Pro-Ictal EEG Scheduling Improves the Yield of Epilepsy Monitoring: Validating the Use of Multiday Seizure Cycles to Optimize Video-EEG Timing.

OBJECTIVE: A significant challenge of video-electroencephalography (vEEG) in epilepsy diagnosis is timing monitoring sessions to capture epileptiform activity. In this study, we introduce and validate "pro-ictal EEG scheduling", a method to schedule vEEG monitoring to coincide with periods of increased seizure likelihood as a low-risk approach to enhance the diagnostic yield. METHODS: A database of long-term ambulatory vEEG monitoring sessions (n = 5,038) of adults and children was examined. Data from linked electronic seizure diaries were extracted (minimum 10 self-reported events) to generate cycle-based estimates of seizure risk. In adults, vEEG monitoring sessions coinciding with periods of estimated high-risk were allocated to the high-risk group (n = 305) and compared to remaining studies (baseline: n = 3,586). Test of proportions and risk-ratios (RR) were applied to index differences in proportions and likelihood of capturing outcome measures (abnormal report, confirmed seizure, and diary event) during monitoring. The impact of clinical and demographic factors (age, sex, epilepsy-type, and medication) was also explored. RESULTS: During vEEG monitoring, the high-risk group was significantly more likely to have an abnormal vEEG report (190/305:62% vs 1,790/3,586:50% [%change = 12%], RR = 1.25, 95% confidence interval [CI] = [1.137-1.370], p < 0.001), present with a confirmed seizure (56/305:18% vs 424/3,586:11% [%change = 7%], RR = 1.63, 95% CI = [1.265-2.101], p < 0.001) and report an event (153/305:50% vs 1,267/3,586:35% (%change = 15%), RR = 1.420, 95% CI = [1.259:1.602], p < 0.001). Similar effects were observed across clinical and demographic features. INTERPRETATION: This study provides the first large-scale validation of pro-ictal EEG scheduling in improving the yield of vEEG. This innovative approach offers a pragmatic and low-risk strategy to enhance the diagnostic capabilities of vEEG monitoring, significantly impacting epilepsy management. ANN NEUROL 2024.

The early life microbiome of giant grouper (Epinephelus lanceolatus) larvae in a commercial hatchery is influenced by microorganisms in feed.

Fish health, growth and disease is intricately linked to its associated microbiome. Understanding the influence, source and ultimately managing the microbiome, particularly for vulnerable early life-stages, has been identified as one of the key requirements to improving farmed fish production. One tropical fish species of aquaculture importance farmed throughout the Asia-Pacific region is the giant grouper (Epinephelus lanceolatus). Variability in the health and survival of E. lanceolatus larvae is partially dependent on exposure to and development of its early microbiome. Here, we examined the development in the microbiome of commercially reared giant grouper larvae, its surrounding environment, and that from live food sources to understand the type of bacterial species larvae are exposed to, and where some of the sources of bacteria may originate. We show that species richness and microbial diversity of the larval microbiome significantly increased in the first 4 days after hatching, with the community composition continuing to shift over the initial 10 days in the hatchery facility. The dominant larval bacterial taxa appeared to be predominantly derived from live cultured microalgae and rotifer feeds and included Marixanthomonas, Candidatus Hepatincola, Meridianimaribacter and Vibrio. In contrast, a commercial probiotic added as part of the hatchery's operating procedure failed to establish in the larvae microbiome. Microbial source tracking indicated that feed was the largest influence on the composition of the giant grouper larvae microbiome (up to 55.9%), supporting attempts to modulate fish microbiomes in commercial hatcheries through improved diets. The marked abundances of Vibrio (up to 21.7% of 16S rRNA gene copies in larvae) highlights a need for rigorous quality control of feed material.

A New Mechanism for Formation of Glycine from Glyoxylic acid: the Aza-Cannizzaro Reaction.

Glyoxylic acid and glycine are widely considered to have been important prebiotic building blocks. Several mechanistic routes have been previously examined for conversion of glyoxylic acid to glycine. Here we provide evidence for a new mechanistic path. Glycine is spontaneously formed from glyoxylic acid in ammonium-rich aqueous solutions at neutral pH; oxamic acid is generated as well. Hydride transfer from the glyoxylate-derived hemiaminal to the corresponding iminium ion appears to underlie this transformation. This proposed mechanism parallels the well-known Cannizzaro reaction mechanism, which leads us to suggest the designation "aza-Cannizzaro reaction." This discovery offers a new perspective on prebiotic nitrogen incorporation because glycine can be a source of nitrogen for more complex molecules, including other α-amino acids.

A γδ T cell-IL-3 axis controls allergic responses through sensory neurons.

In naive individuals, sensory neurons directly detect and respond to allergens, leading to both the sensation of itch and the activation of local innate immune cells, which initiate the allergic immune response1,2. In the setting of chronic allergic inflammation, immune factors prime sensory neurons, causing pathologic itch3-7. Although these bidirectional neuroimmune circuits drive responses to allergens, whether immune cells regulate the set-point for neuronal activation by allergens in the naive state is unknown. Here we describe a γδ T cell-IL-3 signalling axis that controls the allergen responsiveness of cutaneous sensory neurons. We define a poorly characterized epidermal γδ T cell subset8, termed GD3 cells, that produces its hallmark cytokine IL-3 to promote allergic itch and the initiation of the allergic immune response. Mechanistically, IL-3 acts on Il3ra-expressing sensory neurons in a JAK2-dependent manner to lower their threshold for allergen activation without independently eliciting itch. This γδ T cell-IL-3 signalling axis further acts by means of STAT5 to promote neuropeptide production and the initiation of allergic immunity. These results reveal an endogenous immune rheostat that sits upstream of and governs sensory neuronal responses to allergens on first exposure. This pathway may explain individual differences in allergic susceptibility and opens new therapeutic avenues for treating allergic diseases.

Developing non-radioactive, radical methods to screen for radiolytic stability.

Radiolytically generated radicals cause degradation of nutrients in food, materials in satellites and solar cells, and human health. Radiation effects are studied using gamma radiolysis, a low-throughput, high-cost, and low-accessibility method. We developed a higher-throughput, low-cost, non-radioactive, radical assay that produces radicals similar to those generated in gamma radiolysis and examined monoamide degradation. Our radical assay results correspond to those from gamma irradiation in both monoamide stability and decomposition products, establishing this radical assay as a proof-of-concept screening tool for radiolytic stability.

Real-World Implementation of a Genotype-Guided P2Y12 Inhibitor De-Escalation Strategy in Acute Coronary Syndrome Patients.

BACKGROUND: CYP2C19 genotype-guided de-escalation from ticagrelor or prasugrel to clopidogrel may optimize the balance between ischemic and bleeding risk in patients with acute coronary syndrome (ACS). OBJECTIVES: This study sought to compare bleeding and ischemic event rates in genotyped patients vs standard care. METHODS: Since 2015, ACS patients in the multicenter FORCE-ACS (Future Optimal Research and Care Evaluation in Patients with Acute Coronary Syndrome) registry received standard dual antiplatelet therapy (DAPT). Since 2021, genotype-guided P2Y12 inhibitor de-escalation was recommended at a single center, switching noncarriers of the loss-of-function allele CYP2C19∗3 or CYP2C19∗2 from ticagrelor or prasugrel to clopidogrel, whereas loss-of-function carriers remained on ticagrelor or prasugrel. The primary ischemic endpoint, a composite of cardiovascular mortality, myocardial infarction, or stroke, and the primary bleeding endpoint, Bleeding Academic Research Consortium 2, 3, or 5 bleeding, were compared between a genotyped cohort and a cohort treated with standard DAPT after 1 year. RESULTS: Among 5,321 enrolled ACS patients, 406 underwent genotyping compared with 4,915 nongenotyped ACS patients on standard DAPT. In the genotyped cohort, 65.3% (n = 265) were noncarriers, 88.7% (n = 235) of whom were switched to clopidogrel. The primary ischemic endpoint occurred in 5.2% (n = 21) of patients in the genotyped cohort compared to 6.9% (n = 337) in the standard care cohort (adjusted HR: 0.82; 95% CI: 0.53-1.28). The primary bleeding rate was significantly lower in the genotyped cohort compared to the standard care cohort (4.7% vs 9.8%; adjusted HR: 0.47; 95% CI: 0.30-0.76). CONCLUSIONS: The implementation of a CYP2C19 genotype-guided P2Y12 inhibitor de-escalation strategy in a real-world ACS population resulted in lower bleeding rates without an increase in ischemic events compared to a standard DAPT regimen.

Synchronising an IMX219 image sensor and AS7265x spectral sensor to make a novel low-cost spectral camera.

A low-cost novel spectral camera able to be used for near infrared spectroscopy was made by using a Jetson Nano to synchronize a Sony IMX219 NOIR autofocus image sensor, an AMS AS7265x 18-channel spectral sensor and Osram SFH 4737 broadband infrared LED's. Synchronizing an image sensor and spectral sensor augments a standard RGB image with light spectrum information; capturing the light distribution information normally lost in RGB image capture. Sutherland et al. [1] used this novel spectral camera to examine the dorsal surface of juvenile lobsters as a possible pre-moult detector. Having the image and spectrum in combination allowed the incomplete and unmineralized post-moult dorsal surface to be characterized with 86.7% accuracy for the first time. A proposed application for the spectral camera is to omit the local SFH 4737 light source and use the camera in daylight, effectively making a low-cost substitute hyperspectral snapshot camera. In this configuration the camera may have application for low-cost drone deployment for small scale agriculture.

Virus ecology and 7-year temporal dynamics across a permafrost thaw gradient.

Soil microorganisms are pivotal in the global carbon cycle, but the viruses that affect them and their impact on ecosystems are less understood. In this study, we explored the diversity, dynamics, and ecology of soil viruses through 379 metagenomes collected annually from 2010 to 2017. These samples spanned the seasonally thawed active layer of a permafrost thaw gradient, which included palsa, bog, and fen habitats. We identified 5051 virus operational taxonomic units (vOTUs), doubling the known viruses for this site. These vOTUs were largely ephemeral within habitats, suggesting a turnover at the vOTU level from year to year. While the diversity varied by thaw stage and depth-related patterns were specific to each habitat, the virus communities did not significantly change over time. The abundance ratios of virus to host at the phylum level did not show consistent trends across the thaw gradient, depth, or time. To assess potential ecosystem impacts, we predicted hosts in silico and found viruses linked to microbial lineages involved in the carbon cycle, such as methanotrophy and methanogenesis. This included the identification of viruses of Candidatus Methanoflorens, a significant global methane contributor. We also detected a variety of potential auxiliary metabolic genes, including 24 carbon-degrading glycoside hydrolases, six of which are uniquely terrestrial. In conclusion, these long-term observations enhance our understanding of soil viruses in the context of climate-relevant processes and provide opportunities to explore their role in terrestrial carbon cycling.

Outcomes of newly diagnosed atrial fibrillation in patients with acute coronary syndromes.

BACKGROUND: Acute coronary syndrome (ACS) is frequently accompanied by newly diagnosed atrial fibrillation (AF). AIMS: We aimed to compare the risk of major adverse cardiovascular events (MACE) in ACS patients presenting with known, newly diagnosed, or no AF. METHODS: In our multicentre, prospective registry study, we included patients with confirmed ACS. Patients are classified as having known, newly diagnosed or no AF. Newly diagnosed AF is subdivided according to the duration of the episode, time of onset, post-coronary artery bypass graft (CABG) or spontaneous occurrence, and treatment with oral anticoagulants (OAC). The primary endpoint is MACE at 1 year. Key secondary endpoints include ischaemic stroke and bleeding complications. RESULTS: Amongst 4,433 patients with confirmed ACS, 3,598 (81.2%) had no AF, 438 (9.9%) had newly diagnosed AF, and 397 (9.0%) had known AF. The rates of OAC treatment at discharge were 53.4% in patients with newly diagnosed AF and 89.2% in patients with known AF. After adjusting for baseline imbalances, only new AF was independently associated with increased rates of MACE, whereas known AF was not (hazard ratio [HR] 1.52, 95% confidence interval [CI]: 1.19-1.90 and HR 0.93, 95% CI: 0.70-1.23). For ACS patients with newly diagnosed AF, episodes lasting >24 hours were associated with a higher risk of MACE compared to episodes <24 hours (HR 1.99, 95% CI: 1.36-2.93). Episodes of new AF occurring post-CABG had more favourable outcomes compared to spontaneously occurring new AF (HR for MACE 0.52, 95% CI: 0.31-0.86). OAC treatment rates were higher in the new AF subcategories with higher rates of MACE and ischaemic stroke. CONCLUSIONS: Newly diagnosed AF in ACS patients was associated with higher rates of MACE and ischaemic stroke compared to ACS patients without or with known AF. Among the ACS patients with new AF, an episode lasting >24 hours was associated with worse outcomes than shorter episodes, while post-CABG occurrence of AF showed relatively better outcomes compared to spontaneously occurring AF. Only 53% of new AF patients were discharged on OAC therapy versus 89% with known AF.

Barramundi (Lates calcarifer) rare coloration patterns: a multiomics approach to understand the "panda" phenotype.

The barramundi (Lates calcarifer), a significant aquaculture species, typically displays silver to bronze coloration. However, attention is now drawn to rare variants like the "panda" phenotype, characterized by blotch-like patterns of black (PB) and golden (PG) patches. This phenotype presents an opportunity to explore the molecular mechanisms underlying color variations in teleosts. Unlike stable color patterns in many fish, the "panda" variant demonstrates phenotypic plasticity, responding dynamically to unknown cues. We propose a complex interplay of genetic factors and epigenetic modifications, focusing on DNA methylation. Through a multiomics approach, we analyze transcriptomic and methylation patterns between PB and PG patches. Our study reveals differential gene expression related to melanosome trafficking and chromatophore differentiation. Although the specific gene responsible for the PB-PG difference remains elusive, candidate genes like asip1, asip2, mlph, and mreg have been identified. Methylation emerges as a potential contributor to the "panda" phenotype, with changes in gene promoters like hand2 and dynamin possibly influencing coloration. This research lays the groundwork for further exploration into rare barramundi color patterns, enhancing our understanding of color diversity in teleosts. Additionally, it underscores the "panda" phenotype's potential as a model for studying adult skin coloration.

Reactions of the ˙NO3 radical with nuclear extraction ligands in alkane solution.

The reactivity of the nitrate radical (NO3˙) with organophosphorus and amidic actinide and lanthanide complexing agents of interest to nuclear solvent extraction applications was measured, resulting in the first-ever reported bimolecular rate constants for this radicals' reactions in dodecane solution. The order of reactivity for neutral organophosphorus compounds showed faster rate constants with increasing electron density on the phosphoryl phosphorus atom, indicating an increasing facility for electron abstraction reactions occurring in addition to H-atom abstraction from the ligand alkane chains. The only acidic organophosphorus compound investigated, HEH[EHP], showed low reactivity with the NO3˙ radical, attributed to its dimerization in this non-polar solvent. Amide ligand reaction rates were faster than for organophosphorus molecules, suggesting more facile H-atom abstraction from carbonyl activated methylene and amyl groups. While all rate constants were slower than the diffusion-limited rate they were still rapid enough to result in significant oxidation of solvent extraction ligands in dodecane solution.

Activation of AMPD2 drives metabolic dysregulation and liver disease in mice with hereditary fructose intolerance.

Hereditary fructose intolerance (HFI) is a painful and potentially lethal genetic disease caused by a mutation in aldolase B resulting in accumulation of fructose-1-phosphate (F1P). No cure exists for HFI and treatment is limited to avoid exposure to fructose and sugar. Using aldolase B deficient mice, here we identify a yet unrecognized metabolic event activated in HFI and associated with the progression of the disease. Besides the accumulation of F1P, here we show that the activation of the purine degradation pathway is a common feature in aldolase B deficient mice exposed to fructose. The purine degradation pathway is a metabolic route initiated by adenosine monophosphate deaminase 2 (AMPD2) that regulates overall energy balance. We demonstrate that very low amounts of fructose are sufficient to activate AMPD2 in these mice via a phosphate trap. While blocking AMPD2 do not impact F1P accumulation and the risk of hypoglycemia, its deletion in hepatocytes markedly improves the metabolic dysregulation induced by fructose and corrects fat and glycogen storage while significantly increasing the voluntary tolerance of these mice to fructose. In summary, we provide evidence for a critical pathway activated in HFI that could be targeted to improve the metabolic consequences associated with fructose consumption.

Hepatic glucokinase regulatory protein and carbohydrate response element binding protein attenuation reduce de novo lipogenesis but do not mitigate intrahepatic triglyceride accumulation in Aldob deficiency.

OBJECTIVE: Stable isotope studies have shown that hepatic de novo lipogenesis (DNL) plays an important role in the pathogenesis of intrahepatic lipid (IHL) deposition. Furthermore, previous research has demonstrated that fructose 1-phosphate (F1P) not only serves as a substrate for DNL, but also acts as a signalling metabolite that stimulates DNL from glucose. The aim of this study was to elucidate the mediators of F1P-stimulated DNL, with special focus on two key regulators of intrahepatic glucose metabolism, i.e., glucokinase regulatory protein (GKRP) and carbohydrate response element binding protein (ChREBP). METHODS: Aldolase B deficient mice (Aldob-/-), characterized by hepatocellular F1P accumulation, enhanced DNL, and hepatic steatosis, were either crossed with GKRP deficient mice (Gckr-/-) or treated with short hairpin RNAs directed against hepatic ChREBP. RESULTS: Aldob-/- mice showed higher rates of de novo palmitate synthesis from glucose when compared to wildtype mice (p < 0.001). Gckr knockout reduced de novo palmitate synthesis in Aldob-/- mice (p = 0.017), without affecting the hepatic mRNA expression of enzymes involved in DNL. In contrast, hepatic ChREBP knockdown normalized the hepatic mRNA expression levels of enzymes involved in DNL and reduced fractional DNL in Aldob-/- mice (p < 0.05). Of interest, despite downregulation of DNL in response to Gckr and ChREBP attenuation, no reduction in intrahepatic triglyceride levels was observed. CONCLUSIONS: Both GKRP and ChREBP mediate F1P-stimulated DNL in aldolase B deficient mice. Further studies are needed to unravel the role of GKRP and hepatic ChREBP in regulating IHL accumulation in aldolase B deficiency.

AARC Clinical Practice Guideline: Patient-Ventilator Assessment.

Given the important role of patient-ventilator assessments in ensuring the safety and efficacy of mechanical ventilation, a team of respiratory therapists and a librarian used Grading of Recommendations, Assessment, Development, and Evaluation methodology to make the following recommendations: (1) We recommend assessment of plateau pressure to ensure lung-protective ventilator settings (strong recommendation, high certainty); (2) We recommend an assessment of tidal volume (VT) to ensure lung-protective ventilation (4-8 mL/kg/predicted body weight) (strong recommendation, high certainty); (3) We recommend documenting VT as mL/kg predicted body weight (strong recommendation, high certainty); (4) We recommend an assessment of PEEP and auto-PEEP (strong recommendation, high certainty); (5) We suggest assessing driving pressure to prevent ventilator-induced injury (conditional recommendation, low certainty); (6) We suggest assessing FIO2 to ensure normoxemia (conditional recommendation, very low certainty); (7) We suggest telemonitoring to supplement direct bedside assessment in settings with limited resources (conditional recommendation, low certainty); (8) We suggest direct bedside assessment rather than telemonitoring when resources are adequate (conditional recommendation, low certainty); (9) We suggest assessing adequate humidification for patients receiving noninvasive ventilation (NIV) and invasive mechanical ventilation (conditional recommendation, very low certainty); (10) We suggest assessing the appropriateness of the humidification device during NIV and invasive mechanical ventilation (conditional recommendation, low certainty); (11) We recommend that the skin surrounding artificial airways and NIV interfaces be assessed (strong recommendation, high certainty); (12) We suggest assessing the dressing used for tracheostomy tubes and NIV interfaces (conditional recommendation, low certainty); (13) We recommend assessing the pressure inside the cuff of artificial airways using a manometer (strong recommendation, high certainty); (14) We recommend that continuous cuff pressure assessment should not be implemented to decrease the risk of ventilator-associated pneumonia (strong recommendation, high certainty); and (15) We suggest assessing the proper placement and securement of artificial airways (conditional recommendation, very low certainty).

Murine models of erythroid 5ALA synthesis disorders and their conditional synthetic lethal dependency on pyridoxine.

ABSTRACT: X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP) are uncommon diseases caused by loss-of-function and gain-of-function mutations, respectively, in the erythroid form of 5-aminolevulinic acid synthetase (ALAS), ALAS2, which encodes the first enzyme in heme biosynthesis. A related congenital sideroblastic anemia (CSA) is due to mutations in SLC25A38 (solute carrier family 25 member A38), which supplies mitochondrial glycine for ALAS2 (SLC25A38-CSA). The lack of viable animal models has limited the studies on pathophysiology and development of therapies for these conditions. Here, using CRISPR-CAS9 gene editing technology, we have generated knockin mouse models that recapitulate the main features of XLSA and XLPP; and using conventional conditional gene targeting in embryonic stem cells, we also developed a faithful model of the SLC25A38-CSA. In addition to examining the phenotypes and natural history of each disease, we determine the effect of restriction or supplementation of dietary pyridoxine (vitamin B6), the essential cofactor of ALAS2, on the anemia and porphyria. In addition to the well-documented response of XLSA mutations to pyridoxine supplementation, we also demonstrate the relative insensitivity of the XLPP/EPP protoporphyrias, severe sensitivity of the XLSA models, and an extreme hypersensitivity of the SLC25A38-CSA model to pyridoxine deficiency, a phenotype that is not shared with another mouse hereditary anemia model, Hbbth3/+ ß-thalassemia intermedia. Thus, in addition to generating animal models useful for examining the pathophysiology and treatment of these diseases, we have uncovered an unsuspected conditional synthetic lethality between the heme synthesis-related CSAs and pyridoxine deficiency. These findings have the potential to inform novel therapeutic paradigms for the treatment of these diseases.

Comparative Nutritional and Histological Analysis of Malabar Red Snapper (Lutjanus malabaricus) and Asian Seabass (Lates calcarifer).

This study offers a comprehensive morpho-histological analysis of the gastrointestinal tract (GIT) of the Malabar red snapper. A comparison of its GIT morphology with that of the Asian seabass reveals similarities and differences between the two species. Additionally, the moisture content, crude protein, and ash in the fillets of Malabar red snapper and Asian seabass were slightly different, with Malabar red snapper exhibiting higher levels of essential fatty acids. Furthermore, higher levels of the polyunsaturated fatty acid (PUFA)/saturated fatty acid (SFA) ratio and docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) ratio, and a lower omega-6/omega-3 ratio, were observed in Malabar red snapper compared to Asian seabass. The Malabar red snapper's esophagus featured protective mechanisms such as simple columnar epithelial cells, mucous-secreting glands, and goblet cells that were predominantly stained for acid and neutral mucosubstances. Furthermore, its stomach, with mucus cells that were weakly stained for acid mucosubstances, exhibited distinct regions with varying glandular densities, with the pyloric region featuring few glands. The pyloric caeca of the fish were composed of five finger-like structures and few goblet cells. Several goblet cells gradually increased from the anterior to the posterior region of the intestine. These findings provide useful insights for the aquaculture sector, focusing on Malabar red snapper.

Flow-mediated dilation is modified by exercise training status during childhood and adolescence: preliminary evidence of the youth athlete's artery.

Chronic exercise training is associated with an "athlete's artery" phenotype in young adults and an attenuated age-related decline in endothelium-dependent arterial function. Adolescence is associated with an influx of sex-specific hormones that may exert divergent effects on endothelial function, but whether training adaptations interact with biological maturation to produce a "youth athlete's artery" has not been explored. We investigated the influence of exercise-training status on endothelium-dependent arterial function during childhood and adolescence. Brachial artery flow-mediated dilation (FMD) was assessed in n = 102 exercise-trained (males, n = 25; females, n = 29) and untrained (males, n = 23; females, n = 25) youths, characterized as pre (males, n = 25; females, n = 26)- or post (males, n = 23; females, n = 28)-predicted age at peak height velocity (PHV). Baseline brachial artery diameter was larger in post- compared with pre-PHV youths (P ≤ 0.001), males compared with females (P ≤ 0.001), and trained compared with untrained youths (3.26 ± 0.51 vs. 3.11 ± 0.42 mm; P = 0.041). Brachial FMD was similar in pre- and post-PHV youths (P = 0.298), and males and females (P = 0.946). However, exercise-trained youths demonstrated higher FMD when compared with untrained counterparts (5.3 ± 3.3 vs. 3.0 ± 2.6%; P ≤ 0.001). Furthermore, brachial artery diameter (r2 = 0.142; P = 0.007 vs. r2 = 0.004; P = 0.652) and FMD (r2 = 0.138; P = 0.008 vs. r2 = 0.003; P = 0.706) were positively associated with cardiorespiratory fitness in post-, but not pre-PHV youths, respectively. Collectively, our data indicate that exercise training is associated with brachial artery remodeling and enhanced endothelial function during youth. However, arterial remodeling and endothelium-dependent function are only associated with elevated cardiorespiratory fitness during later stages of adolescence.NEW & NOTEWORTHY We report preliminary evidence of the "youth athlete's artery," characterized by training-related arterial remodeling and elevated endothelium-dependent arterial function in children and adolescents. However, training-related adaptations in brachial artery diameter and flow-mediated dilation (FMD) were associated with cardiorespiratory fitness in adolescents, but not in children. Our findings indicate that endothelium-dependent arterial function is modifiable with chronic exercise training during childhood, but the association between FMD and elevated cardiorespiratory fitness is only apparent during later stages of adolescence.

User experience of a seizure risk forecasting app: A mixed methods investigation.

OBJECTIVE: Over recent years, there has been a growing interest in exploring the utility of seizure risk forecasting, particularly how it could improve quality of life for people living with epilepsy. This study reports on user experiences and perspectives of a seizure risk forecaster app, as well as the potential impact on mood and adjustment to epilepsy. METHODS: Active app users were asked to complete a survey (baseline and 3-month follow-up) to assess perspectives on the forecast feature as well as mood and adjustment. Post-hoc, nine neutral forecast users (neither agreed nor disagreed it was useful) completed semi-structured interviews, to gain further insight into their perspectives of epilepsy management and seizure forecasting. Non-parametric statistical tests and inductive thematic analyses were used to analyse the quantitative and qualitative data, respectively. RESULTS: Surveys were completed by 111 users. Responders consisted of "app users" (n = 58), and "app and forecast users" (n = 53). Of the "app and forecast users", 40 % believed the forecast was accurate enough to be useful in monitoring for seizure risk, and 60 % adopted it for purposes like scheduling activities and helping mental state. Feeling more in control was the most common response to both high and low risk forecasted states. In-depth interviews revealed five broad themes, of which 'frustrations with lack of direction' (regarding their current epilepsy management approach), 'benefits of increased self-knowledge' and 'current and anticipated usefulness of forecasting' were the most common. SIGNIFICANCE: Preliminary results suggest that seizure risk forecasting can be a useful tool for people with epilepsy to make lifestyle changes, such as scheduling daily events, and experience greater feelings of control. These improvements may be attributed, at least partly, to the improvements in self-knowledge experienced through forecast use.

A Next-Generation BRAF Inhibitor Overcomes Resistance to BRAF Inhibition in Patients with BRAF-Mutant Cancers Using Pharmacokinetics-Informed Dose Escalation.

RAF inhibitors have transformed treatment for patients with BRAFV600-mutant cancers, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAFV600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by a narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAFV600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in patients with BRAF-mutant cancer who were refractory to approved RAF inhibitors. Significance: PF-07799933 treatment was associated with antitumor activity against BRAFV600- and non-V600-mutant cancers preclinically and in treatment-refractory patients, and PF-07799933 could be safely combined with a MEK inhibitor. The novel, rapid pharmacokinetics (PK)-informed dose escalation design provides a new paradigm for accelerating the testing of next-generation targeted therapies early in clinical development.

Prediction of viral spillover risk based on the mass action principle.

Infectious zoonotic disease emergence, through spillover events, is of global concern and has the potential to cause significant harm to society, as recently demonstrated by COVID-19. More than 70% of the 400 infectious diseases that emerged in the past five decades have a zoonotic origin, including all recent pandemics. There have been several approaches used to predict the risk of spillover through some of the known or suspected infectious disease emergence drivers, largely using correlative approaches. Here, we predict the spatial distribution of spillover risk by approximating general transmission through animal and human interactions. These mass action interactions are approximated through the multiplication of the spatial distribution of zoonotic virus diversity and human population density. Although our results indicate higher risk in regions along the equator and in Southeast Asia where both virus diversity and human population density are high, it should be noted that this is primarily a conceptual exercise. We compared our spillover risk map to key factors, including the model inputs of zoonotic virus diversity estimate map, human population density map, and the spatial distribution of species richness. Despite the limitations of this approach, this viral spillover map is a step towards developing a more comprehensive spillover risk prediction system to inform global monitoring.