middle income countries constitutes an estimated 89% of overall neonatal deaths. Factors contributing to high mortality rates include malnutrition, infectious diseases, poor maternal wellbeing and resource constraints on both equipment and staff, leading to delayed diagnosis and treatment. The incidence of neonatal hypoglycaemia in low and lower-middle income countries remains unclear, as data are not collected.Data from high-resource settings shows that half of all at-risk babies will develop hypoglycaemia, using accepted clinical thresholds for treatment. Most at-risk babies are screened and treated, with treatment aiming to increase blood glucose concentration and, therefore, available cerebral fuel. The introduction of buccal dextrose gel as a first-line treatment for neonatal hypoglycaemia has changed the care of millions of babies and families in high-resource settings. Dextrose gel has now also been shown to prevent neonatal hypoglycaemia.In low and lower-middle income countries, there are considerable barriers to resources which prevent access to reliable blood glucose screening, diagnosis, and treatment, leading to inequitable health outcomes when compared with developed countries. Babies born in low-resource settings do not have access to basic health care and are more likely to suffer from unrecognised neonatal hypoglycaemia, which contributes to the burden of neurosensory delay and death., (© 2023. The Author(s).)

Background: The World Health Organization recommends breastfeeding be commenced as soon as possible after birth. Amongst other benefits, early feeding is expected to support the metabolic transition after birth, but effects on blood glucose concentrations are controversial. We sought to describe the changes in interstitial glucose concentrations after feedings over the first five postnatal days., Participants and Methods: In healthy singleton term infants, all feeds were recorded using a smart phone app. Glucose concentrations were measured by blinded interstitial monitoring, calibrated by heel-prick capillary samples 2-4 times/d. Feeding sessions were included if a start and end time were recorded, and if the interval between the start of successive feeds was >90 min. The area under the glucose concentration curve (AUC) was calculated by trapezoidal addition from baseline (median of the 3 measurements before the beginning of the session). The maximum deviation (MD) was the greatest change in glucose concentration (positive or negative) from baseline to the next feeding session or 180 min, whichever came first. Data were analyzed using Stata V17 and are presented as mean (95% CI) in mmol/L., Results: Data were available for 62 infants and 1,770 feedings. The glucose response to breastfeeding was not different from zero on day 1 [day 1 AUC 0.05 (-0.00, 0.10), MD 0.06 (-0.05, 0.16)], but increased thereafter (day 3 (AUC 0.23 (0.18, 0.28), MD 0.41 (0.32, 0.50), day 5 AUC 0.11 (0.06, 0.16), MD 0.28 (0.18, 0.37), p  < 0.001 for age effect). Glucose response increased with increased duration of breastfeeding (<30 min AUC 0.06 (0.02,0.09), MD 0.12 (0.04,0.19), >30 min AUC 0.20 (0.16, 0.23) MD 0.37 (0.30, 0.44), p  < 0.001 for duration effect) and this was observed even in the first 2 days (<30 min AUC-0.02 (-0.06, 0.03), MD -0.06 (-0.15, 0.03), >30 min AUC 0.12 (0.08, 0.16), MD 0.19 (0.11, 0.27), overall p  < 0.001 for age x duration interaction). In feeding sessions that were not breastfeeding, the glucose response was greater after formula than after expressed human milk [AUC 0.29 (0.15, 0.29), MD 0.48 (-0.12, 0.61)], and greater after feed volumes >20 ml than <10 ml [20-30 ml AUC 0.19 (0.01, 0.27), MD 0.23 (-0.01, 0.46)]., Conclusion: The glucose response to feeding in the days after birth increases with postnatal age and duration of the feeding episode. Breastfeeding for <30 min has little effect on glucose concentrations in the first two days., 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., (© 2023 Harris, Weston and Harding.)

Objective: Dextrose gel is used to treat neonatal hypoglycaemia, but later effects are unknown., Design and Setting: Follow-up of participants in a randomised trial recruited in a tertiary centre and assessed in a research clinic., Patients: Children who were hypoglycaemic (<2.6 mmol/L) recruited to the Sugar Babies Study ( > 35 weeks, <48 hours old) and randomised to treatment with 40% dextrose or placebo gel., Interventions: Assessment of neurological status, cognitive ability (Weschler Preschool and Primary Scale of Intelligence), executive function (five tasks), motor function (Movement Assessment Battery for Children-2 (MABC-2)), vision, visual processing (Beery-Buktenica Development Test of Visual Motor Integration (Beery VMI) and motion coherence thresholds) and growth at 2 years., Main Outcome Measures: Neurosensory impairment (cerebral palsy; visual impairment; deafness; intelligence quotient <85; Beery VMI <85; MABC-2 score <15th centile; low performance on executive function or motion coherence)., Results: Of 237 babies randomised, 185 (78%) were assessed; 96 randomised to dextrose and 89 to placebo gel. Neurosensory impairment was similar in both groups (dextrose 36/96 (38%) vs placebo 34/87 (39%), relative risk 0.96, 95% CI 0.66 to 1.34, p=0.83). Secondary outcomes were also similar, except children randomised to dextrose had worse visual processing scores (mean (SD) 94.5 (15.9) vs 99.8 (15.9), p=0.02) but no differences in the proportion with visual processing scores <85 or other visual test scores. Children randomised to dextrose gel were taller (z-scores 0.18 (0.97) vs -0.17 (1.01), p=0.001) and heavier (0.57 (1.07) vs 0.29 (0.92), p=0.01)., Conclusions: Treatment of neonatal hypoglycaemia (<2.6 mol/L) with dextrose gel does not alter neurosensory impairment at 4.5 years. However, further assessment of visual processing and growth may be warranted., Trial Registration Number: ACTRN1260800062392., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Dextrose gel is widely used as first-line treatment for neonatal hypoglycaemia given its cost-effectiveness and ease of use. The Sugar Babies randomized trial first showed that 40% dextrose gel was more effective in reversing hypoglycaemia than feeding alone. Follow-up of the Sugar Babies Trial cohort at 2 and 4.5 years of age reported that dextrose gel appeared safe, with similar rates of neurosensory impairment in babies randomized to dextrose or placebo gel. However, some effects of neonatal hypoglycaemia may not become apparent until school age., Methods: Follow-up of the Sugar Babies Trial cohort at 9-10 years of age was reported. The primary outcome was low educational achievement in reading or mathematics. Secondary outcomes included other aspects of educational achievement, executive function, visual-motor function, and psychosocial adaptation., Results: Of 227 eligible children, 184 (81%) were assessed at a mean (SD) age of 9.3 (0.2) years. Low educational achievement was similar in dextrose and placebo groups (36/86 [42%] vs. 42/94 [45%]; RR 1.04, 95% CI 0.76, 1.44; p = 0.79). Children allocated to dextrose gel had lower visual perception standard scores (95.2 vs. 100.6; MD -5.68, 95% CI -9.79, -1.57; p = 0.006) and a greater proportion had low (<85) visual perception scores (20/88 [23%] vs. 10/95 [11%]; RR 2.23, 95% CI 1.13, 4.37; p = 0.02). Other secondary outcomes, including other aspects of visual-motor function, were similar in both groups., Conclusion: Treatment dextrose gel does not appear to result in any clinically significant differences in educational achievement or other neurodevelopmental outcomes at mid-childhood., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Severe and prolonged neonatal hypoglycemia can cause brain injury, while the long-term consequences of mild or transitional hypoglycemia are uncertain. As neonatal hypoglycemia is often asymptomatic it is routine practice to screen infants considered at risk, including infants of mothers with diabetes and those born preterm, small or large, with serial blood tests over the first 12-24 h after birth. However, to prevent brain injury, the gold standard would be to determine if an infant has neuroglycopenia, for which currently there is not a diagnostic test. Therefore, screening of infants at risk for neonatal hypoglycemia with blood glucose monitoring does not meet several screening test principles. Specifically, the long-term neurodevelopmental outcomes of transient neonatal hypoglycemia are not well understood and there is no direct evidence from randomized controlled trials that treatment of hypoglycemia improves long-term neurodevelopmental outcomes. There have been no studies that have compared the long-term neurodevelopmental outcomes of at-risk infants screened for neonatal hypoglycemia and those not screened. However, screening infants at risk of hypoglycemia and treating those with hypoglycaemic episodes to maintain the blood glucose concentrations ≥2.6 mmol/L appears to preserve cognitive function compared to those without episodes. This narrative review explores the evidence for screening for neonatal hypoglycemia, the effectiveness of blood glucose screening as a screening test and recommend future research areas to improve screening for neonatal hypoglycemia. Screening babies at-risk of neonatal hypoglycemia continues to be necessary, but as over a quarter of all infants may be screened for neonatal hypoglycemia, further research is urgently needed to determine the optimal method of screening and which infants would benefit from screening and treatment., 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 Alsweiler, Heather, Harris and McKinlay.)

Blockade of lysophosphatidic acid receptor 5 (LPA5) by a recently reported antagonist AS2717638 (2) attenuated inflammatory and neuropathic pains, although it showed moderate in vivo efficacy and its structure-activity relationships and the ADME properties are little studied. We therefore designed and synthesized a series of isoquinolone derivatives and evaluated their potency in LPA5 calcium mobilization and cAMP assays. Our results show that substituted phenyl groups or bicyclic aromatic rings such as benzothiophenes or benzofurans are tolerated at the 2-position, 4-substituted piperidines are favored at the 4-position, and methoxy groups at the 6- and 7-positions are essential for activity. Compounds 65 and 66 showed comparable in vitro potency, excellent selectivity against LPA1-LPA4 and >50 other GPCRs, moderate metabolic stability, and high aqueous solubility and brain permeability. Both 65 and 66 significantly attenuated nociceptive hypersensitivity at lower doses than 2 and had longer-lasting effects in an inflammatory pain model, and 66 also dose-dependently reduced mechanical allodynia in the chronic constriction injury model and opioid-induced hyperalgesia at doses that had no effect on the locomotion in rats. These results suggest that these isoquinolone derivatives as LPA5 antagonists are of promise as potential analgesics., 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 Masson SAS. All rights reserved.)

Background: The feeding patterns of healthy newborns have been poorly described., Research Aim: To determine the feeding patterns of healthy term newborns soon after birth, and if these differed with sex, gestation, and mode of birth., Methods: This study was a prospective, longitudinal observational cohort study. Term, appropriately grown newborns ( N = 66) were fed according to maternal choice and details were recorded. Data were analyzed using generalized Poisson regression for feeding frequencies, and mixed model regression of log-transformed data for durations., Results: The participants completing the study had a M = 3589 g ( SD = 348 g) birthweight, with a gestation age of M = 40.1 (1.2) weeks. All participants were breastfed; 23 (35%) also received expressed human milk and 10 (15%) received formula. Participants had fewer feeding sessions on Day 1, ( M = 7.3 [1.9] sessions/day) increasing to ( M = 9.4 [2.4] sessions/day) by Day 3, then reducing to ( M = 9.0 [2.2] sessions/day) on Day 5, p < .001. The overall duration of breastfeeding sessions varied widely ( Mdn = 29 [range = 1-447] min). Feed frequency but not duration was higher in males than females ( M = 8.9, SE = 0.2 vs. 8.1, 02, sessions/day, p = .03), in newborns born ≥ 40 weeks' gestation ( M = 8.9, SE = 0.3 vs. 8.2, 02, sessions/day, p = .04), and in newborns born by Caesarean section ( M = 9.4, SE = 0.3 vs. 8.4, 02, sessions/day, for vaginal birth, p = .003)., Conclusion: Feeding patterns of healthy term newborns vary widely, but frequency increases during the first 3 days, and is greater in males, newborns born late term, and born by Caesarean section., Clinical Trial Registration: The Australian and New Zealand Clinical Trials Registry Ref: ACTRN12615000986572. The study protocol is available online: http://hdl.handle.net/2292/32066.

Background: Most babies admitted to a Neonatal Intensive Care Unit (NICU) require a peripheral intravenous catheter (PIVC). PIVCs are secured using splints and adhesive dressings applied to the skin. Removing the dressings causes skin injury, pain, and risks infection. We designed the Pēpi Splint, which supports PIVCs without the application of adhesive dressings to the skin. We sought to determine the effectiveness and acceptability of the Pēpi Splint using a proof-of-concept design., Methods: Eligible babies were > 1000 g and > 30 weeks' corrected gestation admitted to Wellington Regional NICU and who required a PIVC. All babies received the same care as those not in the study, with the addition of the Pēpi Splint. Primary outcomes were the proportion of babies in which the Pēpi Splint secured the PIVC for the required time and proportion of babies who experience an adverse event. Secondary outcomes were the acceptability of the Pēpi Splint as reported by the parents., Results: Thirty-eight babies, median (range) birth weight 2625 g (396-4970) and gestation 37wk (22-41). When the Pēpi was applied the postnatal weight was 2969 g (1145 - 4970) and gestation 37wk (29 - 41). The Pēpi Splint held the PIVC secure for 34/38 babies (89%), for a duration of 37 h (6 to 97). There were no adverse events. Of the four babies reported to have unsecure PIVCs, two were due to the securement two were displaced during feeding. Fifty-eight parents responded to a questionnaire (32 mothers, 26 fathers). Of these parents 52 (90%) would participate again and 52 (90%) would recommend participating to others. Overall, clinicians reported the Pēpi Splint was easy to use 33/38 (87%)., Conclusion: The Pēpi Splint safely secures PIVCs without adhesive dressings being applied to the skin and is acceptable to both parents and clinicians. Our findings provide support for a larger multicentred randomised controlled trial., Trial Registration: Registered with the Australian and New Zealand Clinical Trials Registry Reference ACTRN12620001335987 ., (© 2022. The Author(s).)

Importance: Neonatal hypoglycemia is associated with increased risk of poor executive and visual-motor function, but implications for later learning are uncertain., Objective: To test the hypothesis that neonatal hypoglycemia is associated with educational performance at age 9 to 10 years., Design, Setting, and Participants: Prospective cohort study of moderate to late preterm and term infants born at risk of hypoglycemia. Blood and masked interstitial sensor glucose concentrations were measured for up to 7 days. Infants with hypoglycemic episodes (blood glucose concentration <47 mg/dL [2.6 mmol/L]) were treated to maintain a blood glucose concentration of at least 47 mg/dL. Six hundred fourteen infants were recruited at Waikato Hospital, Hamilton, New Zealand, in 2006-2010; 480 were assessed at age 9 to 10 years in 2016-2020., Exposures: Hypoglycemia was defined as at least 1 hypoglycemic event, representing the sum of nonconcurrent hypoglycemic and interstitial episodes (sensor glucose concentration <47 mg/dL for ≥10 minutes) more than 20 minutes apart., Main Outcomes and Measures: The primary outcome was low educational achievement, defined as performing below or well below the normative curriculum level in standardized tests of reading comprehension or mathematics. There were 47 secondary outcomes related to executive function, visual-motor function, psychosocial adaptation, and general health., Results: Of 587 eligible children (230 [48%] female), 480 (82%) were assessed at a mean age of 9.4 (SD, 0.3) years. Children who were and were not exposed to neonatal hypoglycemia did not significantly differ on rates of low educational achievement (138/304 [47%] vs 82/176 [48%], respectively; adjusted risk difference, -2% [95% CI, -11% to 8%]; adjusted relative risk, 0.95 [95% CI, 0.78-1.15]). Children who were exposed to neonatal hypoglycemia, compared with those not exposed, were significantly less likely to be rated by teachers as being below or well below the curriculum level for reading (68/281 [24%] vs 49/157 [31%], respectively; adjusted risk difference, -9% [95% CI, -17% to -1%]; adjusted relative risk, 0.72 [95% CI, 0.53-0.99; P = .04]). Groups were not significantly different for other secondary end points., Conclusions and Relevance: Among participants at risk of neonatal hypoglycemia who were screened and treated if needed, exposure to neonatal hypoglycemia compared with no such exposure was not significantly associated with lower educational achievement in mid-childhood.

Empathy is positively related to healthcare workers and patients' wellbeing. There is, however, limited research on the effects of empathy education delivered in acute clinical settings and its impact on healthcare consumers. This research tests the feasibility and the potential efficacy outcomes of an immersive education programme developed by the research team in collaboration with clinical partners and a multidisciplinary advisory group. Healthcare worker participants in the intervention ward will receive an 8-week immersive empathy education. The primary outcome (feasibility) will be assessed by evaluating the acceptability of the intervention and the estimated resources. The secondary outcome (efficacy) will be assessed using a quasi-experimental study design. Non-parametric tests will be used to test healthcare worker participants' empathy, burnout, and organisational satisfaction (within-group and across groups), and healthcare consumer participants' satisfaction (between-group) over time. Despite growing interest in the importance of empathy in professional relationships, to our knowledge, the present pilot study is the first to explore the feasibility and efficacy of an immersive empathy education in New Zealand. Our findings will provide critical evidence to support the development of a randomised cluster trial and potentially provide preliminary evidence for the effectiveness of this type of empathy education.

In sorghum ( Sorghum bicolor ) and other C 4 grasses, brown midrib ( bmr ) mutants have long been associated with plants impaired in their ability to synthesize lignin. The brown midrib 30 ( Bmr30 ) gene, identified using a bulk segregant analysis and next-generation sequencing, was determined to encode a chalcone isomerase (CHI). Two independent mutations within this gene confirmed that loss of its function was responsible for the brown leaf midrib phenotype and reduced lignin concentration. Loss of the Bmr30 gene function, as shown by histochemical staining of leaf midrib and stalk sections, resulted in altered cell wall composition. In the bmr30 mutants, CHI activity was drastically reduced, and the accumulation of total flavonoids and total anthocyanins was impaired, which is consistent with its function in flavonoid biosynthesis. The level of the flavone lignin monomer tricin was reduced 20-fold in the stem relative to wild type, and to undetectable levels in the leaf tissue of the mutants. The bmr30 mutant, therefore, harbors a mutation in a phenylpropanoid biosynthetic gene that is key to the interconnection between flavonoids and monolignols, both of which are utilized for lignin synthesis in the grasses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tetreault, Gries, Liu, Toy, Xin, Vermerris, Ralph, Funnell-Harris and Sattler.)

Background: As effects of global climate change intensify, the interaction of biotic and abiotic stresses increasingly threatens current agricultural practices. The secondary cell wall is a vanguard of resistance to these stresses. Fusarium thapsinum (Fusarium stalk rot) and Macrophomina phaseolina (charcoal rot) cause internal damage to the stalks of the drought tolerant C4 grass, sorghum (Sorghum bicolor (L.) Moench), resulting in reduced transpiration, reduced photosynthesis, and increased lodging, severely reducing yields. Drought can magnify these losses. Two null alleles in monolignol biosynthesis of sorghum (brown midrib 6-ref, bmr6-ref; cinnamyl alcohol dehydrogenase, CAD; and bmr12-ref; caffeic acid O-methyltransferase, COMT) were used to investigate the interaction of water limitation with F. thapsinum or M. phaseolina infection., Results: The bmr12 plants inoculated with either of these pathogens had increased levels of salicylic acid (SA) and jasmonic acid (JA) across both watering conditions and significantly reduced lesion sizes under water limitation compared to adequate watering, which suggested that drought may prime induction of pathogen resistance. RNA-Seq analysis revealed coexpressed genes associated with pathogen infection. The defense response included phytohormone signal transduction pathways, primary and secondary cell wall biosynthetic genes, and genes encoding components of the spliceosome and proteasome., Conclusion: Alterations in the composition of the secondary cell wall affect immunity by influencing phenolic composition and phytohormone signaling, leading to the action of defense pathways. Some of these pathways appear to be activated or enhanced by drought. Secondary metabolite biosynthesis and modification in SA and JA signal transduction may be involved in priming a stronger defense response in water-limited bmr12 plants., (© 2021. The Author(s).)

Objective: To quantify the extent that professional skills topics were presented to veterinary students at US colleges and schools of veterinary medicine (ie, veterinary schools) in 2019 and compare findings with similar data collected in 1999 and 2009., Sample: All 30 US veterinary schools in 2019., Procedures: An electronic questionnaire was sent to the associate deans for academic affairs of all 30 veterinary schools in the United States during fall of 2019. Results were compared with published results of a similar survey performed in 1999 and 2009., Results: A 100% (30/30) response rate was achieved for 2019. A total of 173 courses on professional skills topics were reported, of which 115 (66%) were required. The most common topic was communication (79/136 [58%] courses). Overall, courses were most frequently delivered in the first 3 years of the curriculum (129/158 [82%]), with required courses most common in years 1 and 2 (79/112 [71%]). Most courses (116/150 [77%]) were assigned 1 or 2 credit hours. These results represented continuation of a substantial increase in the teaching of professional skills, compared with findings for 1999 and 2009., Conclusions and Clinical Relevance: Results suggested a growing commitment to the teaching of professional skills on the part of US veterinary schools and the willingness to change on the basis of the current perceived needs of their graduates. The observed increases align nicely with the emerging framework for competency-based veterinary education and its substantial focus on assessing competency in professional skills as an important outcome of veterinary medical education.

Allosteric modulation offers an alternate approach to target the cannabinoid type-1 receptor (CB 1 ) for therapeutic benefits. Examination of the two widely studied prototypic CB 1 negative allosteric modulators (NAMs) Org27569 and PSNCBAM-1 revealed structural resemblance and similar structure-activity relationships (SARs). In silico docking and dynamics simulation studies using the crystal structure of CB 1 co-bound with CP55,940 and Org27569 suggested that Org27569 and PSNCBAM-1 occupied the same binding pocket and several common interactions were present in both series with the CB 1 receptor. A new scaffold was therefore designed by merging the key structural features from the two series and the hybrids retained these binding features in the in silico docking studies. In addition, one such hybrid displayed similar functions to Org27569 in dynamic simulations by preserving a key R214 3.50 -D338 6.30 salt bridge and maintaining an antagonist-like Helix3-Helix6 interhelical distance. Based on these results, a series of hybrids were synthesized and assessed in calcium mobilization, [ 35 S]GTPγS binding and cAMP assays. Several compounds displayed comparable potencies to Org27569 and PSNCBAM-1 in these assays. This work offers new insight of the SAR requirement at the allosteric site of the CB 1 receptor and provides a new scaffold that can be optimized for the development of future CB 1 allosteric modulators., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Neonatal hypoglycaemia is associated with adverse development, particularly visual-motor and executive function impairment, in childhood. As neonatal hypoglycaemia is common and frequently asymptomatic in at-risk babies-ie, those born preterm, small or large for gestational age, or to mothers with diabetes, it is recommended that these babies are screened for hypoglycaemia in the first 1-2 days after birth with frequent blood glucose measurements. Neonatal hypoglycaemia can be prevented and treated with buccal dextrose gel, and it is also common to treat babies with hypoglycaemia with infant formula and intravenous dextrose. However, it is uncertain if screening, prophylaxis, or treatment improves long-term outcomes of babies at risk of neonatal hypoglycaemia. This narrative review assesses the latest evidence for screening, prophylaxis, and treatment of neonates at risk of hypoglycaemia to improve long-term neurodevelopmental outcomes., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Loss of orexin-producing neurons results in narcolepsy with cataplexy, and orexin agonists have been shown to increase wakefulness and alleviate narcolepsy symptoms in animal models. Several OX2R agonists have been reported but with little or no activity at OX1R. We conducted structure-activity relationship studies on the OX2R agonist YNT-185 ( 2 ) and discovered dual agonists such as RTOXA-43 ( 40 ) with EC 50 's of 24 nM at both OX2R and OX1R. Computational modeling studies based on the agonist-bound OX2R cryogenic electron microscopy structures showed that 40 bound in the same binding pocket and interactions of the pyridylmethyl group of 40 with OX1R may have contributed to its high OX1R potency. Intraperitoneal injection of 40 increased time awake, decreased time asleep, and increased sleep/wake consolidation in 12-month old mice. This work provides a promising dual small molecule agonist and supports development of orexin agonists as potential treatments for orexin-deficient disorders such as narcolepsy.

Objectives: To determine plasma lactate and beta-hydroxybutyrate (BHB) concentrations of healthy infants in the first 5 days and their relationships with glucose concentrations., Study Design: Prospective masked observational study in Hamilton, New Zealand. Term, appropriately grown singletons had heel-prick blood samples, 4 in the first 24 hours then twice daily., Results: In 67 infants, plasma lactate concentrations were higher in the first 12 hours (median, 20; range, 10-55 mg/dL [median, 2.2 mmol/L; range, 1.1-6.2 mmol/L]), decreasing to 12 mg/dL (range, 7-29 mg/dL [median, 1.4 mmol/L; range, 0.8-3.3 mmol/L]) after 48 hours. Plasma BHB concentrations were low in the first 12 hours (median, 0.9 mg/dL; range, 0.5-5.2 mg/dL [median, 0.1 mmol/L; range, 0.05-0.5 mmol/L]), peaked at 48-72 hours (median, 7.3 mg/dL; range, 1.0-25.0 mg/dL [median, 0.7 mmol/L; range, 0.05-2.4 mmol/L]), and decreased by 96 hours (median, 0.9 mg/dL; range, 0.5-16.7 mg/dL [median, 0.1 mmol/L; range, 0.05-1.6 mmol/L]). Compared with infants with plasma glucose concentrations above the median (median, 67 mg/dL [median, 3.7 mmol/L]), those with lower glucose had lower lactate concentrations in the first 12 hours and higher BHB concentrations between 24 and 96 hours. Lower interstitial glucose concentrations were also associated with higher plasma BHB concentrations, but only if the lower glucose lasted greater than 12 hours. Glucose contributed 72%-84% of the estimated potential adenosine triphosphate throughout the 5 days, with lactate contributing 25% on day 1 and BHB 7% on days 2-3., Conclusions: Lactate on day 1 and BHB on days 2-4 may contribute to cerebral fuels in healthy infants, but are unlikely to provide neuroprotection during early or acute hypoglycemia., Trial Registration: The Australian and New Zealand Clinical Trials Registry: ACTRN12615000986572., (Copyright © 2021 Elsevier Inc. All rights reserved.)