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Abstract Study Objectives Periodic limb movements (PLMs) of sleep, which may be linked to increased vascular events via nighttime sympathetic overactivity, have shown associations with cerebral small vessel disease (CSVD) in small studies. This study examined the relationship between PLMs and CSVD in a larger cohort, accounting for comorbidities. Methods Patients with first-ever stroke or transient ischemic attack (TIA) were retrospectively analyzed. Polysomnography assessed the PLM index (PLMI) and PLM arousal index (PLMAI). CSVD was measured using radiographic markers, including the Fazekas score, total age-related white matter changes (ARWMC) score, microbleed counts, and lacunar infarcts. Multivariable regression models analyzed the association between an elevated PLMI and PLMAI with CSVD markers. Results This study included 86 patients (mean age 62.2 ± 14.3 years, 66.3% male, mean BMI 28.1 ± 5.7), 36 with a PLMI ≥ 5 (41.9%) and 11 with a PLMAI ≥ 5 (12.8%). Regression analyses showed that PLMI ≥ 5 and PLMAI ≥ 5 both predicted increased Fazekas and ARWMC total scores after adjusting for age, sex, BMI, and other comorbidities. Sensitivity analyses using age- and sex-specific PLMI cutoffs also showed that a PLMI exceeding the upper limit of normal predicted an increased Fazekas score and approached significance for the ARWMC score. PLMI was not significantly associated with cerebral microbleeds or lacunar infarcts. Conclusions In patients with first-ever minor stroke and TIA, a significant association was observed between PLMI and PLMAI with white matter hyperintensities (WMHs) after adjusting for confounders. Future studies may help determine the directionality of this association and whether PLMs independently predict CSVD. Clinical Trial Information Name: Sleep Disorders Managed and Assessed Rapidly in Transient Ischemic Attack (TIA) and In Early Stroke (SMARTIES). URL: https://clinicaltrials.gov/study/NCT01528462 ClinicalTrials.gov ID: NCT01528462. Name: SLEep APnea Screening Using Mobile Ambulatory Recorders After TIA/Stroke (SLEAP SMART). URL: https://clinicaltrials.gov/study/NCT02454023. ClinicalTrials.gov ID: NCT02454023. Graphical Abstract Graphical Abstract

Periodic limb movements (PLMs) of sleep, which may be linked to increased vascular events via nighttime sympathetic overactivity, have shown associations with cerebral small vessel disease (CSVD) in small studies. This study examined the relationship between PLMs and CSVD in a larger cohort, accounting for comorbidities.STUDY OBJECTIVESPeriodic limb movements (PLMs) of sleep, which may be linked to increased vascular events via nighttime sympathetic overactivity, have shown associations with cerebral small vessel disease (CSVD) in small studies. This study examined the relationship between PLMs and CSVD in a larger cohort, accounting for comorbidities.Patients with first-ever stroke or transient ischemic attack (TIA) were retrospectively analyzed. Polysomnography assessed the PLM index (PLMI) and PLM arousal index (PLMAI). CSVD was measured using radiographic markers, including the Fazekas score, total age-related white matter changes (ARWMC) score, microbleed counts, and lacunar infarcts. Multivariable regression models analyzed the association between an elevated PLMI and PLMAI with CSVD markers.METHODSPatients with first-ever stroke or transient ischemic attack (TIA) were retrospectively analyzed. Polysomnography assessed the PLM index (PLMI) and PLM arousal index (PLMAI). CSVD was measured using radiographic markers, including the Fazekas score, total age-related white matter changes (ARWMC) score, microbleed counts, and lacunar infarcts. Multivariable regression models analyzed the association between an elevated PLMI and PLMAI with CSVD markers.This study included 86 patients (mean age 62.2±14.3 years, 66.3% male, mean BMI 28.1±5.7), 36 with a PLMI ≥5 (41.9%) and 11 with a PLMAI ≥5 (12.8%). Regression analyses showed that PLMI ≥5 and PLMAI ≥5 both predicted increased Fazekas and ARWMC total scores after adjusting for age, sex, BMI, and other comorbidities. Sensitivity analyses using age- and sex-specific PLMI cut-offs also showed that a PLMI exceeding the upper limit of normal predicted an increased Fazekas score and approached significance for the ARWMC score. PLMI was not significantly associated with cerebral microbleeds or lacunar infarcts.RESULTSThis study included 86 patients (mean age 62.2±14.3 years, 66.3% male, mean BMI 28.1±5.7), 36 with a PLMI ≥5 (41.9%) and 11 with a PLMAI ≥5 (12.8%). Regression analyses showed that PLMI ≥5 and PLMAI ≥5 both predicted increased Fazekas and ARWMC total scores after adjusting for age, sex, BMI, and other comorbidities. Sensitivity analyses using age- and sex-specific PLMI cut-offs also showed that a PLMI exceeding the upper limit of normal predicted an increased Fazekas score and approached significance for the ARWMC score. PLMI was not significantly associated with cerebral microbleeds or lacunar infarcts.In patients with first-ever minor stroke and TIA, a significant association was observed between PLMI and PLMAI with white matter hyperintensities (WMHs) after adjusting for confounders. Future studies may help determine the directionality of this association and whether PLMs independently predict CSVD.CONCLUSIONSIn patients with first-ever minor stroke and TIA, a significant association was observed between PLMI and PLMAI with white matter hyperintensities (WMHs) after adjusting for confounders. Future studies may help determine the directionality of this association and whether PLMs independently predict CSVD.

Active galactic nuclei (AGN) can vary significantly in their rest-frame optical/UV continuum emission, and with strong associated changes in broad line emission, on much shorter timescales than predicted by standard models of accretion disks around supermassive black holes. Most such changing-look or changing-state AGN—and at higher luminosities, changing-look quasars (CLQs)—have been found via spectroscopic follow-up of known quasars showing strong photometric variability. The Time Domain Spectroscopic Survey of the Sloan Digital Sky Survey IV (SDSS-IV) includes repeat spectroscopy of large numbers of previously known quasars, many selected irrespective of photometric variability, and with spectral epochs separated by months to decades. Our visual examination of these repeat spectra for strong broad line variability yielded 61 newly discovered CLQ candidates. We quantitatively compare spectral epochs to measure changes in continuum and Hβ broad line emission, finding 19 CLQs, of which 15 are newly recognized. The parent sample includes only broad line quasars, so our study tends to find objects that have dimmed, i.e., turn-off CLQs. However, we nevertheless find four turn-on CLQs that meet our criteria, albeit with broad lines in both dim and bright states. We study the response of Hβ and Mg ii emission lines to continuum changes. The Eddington ratios of CLQs are low, and/or their Hβ broad line width is large relative to the overall quasar population. Repeat quasar spectroscopy in the upcoming SDSS-V black hole Mapper program will reveal significant numbers of CLQs, enhancing our understanding of the frequency and duty cycle of such strong variability, and the physics and dynamics of the phenomenon.

Gyrochronology, a valuable tool for determining ages of low-mass stars where other techniques fail, relies on accurate calibration. We present a sample of 185 wide (>100 au) white dwarf + main sequence (WD + MS) binaries. Total ages of WDs are computed using all-sky survey photometry, Gaia parallaxes, and WD atmosphere models. Using a magnetic braking law calibrated against open clusters, along with assumptions about initial conditions and angular momentum transport, we construct gyrochrones to predict the rotation periods of MS stars. Both data and models show that, at the fully convective boundary (FCB), MS stars with WD ages of up to 7.5 Gyr and within a <50 K effective temperature range experience up to a threefold increase in rotation period relative to stars slightly cooler than the FCB. We suggest that rapid braking at this boundary is driven by a sharp rise in the convective overturn timescale (τ cz) caused by structural changes between partially and fully convective stars and the 3He instability occurring at this boundary. While the specific location in mass (or temperature) of this feature varies with model physics, we argue that its existence remains consistent. Stars along this feature exhibit rotation periods that can be mapped, within 1σ, to a range of gyrochrones spanning ≈6 Gyr. Due to current temperature errors (≃50 K), this implies that a measured rotation period cannot be uniquely associated to a single gyrochrone, implying that gyrochronology may not be feasible for M dwarfs very close to the FCB.

There are currently no specific biomarkers to identify patients with abdominal aortic aneurysms (AAAs). Circulating exosomes contain microRNAs (miRNA) that are potential biomarkers for the presence of disease. This study aimed to characterize the exosomal miRNA expression profile of patients with AAAs in order to identify novel biomarkers of disease. Patients undergoing duplex ultrasound (US) or computed tomography (CT) for screening or surveillance of an AAA were screened to participate in the study. Cases with AAA were defined as having a max aortic diameter >3 cm. Circulating plasma exosomes were isolated using Cushioned-Density Gradient Ultracentrifugation and total RNA was extracted. Next Generation Sequencing was performed on the Illumina HiSeq4000 SE50. Differential miRNA expression analysis was performed using DESeq2 software with a Benjamini-Hochberg correction. MicroRNA expression profiles were validated by Quantitative Real-Time PCR. A total of 109 patients were screened to participate in the study. Eleven patients with AAA and 15 non-aneurysmal controls met study criteria and were enrolled. Ultrasound measured aortic diameter was significantly larger in the AAA group (mean maximum diameter 4.3 vs 2.0 cm, P = 6.45x10-6). More AAA patients had coronary artery disease (5/11 vs 1/15, P = 0.05) as compared to controls, but the groups did not differ significantly in the rates of peripheral arterial disease and chronic obstructive pulmonary disease. A total of 40 miRNAs were differentially expressed (P<0.05). Of these, 18 miRNAs were downregulated and 22 were upregulated in the AAA group compared to controls. After false discovery rate (FDR) adjustment, only miR-122-5p was expressed at significantly different levels in the AAA group compared to controls (fold change = 5.03 controls vs AAA; raw P = 1.8x10-5; FDR P = 0.02). Plasma exosomes from AAA patients have significantly reduced levels of miRNA-122-5p compared to controls. This is a novel exosome-associated miRNA that warrants further investigation to determine its use as a diagnostic biomarker and potential implications in AAA pathogenesis.

Oxidative catalytic depolymerization of polystyrene (PS) can produce benzoic acid, but the annual consumption of benzoic acid is ~40 times lower than PS. For this catalytic oxidation method to be a viable means to manage PS waste, benzoic acid should be converted to higher-volume chemicals. We demonstrate a hybrid chemical and biological process that uses PS as feedstock for production of adipic acid, a high-volume co-monomer for nylon 6,6 via benzoic acid. Mn/Br co-catalyzed autoxidation of PS to benzoic acid proceeds with a yield of up to 94% in a solvent mixture of benzoic acid and water. The PS-derived benzoic acid undergoes bioconversion at near-quantitative yield to muconic acid, which is readily converted to adipic acid through catalytic hydrogenation. Process modeling, techno-economic analysis, and life cycle assessment estimate an adipic acid minimum selling price of $3.18/kg, with a 61% decrease in greenhouse gas emissions relative to production from fossil fuels. Oxidative catalytic depolymerization of polystyrene (PS) can produce benzoic acid, but the annual consumption of benzoic acid is ~40 times lower than PS, so benzoic acid should be converted to higher-volume chemicals for the process to be viable. Here, the authors report a hybrid chemical and biological process that uses PS as feedstock for production of adipic acid, a high-volume co-monomer for nylon 6,6, via benzoic acid.

Malnutrition is common in haemodialysis patients and closely related to morbidity and mortality. We evaluated the effect of twelve weeks of supplementation with resveratrol and curcumin on recovery of bone and muscle mass and protein oxidation, lipid peroxidation on patients with chronic kidney disease and iron overload undergoing hemodialysis, we performed a randomized, double-blind, placebo-controlled trial. We included a total of 40 patients, were randomly assigned to two groups, 20 to the group with antioxidant supplementation (Resveratrol + Curcumin) (Group A), treated with a daily oral dose of 500 mg of Resveratrol and 500 mg of Curcumin, and 20 to the control group treated with placebo (Group B). Significant differences were found in the body composition of the patients between both groups. There was a significant difference in Body Mass Index (BMI) values (p = 0.002), fat percentage (p = 0.007), muscle mass (p = 0.01) bone mass (p = 0.01), as well as in the score of the subjective global evaluation (p = 0.03). Also differences were found between the basal and final serum levels of Triglycerides (TG) (p = 0.01), VLDL (p = 0.003). A significant decrease in the levels of serum ferritin (2003.69 ± 518.73 vs 1795.65 ± 519.00 ng/mL; p = 0.04). Nor were significant differences observed between the baseline and the final Thiobarbituric Acid Reactive Substances (TBARS) values (70.45 ± 69.21 vs 50.19 ± 32.62, p = 0.24). The same results was obtained for carbonyl values (2.67 ± 0.75 vs 2.50 ± 0.85; p = 0.50). The present study is the first assay on patients with chronic kidney disease and iron overload that demonstrates the beneficial effects of combined supplementation with Curcumin and Resveratrol on muscle and bone mass. There was a significant decrease in circulating levels of ferritin, to finding that remarkably novel.

Abstract Background The National Cancer Institute-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice (MATCH) precision oncology platform trial enrolled children aged 1-21 years with treatment-refractory solid tumors and predefined actionable genetic alterations. Patients with tumors harboring alterations in DNA damage repair (DDR) genes were assigned to receive olaparib. Methods Tumor and blood samples were submitted for centralized molecular testing. Tumor and germline sequencing were conducted in parallel. Olaparib was given twice daily for 28-day cycles starting at a dose 30% lower than the adult recommended phase 2 dose (RP2D). The primary endpoint was the objective response. Results Eighteen patients matched (1.5% of those screened) based on the presence of a deleterious gene alteration in BRCA1/2, RAD51C/D, or ATM detected by tumor sequencing without germline subtraction or analysis of loss of heterozygosity (LOH). Eleven (61%) harbored a germline mutation, with only one exhibiting LOH. Six patients enrolled and received the olaparib starting dose of 135 mg/m2/dose. Two participants were fully evaluable; 4 were inevaluable because <85% of the prescribed dose was administered during cycle 1. There were no dose-limiting toxicities or responses. Minimal hematologic toxicity was observed. Conclusion Most DDR gene alterations detected in Pediatric MATCH were germline, monoallelic, and unlikely to confer homologous recombination deficiency predicting sensitivity to olaparib monotherapy. The study closed due to poor accrual. ClinicalTrials.gov Identifier NCT03233204. IRB approved: initial July 24, 2017. This article reports clinical trial results of the National Cancer Institute-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice precision oncology platform trial, which enrolled patients aged 1-21 years with treatment-refractory solid tumors and predefined actionable genetic alterations. Those with tumors harboring alterations in DNA damage repair genes were assigned to receive olaparib.

Brewers’ spent grain (BSG) is the most abundant byproduct generated from the beer-brewing process. BSG is a material rich in hemicellulose, composed of arabinoxylans (AX). However, the high crosslinking of this material causes low availability of AX, for which it is necessary to apply different treatments. The objective of this research is to increase the release of arabinoxylans through solid-state fermentation with Fusarium oxysporum f. sp. lycopersici using extruded brewery spent grain. First, the BSG is subjected to two types of physical treatments: extrusion at 20% moisture, 200 rpm and 50 °C (BSGe), and blade milling (BSGm). The chemical composition is determined for each sample (BSG, BSGe and BSGm). Subsequently, the solid-state fermentation process (SSF) is carried out on each sample. The fermentation kinetics at 30 °C are monitored for 7 days. Once the SSF concludes, AX are extracted, and the purity of AX is determined by the phloroglucinol colorimetric assay. Finally, the total phenolic compounds, phenolic acids and antioxidant capacity by DPPH are quantified. No significant differences (p ≥ 0.05) in the protein, lipid, ash or total dietary fiber contents are found among the samples. No significant difference (p ≥ 0.05) in the content of soluble fiber is found, although BSGe and BSGm have higher values than BSG. On the other hand, the yields of soluble AX exhibit significant differences (p ≤ 0.05) among nonfermented samples (BSG, 0.03%; BSGm, 0.53%; BSGe, 0.70%) and with SSF (BSG, 2.95%; BSGm, 6.24%; and BSGe, 9.58%). In addition, the contents of free phenolic compounds and free phenolic acids and the percent inhibition of free extracts by 2,2-diphenyl-1-picrylhydrazyl (DPPH) differ significantly (p ≤ 0.05) between samples subjected to SSF and nonfermented samples. Therefore, extrusion and SSF treatment increase AX release from BSG as well as the antioxidant capacity of the extracts.

Theory and models suggest the Gulf Stream may shift northwards under projected Atlantic Meridional Overturning Circulation weakening. Yet Gulf Stream behaviour during past abrupt cold events remains poorly constrained. Here we present high-resolution paleoceanographic records from the Northwest Atlantic during the last deglaciation. During the Younger Dryas cold period, we document a northward Gulf Stream shift evidenced from coherent surface and subsurface warming. Our sortable silt data suggest a strengthening of upper North Atlantic Deep Water that opposes weakening lower North Atlantic Deep Water, consistent with a seesaw feedback between the Nordic overflows and subpolar gyre. Our results constrain a co-ordinated sequence at the Younger Dryas onset: initial lower North Atlantic Deep Water weakening and subpolar sea‑ice expansion, lagged (58 ± 38 yr) by an increase in upper North Atlantic Deep Water and an eventual atmospheric reorganization (84 ± 51 yr after onset). These findings provide empirical support for model projections of future Gulf Stream shifts. Paleoceanographic reconstructions from the Northwest Atlantic reveal coordinated shifts in Gulf Stream position and upper and lower North Atlantic Deep Water formation during past abrupt climate events, offering insights for future climate change.