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Competing Interests: Conflict of interest: None declared.

Selective imaging of specific subcellular structures provides valuable information about the cellular microenvironment. Materials exhibiting thermally activated delayed fluorescence (TADF) are rapidly emerging as metal-free probes with long-lived emission for intracellular time-gated imaging applications. Polymers incorporating TADF emitters can self-assemble into luminescent nanoparticles, termed polymer dots (Pdots), and this strategy enables them to circumvent the limitations of commercial organelle trackers and small molecule TADF emitters. In this study, diblock copolymers comprised of a hydrophilic block containing organelle-targeting monomers and a hydrophobic TADF-active block were synthesized by ring-opening metathesis polymerization (ROMP). Oxanorbornene-based monomers incorporating morpholine and triphenylphosphonium groups for lysosome and mitochondria targeting, respectively, were also synthesized. ROMP by sequential addition yielded well-defined diblock copolymers with dispersities <1.28. To analyze the effect of tuning the hydrophilic corona on cellular viability and uptake, we prepared Pdots with poly(ethylene glycol) (PEG) and bis-guanidinium (BGN) coronas, resulting in limited and efficient cellular uptake, respectively. Red-emissive Pdots with BGN-based coronas and organelle-targeting functionality were obtained with quantum yields up to 12% in water under air. Colocalization analysis confirmed that lysosome and mitochondria labeling in live HeLa cells was accomplished within 2 h of incubation, affording Pearson's correlation coefficients of 0.37 and 0.70, respectively. The potential application of these Pdots for time-resolved imaging is highlighted by a proof of concept using time-gated spectroscopy, which effectively separates the delayed emission of the TADF Pdots from the background autofluorescence of biological serum.

Multi-resonance thermally activated delayed fluorescence (MR-TADF) materials are of interest for light-emitting applications due to their narrow emission bandwidths and high photoluminescence quantum yields. Whilst there have been numerous examples of multi-resonance molecules exhibiting efficient TADF, the photophysics and mechanism of TADF in multi-resonance emitters have not been investigated to the same extent as the more conventional spatially separated donor-acceptor TADF materials, limiting the development of MR-TADF devices. Here we study the photophysics of a multi-resonance TADF material, OQAO(mes) 2 , using transient absorption spectroscopy to spectrally resolve the triplet population(s). We identify multiple triplet populations with distinct spectral contributions, and resolve the dynamics between them. Unlike conventional donor-acceptor TADF materials that have previously been studied, we find these triplet states are not formed in equilibrium, instead exhibiting a slow evolution from a high-energy triplet to a low-energy triplet. Delayed fluorescence predominantly reflects the lifetime of the high-energy triplet state, indicating that the formation of the low-energy triplet is a loss pathway for TADF. We also find that greater amounts of the low-energy triplet are formed in a higher dielectric environment, which leads to less delayed fluorescence. These triplet dynamics have significant implications for TADF in devices, as depending on the identity of the triplet formed by electrical excitation, there will either be a significant barrier to TADF, or a competing nonradiative decay pathway., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The Knight-Alzheimer Disease Research Center (Knight-ADRC) at Washington University in St. Louis has pioneered and led worldwide seminal studies that have expanded our clinical, social, pathological, and molecular understanding of Alzheimer Disease. Over more than 40 years, research volunteers have been recruited to participate in cognitive, neuropsychologic, imaging, fluid biomarkers, genomic and multi-omic studies. Tissue and longitudinal data collected to foster, facilitate, and support research on dementia and aging. The Genetics and high throughput -omics core (GHTO) have collected of more than 26,000 biological samples from 6,625 Knight-ADRC participants. Samples available include longitudinal DNA, RNA, non-fasted plasma, cerebrospinal fluid pellets, and peripheral blood mononuclear cells. The GHTO has performed deep molecular profiling (genomic, transcriptomic, epigenomic, proteomic, and metabolomic) from large number of brain (n = 2,117), CSF (n = 2,012) and blood/plasma (n = 8,265) samples with the goal of identifying novel risk and protective variants, identify novel molecular biomarkers and causal and druggable targets. Overall, the resources available at GHTO support the increase of our understanding of Alzheimer Disease., (© 2024. The Author(s).)

Alzheimer's Disease (AD) biomarker measurement is key to aid in the diagnosis and prognosis of the disease. In the research setting, participant recruitment and retention and optimization of sample use, is one of the main challenges that observational studies face. Thus, obtaining accurate established biomarker measurements for stratification and maximizing use of the precious samples is key. Accurate technologies are currently available for established biomarkers, mainly immunoassays and immunoprecipitation liquid chromatography-mass spectrometry (IP-MS), and some of them are already being used in clinical settings. Although some immunoassays- and IP-MS based platforms provide multiplexing for several different coding proteins there is not a current platform that can measure all the stablished and emerging biomarkers in one run. The NUcleic acid Linked Immuno-Sandwich Assay (NULISA ™ ) is a mid-throughput platform with antibody-based measurements with a sequencing output that requires 15μL of sample volume to measure more than 100 analytes, including those typically assayed for AD. Here we benchmarked and compared the AD-relevant biomarkers including in the NULISA against validated assays, in both CSF and plasma. Overall, we have found that CSF measures of Aß42/40, NfL, GFAP, and p-tau217 are highly correlated and have similar predictive performance when measured by immunoassay, mass-spectrometry or NULISA. In plasma, p-tau217 shows a performance similar to that reported with other technologies when predicting amyloidosis. Other established and exploratory biomarkers (total tau, p-tau181, NRGN, YKL40, sTREM2, VILIP1 among other) show a wide range of correlation values depending on the fluid and the platform. Our results indicate that the multiplexed immunoassay platform produces reliable results for established biomarkers in CSF that are useful in research settings, with the advantage of measuring additional novel biomarkers using minimal sample volume., Competing Interests: RB has received funding from NIH, Alzheimer’s Association, Biogen, AbbVie, Bristol Meyer Squibbs, Novartis, and EISAI. RB has equity and is on the scientific advisory board of C2N Diagnostics. SES has served on advisory boards and consulted on biomarker testing for Eisai, and she has received speaker fees from Eli Lilly. DMH has equity and is on the scientific advisory board of C2N Diagnostics. DMH is on the scientific advisory board of Denali, Genentech, and Cajal Neuroscience and consults for Asteroid. TLSB received research funding from Siemens and is an investigator on clinical trials and studies of AD with partial support from Eisai, Lilly, Roche, Janssen, and Biogen. TLSB is a consultant to Eisai. CC has received research support from: GSK and Eisai. CC is a member of the advisory board of Circular Genomics and owns stocks. CC is a member of the advisory board of ADmit. The other authors report no conflict of interest. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Alzheimer Disease (AD) is a highly polygenic disease that presents with relatively earlier onset (≤70yo; EOAD) in about 5% of cases. Around 90% of these EOAD cases remain unexplained by pathogenic mutations. Using data from EOAD cases and controls, we performed a genome-wide association study (GWAS) and trans-ancestry meta-analysis on non-Hispanic Whites (NHW, NCase=6,282, NControl=13,386), African Americans (AA NCase=782, NControl=3,663) and East Asians (NCase=375, NControl=838 CO). We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, eQTL, pQTL and functional annotations, we nominate four novel genes that are involved in microglia activation, glutamate production, and signaling pathways. These results indicate that EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.

Objective: To determine whether pediatric emergency medicine physicians are compliant with the 9-year-old simple febrile seizure guideline created by the American Academy of Pediatrics (AAP)., Methods: A retrospective chart review of patients, ages 6 to 60 months, who presented to the emergency department between May 2011 and December 2019. Key variables abstracted were urine, blood, nasal viral swab, and radiographic results., Results: The retrospective cohort of 285 children met inclusion criteria. Among 285 children, 342 studies were performed with a median of 1.2 studies per patient. There were 77 urine cultures obtained with 6 bacterial pathogens. Nasal viral swabs were performed on 65 children with 9 positive results. Blood cultures were obtained for 28 children and none were positive. Chest radiographs were performed on 37 children with 4 showing pneumonia., Conclusion: The study results reflect areas of opportunity to update guidelines with a focus to consider obtaining urine studies, viral sampling, and chest x-rays., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In recent years, hydrogen bonding (H bonding) as an intramolecular locking strategy has been proposed to enhance photoluminescence, color purity, and photostability in thermally activated delayed fluorescence (TADF) materials. Rigidification as a design strategy is particularly relevant when using electron-deficient N -heterocycles as electron acceptors, because these materials often suffer from poor performance as orange to near-infrared emitters as a result of the energy gap law. To critically evaluate the presence of H bonding in such materials, two TADF-active donor-acceptor dyads, ACR-DQ and ACR-PQ, were synthesized. Despite their potential sites for intramolecular H bonding and emissions spanning yellow to deep red, computational analyses (including frequency, natural bond orbital, non-covalent interaction, and potential energy surface assessments) and crystal structure examinations collectively suggest the absence of H bonding in these materials. Our results indicate that invoking intramolecular H bonding should be done with caution in the design of rigidified TADF materials.

Background: Left ventricular hypertrophy (LVH) in patients with end stage renal disease undergoing renal replacement is linked to an increased risk for cardiovascular diseases. Dialysis does not completely prevent or correct this abnormality, and the evidence for kidney transplantation (KT) varies. This analysis aims to explore the relationship between KT and LVH., Methods: MEDLINE and Scopus were systematically searched in October 2023. All cross-sectional and longitudinal studies that fulfilled our inclusion criteria were included. Outcome was left ventricular mass index (LVMI) changes. We conducted a meta-analysis using a random effects model. Meta-regression was applied to examine the LVMI changes dependent on various covariates. Sensitivity analysis was used to handle outlying or influential studies and address publication bias., Results: From 7416 records, 46 studies met the inclusion criteria with 4122 included participants in total. Longitudinal studies demonstrated an improvement of LVMI after KT -0.44 g/m 2 (-0.60 to -0.28). Blood pressure was identified as a predictor of LVMI change. A younger age at the time of KT and well-controlled anemia were also associated with regression of LVH. In studies longitudinally comparing patients on dialysis and renal transplant recipients, no difference was detected -0.09 g/m 2 (-0.33 to 0.16). Meta-regression using changes of systolic blood pressure as a covariate showed an association between higher blood pressure and an increase in LVMI, regardless of the modality of renal replacement treatment., Conclusions: In conclusion, our results indicated a potential cardiovascular benefit, defined as the regression of LVH, after KT. This benefit was primarily attributed to improved blood pressure control rather than the transplantation itself., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Recent work demonstrated stimulated Raman adiabatic passage-type transfer of energy along 3 acoustic cavities. After brief comments on the stimulated Raman adiabatic passage method, remarks on the scientific and technological relevance of this work are presented, followed by noting other recent important applications of the process., Competing Interests: Competing interests: The author declares he has no competing interests., (Copyright © 2024 Klaas Bergmann.)

Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical and neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal molecular profiles, one of them showing signs of poor cognitive function, a faster pace of disease progression, shorter survival with the disease, severe neurodegeneration and astrogliosis, and reduced levels of metabolomic profiles. We found this molecular profile to be present in multiple affected cortical regions associated with higher Braak tau scores and significant dysregulation of synapse-related genes, endocytosis, phagosome, and mTOR signaling pathways altered in AD early and late stages. AD cross-omics data integration with transcriptomic data from an SNCA mouse model revealed an overlapping signature. Furthermore, we leveraged single-nuclei RNA-seq data to identify distinct cell-types that most likely mediate molecular profiles. Lastly, we identified that the multimodal clusters uncovered cerebrospinal fluid biomarkers poised to monitor AD progression and possibly cognition. Our cross-omics analyses provide novel critical molecular insights into AD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Eteleeb et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purely organic materials exhibiting room temperature phosphorescence (RTP) are promising candidates for oxygen sensors and information encryption owing to their cost-effective and environmentally friendly nature. Herein, we report a bimolecular RTP system where DTBU acts as the guest and TBBU serves as the host. In contrast to previously reported results, we find that both pure DTBU and TBBU do not exhibit RTP in the solid state even under N 2 atmosphere. A DTBU/TBBU system with a low doping ratio (0.1 mol %) exhibits persistent yellowish-green afterglow with a lifetime of 340 ms and is highly sensitive to oxygen. A DTBU/TBBU system with a higher doping ratio (10 mol %) maintains a phosphorescence lifetime of 179 ms under air. Applications of DTBU/TBBU at varied doping ratios in both oxygen sensing and information encryption are demonstrated. We propose that the T 1 state of TBBU acts as an energy transfer intermediate between T n and T 1 of DTBU, ultimately leading to the generation of persistent RTP. Overall, this work demonstrates the critical importance of material purity in the design of RTP systems, and how an understanding of host-guest doping enables their photophysical properties to be precisely tuned., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Heptazine-based materials have recently emerged as a promising motif for thermally activated delayed fluorescence, as their near-zero or negative singlet-triplet energy gaps enable extremely fast reverse intersystem crossing (rISC) rates. Another method for achieving a high rate of rISC is through the use of highly symmetric emitters, which benefit from energy-level degeneracies and a high density of states. Here, we investigate the effect of combining these two design strategies on the excited-state dynamics of C 3 -symmetric emitters containing heptazine cores. We find that in two of the four emitters studied, the S 1 state has a high degree of locally excited (LE) character with density on the heptazine moiety, preventing excited-state localization and a loss of symmetry in the energy-minimized S 1 geometry. Surprisingly, these symmetric molecules still suffer from a loss of density of triplet states below the S 1 state. Overall, we find that maintaining C 3 symmetry will not necessarily maintain density of states, but that heptazine-based materials with LE S 1 states still benefit from maximized rISC rates via increased spin-orbit coupling with low-lying charge-transfer triplet states and exhibit advantageous photophysical properties, such as near-unity photoluminescence quantum yields and high colour purity.

Clusters supported by solid substrates are prime candidates for heterogeneous catalysis and can be prepared in various ways. While mass-selected soft-landing methods are often used for the generation of monodisperse particles, self-assembly typically leads to a range of different cluster sizes. Here we show by scanning tunneling microscopy measurements that in the initial stages of growth, Mn forms trimers on a close-packed hexagonal Ir surface, providing a route for self-organized monodisperse cluster formation on an isotropic metallic surface. For an increasing amount of Mn, first a phase with reconstructed monolayer islands is formed, until at full coverage a pseudomorphic Mn phase evolves, which is the most densely packed one of the three different observed Mn phases on Ir(111). The magnetic state of both the reconstructed islands and the pseudomorphic film is found to be the prototypical antiferromagnetic Néel state with a 120° spin rotation between all nearest neighbors in the hexagonal layer.

Metabolic dysfunction-associated fatty liver disease (MAFLD) may progress to advanced liver fibrosis (ALF). We evaluated the diagnostic accuracy of a novel Liver Fibrosis Risk Index (LFRI) in MAFLD subjects using transient elastography (TE) as the reference method for liver fibrosis measurement and then the diagnostic performance of a new two-step non-invasive algorithm for the detection of ALF risk in MAFLD, using Fibrosis-4 (FIB-4) followed by LFRI and comparing it to the reference algorithm based on FIB-4 and TE. We conducted a prospective study on 104 MAFLD European adult subjects. All consenting subjects underwent TE and measurements of FIB-4 and LFRI. For FIB-4 and TE, validated cut-offs were used. An ROC analysis showed that LFRI diagnosed severe fibrosis with moderate accuracy in MAFLD subjects with a negative predictive value above 90%. Using the new algorithm with LFRI thresholds recommended by the manufacturer, the number of subjects classified into ALF risk groups (low, intermediate, or high) differed significantly when compared with the reference algorithm ( p = 0.001), with moderate agreement between them (weighted kappa (95% CI) = 0.59 (0.41-0.77)). To improve the performance of the LFRI-based algorithm, we modified cut-off points based on ROC curves obtained by dividing the study population according to the reference algorithm and observed no difference between algorithms ( p = 0.054) in categorizing ALF risk, with a slight increase in the total agreement (weighted kappa (95% CI) = 0.63 (0.44-0.82)). Our findings suggest that using the novel LFRI as a second-line test may represent a potential alternative for liver fibrosis risk stratification in MAFLD patients; however, modified cut-offs are needed to optimize its performance.

There is a need for affordable, scalable, and specific blood-based biomarkers for Alzheimer's disease that can be applied to a population level. We have developed and validated disease-specific cell-free transcriptomic blood-based biomarkers composed by a scalable number of transcripts that capture AD pathobiology even in the presymptomatic stages of the disease. Accuracies are in the range of the current CSF and plasma biomarkers, and specificities are high against other neurodegenerative diseases., Competing Interests: The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of Vivid Genetics, Halia Therapeutics, and ADx Healthcare and has received research support from Biogen, EISAI, Alector and Parabon. The rest of the authors report no conflict of interest. Patent Pending., (© 2023 The Author(s).)

Multiple resonance thermally activated delayed fluorescent (MR-TADF) materials offer higher color purity than conventional TADF materials but suffer from aggregation-caused quenching (ACQ) and rarely exhibit red emission. Herein, two malononitrile-substituted emitters are synthesized from a quinolino[3,2,1- de ]acridine-5,9-dione ( QAO ) MR-TADF precursor. Both materials maintain MR-TADF, while they display red-shifted fluorescence. They also overcome ACQ, displaying enhanced emission upon aggregation in solution and forming red-emissive J-aggregates in the solid state with photoluminescent quantum yields of 9 and 11%.

Background: Finding the appropriate endovascular revascularization strategy for patients with peripheral artery disease and a popliteal artery lesion remains particulary challenging. Data regarding predictors for a beneficial outcome are scarce. Patients and methods: All endovascular procedures of popliteal artery lesions (n=227) performed in 197 patients between February 2009 and May 2018 at our institution were retrospectively analyzed. Hemodynamically relevant restenosis represented the primary endpoint. Results: The overall technical success rate was 98% and yielded 99% for stenoses (n=145) and 97% for occlusions (n=82). In a median follow-up of 10 months, the overall rate of restenosis was 23%. After 1 and 2 years, the primary patency rates were 76% and 55% and the secondary patency rate was 100%, respectively. The estimated probability of restenosis was significantly higher in stented lesions (stent vs. no stent; 36.0% vs. 19.1%; p=0.030). Multivariate analysis identified stent implantation (hazard ratio: 2.4; overall P=0.010) and diabetes (hazard ratio 2.0; P=0.023) as significant predictors for the development of restenosis. Conclusions: Endovascular therapy for popliteal artery disease was associated with high technical success rates and accompanied with a promising mid-term outcome, particularly in lesions treated with balloon angioplasty alone.

Background: Cardiac myosin-binding protein C (cMyC) is a novel cardio-specific biomarker of potential diagnostic and prognostic value for cardiovascular events. This study aims to determine reference values for cMyC and identify biological determinants of its concentration., Methods: A population of 488 presumably healthy adults were enrolled to define biological determinants which affect cMyC concentrations in serum. Concentrations of cMyC were assessed using enzyme-linked immunosorbent assays from commercially available kits. Eligibility for inclusion in this study evaluated all subjects' anthropometric, demographic and laboratory measurements. After applying strict inclusion criteria, a reference population (n=150) was defined and used to determine reference values. Reference values were derived using a robust method., Competing Interests: All the authors declare that they have no conflict of interest in this work.Conflict of Interest: The authors stated that they have no conflicts of interest regarding the publication of this article., (2023 Sylwester M. Kloska, Marek Kozinski, Anna Stefanska, Katarzyna Bergmann, Aneta Mankowska-Cyl, Joanna Siodmiak, Grazyna Sypniewska, Magdalena Krintus, published by CEON/CEES.)

Triplet-triplet energy transfer (EnT) is a powerful activation pathway in photocatalysis that unlocks new organic transformations and improves the sustainability of organic synthesis. Many current examples, however, still rely on platinum-group metal complexes as photosensitizers, with associated high costs and environmental impacts. Photosensitizers that exhibit thermally activated delayed fluorescence (TADF) are attractive fully organic alternatives in EnT photocatalysis. However, TADF photocatalysts incorporating heavy atoms remain rare, despite their utility in inducing efficient spin-orbit-coupling, intersystem-crossing, and consequently a high triplet population. Here, we describe the synthesis of imidazo-phenothiazine (IPTZ), a sulfur-containing heterocycle with a locked planar structure and a shallow LUMO level. This acceptor is used to prepare seven TADF-active photocatalysts with triplet energies up to 63.9 kcal mol -1 . We show that sulfur incorporation improves spin-orbit coupling and increases triplet lifetimes up to 3.64 ms, while also allowing for tuning of photophysical properties via oxidation at the sulfur atom. These IPTZ materials are applied as photocatalysts in five seminal EnT reactions: [2 + 2] cycloaddition, the disulfide-ene reaction, and Ni-mediated C-O and C-N cross-coupling to afford etherification, esterification, and amination products, outcompeting the industry-standard TADF photocatalyst 2CzPN in four of the five studied scenarios. Detailed photophysical and theoretical studies are used to understand structure-activity relationships and to demonstrate the key role of the heavy atom effect in the design of TADF materials with superior photocatalytic performance.

Introduction: Metabolic dysfunction-associated fatty liver disease (MAFLD)-a new definition for non-alcoholic fatty liver disease-reflects the impact of metabolic abnormalities on liver function. We assessed the diagnostic accuracy of biomarker-based scores for prediction of MAFLD in apparently healthy children., Methods: This study included 144 children aged 9-11. MAFLD was recognized in 14 girls and 29 boys. Anthropometric indices, glycemia, insulin resistance, lipid profile, enzymes (ALT, AST, GGT, ALP), CRP, N -terminal propeptide of type I procollagen (P1NP) and collagen type I C-telopeptide (CTX-1) levels were measured. Fatty liver and hepatic steatosis index (FLI, HSI) and potential indicators of liver fibrogenesis: P1NP/ALP, P1NP/ALPxALT, P1NP/ALPxCRP were calculated., Results: P1NP/ALPxALT and P1NP/ALPxCRP were significantly higher in subjects with MAFLD. FLI was a good, significant predictor of MAFLD occurrence, regardless of sex. In boys, P1NP/ALPxCRP was a comparable predictor as CRP (OR 1.14 vs. 1.17; p < 0.001). P1NP/ALPxCRP had better discrimination capability in boys (AUC = 0.79; p < 0.001). However, the use of this algorithm did not improve discriminatory power in comparison to CRP (AUC = 0.81; p < 0.001), but gave a better sensitivity for MAFLD prediction (86% vs. 59%)., Conclusions: We suggest that P1NP/ALPXCRP is a reliable tool for MAFLD prediction in routine pediatric practice.

Introduction: Adherence to controller medication is a major problem in asthma management, being difficult to assess and tackle. mHealth apps can be used to assess adherence. We aimed to assess the adherence to inhaled corticosteroids+long-acting β2-agonists (ICS+LABA) in users of the MASK-air® app, comparing the adherence to ICS+formoterol (ICS+F) with that to ICS+other LABA., Materials and Methods: We analysed complete weeks of MASK-air® data (2015-2022; 27 countries) from patients with self-reported asthma and ICS+LABA use. We compared patients reporting ICS+F versus ICS+other LABA on adherence levels, symptoms and symptom-medication scores. We built regression models to assess whether adherence to ICS+LABA was associated with asthma control or short-acting beta-agonist (SABA) use. Sensitivity analyses were performed considering the weeks with no more than one missing day., Results: In 2598 ICS+LABA users, 621 (23.9%) reported 4824 complete weeks and 866 (33.3%) reported weeks with at most one missing day. Higher adherence (use of medication ≥80% of weekly days) was observed for ICS+other LABA (75.1%) when compared to ICS+F (59.3%), despite both groups displaying similar asthma control and work productivity. The ICS+other LABA group was associated with more days of SABA use than the ICS+F group (median=71.4% versus 57.1% days). Each additional weekly day of ICS+F use was associated with a 4.1% less risk in weekly SABA use (95%CI=-6.5;-1.6%;p=0.001). For ICS+other LABA, the percentage was 8.2 (95%CI=-11.6;-5.0%;p<0.001)., Conclusions: In asthma patients adherent to the MASK-air app, adherence to ICS+LABA was high. ICS+F users reported lower adherence but also a lower SABA use and a similar level of control., Competing Interests: Conflicts of interest JS reports grants and personal fees from SANOFI, personal fees from GSK, personal fees from NOVARTIS, personal fees from ASTRA ZENECA, personal fees from MUNDIPHARMA, personal fees from FAES FARMA, outside the submitted work. BS reports personal fees from Polpharma, personal fees from Viatris, grants and personal fees from AstraZeneca, personal fees from TEVA, personal fees from patient ombudsman, personal fees from Polish Allergology Society, grants from GSK, outside the submitted work. SBA reports grants from TEVA, personal fees from TEVA, personal fees from TEVA, personal fees from AstraZeneca, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Boehringer Ingelheim, personal fees from GSK, personal fees from Sanofi, personal fees from Mylan, personal fees from Menarini, outside the submitted work. BG reports grants from Chiesi, grants from Sandoz, grants from GSK, grants from AstraZeneca, grants from Deva, grants from Abdi İbrahim, outside the submitted work. RL reports grants and personal fees from AZ, grants and personal fees from GSK, grants from Chiesi, outside the submitted work. MK reports personal fees from Astra Zeneca, personal fees from Chiesi, personal fees from GSK, personal fees from Novartis, personal fees from Berlin Chemie, personal fees from Zentiva, personal fees from Allergopharma, personal fees from LEK-AM, personal fees from Polpharma, personal fees from Teva, personal fees from Sanofi, personal fees from Adamed, personal fees from Sandoz, personal fees from EMMA, outside the submitted work. FDB reports other from NOVARTIS, other from ALK, other from STALLERGENES, other from REGENERON, other from DBV, other from SANOFI, other from BOEHRINGER, other from ASTRAZENECA, outside the submitted work. CSU reports grants and personal fees from AZ, personal fees from GSK, personal fees from TEVA, grants and personal fees from Sanofi, grants and personal fees from BI, personal fees from Novartis, personal fees and non-financial support from Orion Pharma, personal fees from Chiesi, personal fees from TFF Pharmaceuticals, personal fees from Takeda, personal fees from Pfizer, personal fees from Covis Pharma, outside the submitted work. NP reports grants from Capricare, personal fees from Nestle, personal fees from Numil, personal fees from Vianex, outside the submitted work. FR reports personal fees from Novartis, personal fees from Sanofi, personal fees from AstraZeneca, personal fees from GSK, personal fees from Medinfar, personal fees from Azentis, outside the submitted work. TZ reports grants and personal fees from Novartis, grants and personal fees from Henkel, personal fees from Bayer, personal fees from FAES, personal fees from Astra Zeneca, personal fees from AbbVie, personal fees from ALK, personal fees from Almirall, personal fees from Astellas, personal fees from Bayer, personal fees from Bencard, personal fees from Berlin Chemie, personal fees from FAES, personal fees from Hal, personal fees from Leti, personal fees from Mesa, personal fees from Menarini, personal fees from Merck, personal fees from MSD, personal fees from Novartis, personal fees from Pfizer, personal fees from Sanofi, personal fees from Stallergenes, personal fees from Takeda, personal fees from Teva, personal fees from UCB, personal fees from Henkel, personal fees from Kryolan, personal fees from L'Oreal, outside the submitted work; and Organizational affiliations: Commitee member: WHO-Initiative "Allergic Rhinitis and Its Impact on Asthma" (ARIA); Member of the Board: German Society for Allergy and Clinical Immunology (DGAKI); Head: European Centre for Allergy Research Foundation (ECARF); President: Global Allergy and Asthma European Network (GA2LEN); Member: Committee on Allergy Diagnosis and Molecular Allergology, World Allergy Organization (WAO). AP reports grants from CHIESI, ASTRAZENECA, GSK, SANOFI, personal fees from CHIESI, ASTRAZENECA, GSK, NOVARTIS, SANOFI, IQVIA, AVILLION, ELPEN PHARMACEUTICALS, personal fees from CHIESI, ASTRAZENECA, GSK, BI, MENARINI, NOVARTIS, ZAMBON, MUNDIPHARMA, TEVA, SANOFI, EDMOND PHARMA, IQVIA, MSD, AVILLION, ELPEN PHARMACEUTICALS, outside the submitted work. RB reports grants from Boehringer Ingelheim, GlaxoSmithKline, Novartis and Roche, personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Novartis, Sanofi, Roche and Teva, outside the submitted work. LTB reports personal fees from DIATER, personal fees from Novartis, personal fees from LETI, outside the submitted work. JF reports personal fees from Viatris/Mylan, personal fees from AstraZeneca, outside the submitted work; and being co-founder of an SME that develops mHealth technologies, such as digital biomarkers and has the copyright of the CARAT anda CARATkids PROM. VK reports non-financial support from Norameda, non-financial support from Berlin CHemie Menarini, outside the submitted work. NR reports grants and personal fees from Boehringer Ingelheim, grants and personal fees from Novartis, grants and personal fees from GSK, personal fees from AstraZeneca, personal fees from Chiesi, grants and personal fees from Pfizer, personal fees from Sanofi, personal fees from Zambon, personal fees from MSD, personal fees from Austral, outside the submitted work. SB reports personal fees from Sanofi Genzyme, personal fees from AstraZeneca, grants from Auris medical, personal fees from Allergopharma, personal fees from ALK Abello, grants, personal fees and non-financial support from Bencard Allergy, personal fees from Allergy Therapeutics, non-financial support from Smart Reporting, personal fees from Stryker, personal fees from MSD, personal fees from Mylan, personal fees from GSK, outside the submitted work. JB reports personal fees from Cipla, Menarini, Mylan, Novartis, Purina, Sanofi-Aventis, Teva, Uriach, other from KYomed-Innov, other from Mask-air-SAS, outside the submitted work. TH reports personal fees from Orion Pharma, outside the submitted work. LC reports personal fees from Thermofisher, personal fees from Novartis, personal fees from ALK, personal fees from Sanofi, personal fees from GSK, personal fees from Astra Zeneca, outside the submitted work. LPB reports grants from Time frame: past 36 months Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis, Sanofi-Regeneron, personal fees from Astra Zeneca, Novartis, GlaxoSmithKline, Merck, Sanofi-Regeneron, personal fees from AstraZeneca, Covis, Cipla, GlaxoSmithKline, Novartis, Merck, Sanofi, outside the submitted work. SDG reports grants and personal fees from AstraZeneca, personal fees from Chiesi, grants and personal fees from GSK, grants and personal fees from Novartis, personal fees from Guidotti, personal fees from Sanofi, outside the submitted work. PK reports personal fees from Adamed, personal fees from Berlin Chemie Menarini, personal fees from Boehringer Ingelheim, personal fees from AstraZeneca, personal fees from Glenmark, personal fees from Novartis, personal fees from Polpharma, personal fees from GSK, personal fees from Sanofi, personal fees from Chiesi, personal fees from Celon Pharma, outside the submitted work. AC reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GSK, personal fees from Eurofarma, personal fees from Novartis, personal fees from Sanofi, outside the submitted work. MS reports grants from Immune Tolerance Network, grants from Medical Research Council, grants and personal fees from Allergy Therapeutics, grants and personal fees from LETI Laboratorios, grants from Revolo biotherapeutics, grants from Angany Inc, personal fees from Bristol Myers Squibb, outside the submitted work. GB reports personal fees from Astra Zeneca, personal fees from Boehringer-Ingelheim, personal fees from Chiesi, personal fees from GlaxoSmithKline, personal fees from Novartis, personal fees from Sanofi, grants from MerckSharp&Dohme, outside the submitted work. MJ reports personal fees from ALK-Abello, personal fees from Allergopharma, personal fees from Stallergenes, personal fees from Anergis, personal fees from Allergy Therapeutics, personal fees from Leti, personal fees from HAL, during the conduct of the study; personal fees from GSK, personal fees from Novartis, personal fees from Teva, personal fees from Takeda, personal fees from Chiesi, outside the submitted work. DLL reports personal fees from ALK, Astrazeneca national and global, Bayer, Chiesi, Grunenthal, Grin, GSK national and global, Viatris, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, Carnot, grants from Abbvie, Bayer, Lilly, Sanofi, Astrazeneca, Lilly, Pfizer, Novartis, Circassia, UCB, GSK, Purina institute., outside the submitted work. OP reports grants and personal fees from ALK-Abelló, grants and personal fees from Allergopharma, grants and personal fees from Stallergenes Greer, grants and personal fees from HAL Allergy Holding B.V./HAL Allergie GmbH, grants from Bencard Allergie GmbH/Allergy Therapeutics, grants from Lofarma, grants and personal fees from ASIT Biotech Tools S.A., grants and personal fees from Laboratorios LETI/LETI Pharma, grants and personal fees from GlaxoSmithKline, personal fees from ROXALL Medizin, personal fees from Novartis, grants and personal fees from Sanofi-Aventis and Sanofi-Genzyme, personal fees from Med Update Europe GmbH, personal fees from streamedup! GmbH, grants from Pohl-Boskamp, grants from Inmunotek S.L., personal fees from John Wiley and Sons, AS, personal fees from Paul-Martini-Stiftung (PMS), personal fees from Regeneron Pharmaceuticals Inc., personal fees from RG Aerztefortbildung, personal fees from Institut für Disease Management, personal fees from Springer GmbH, grants and personal fees from AstraZeneca, personal fees from IQVIA Commercial, personal fees from Ingress Health, personal fees from Wort&Bild Verlag, personal fees from Verlag ME, personal fees from Procter&Gamble, personal fees from ALTAMIRA, personal fees from Meinhardt Congress GmbH, personal fees from Deutsche Forschungsgemeinschaft, personal fees from Thieme, grants from Deutsche AllergieLiga e.V., personal fees from AeDA, personal fees from Alfried-Krupp Krankenhaus, personal fees from Red Maple Trials Inc., personal fees from TU Dresden, outside the submitted work. YO reports personal fees from Torii pharmaceutical Co., LTD., personal fees from Tanabe-Mitsubishi Pharmaceutical Co., Ltd., personal fees from Kirin Holdings Co., Ltd., personal fees from Novartis Co., Ltd., personal fees from Allergologisk Laboratorium København, personal fees from Shionogi Co., Ltd., outside the submitted work. JCI reports personal fees and non-financial support from Laboratorios Casasco, personal fees from Abbott Ecuador, personal fees from Laboratorios Bago Bolvia, personal fees from Faes Farma, outside the submitted work. HK reports personal fees from Mylan/Viatris, personal fees from Sanofi, outside the submitted work. MO reports personal fees from Hycor Diagnostics, outside the submitted work; and Scientific Co-Founder, Tolerogenics SARL, Luxembourg. The other authors have no COIs to disclose, outside the submitted work., (Copyright © 2023 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The self-reporting of asthma frequently leads to patient misidentification in epidemiological studies. Strategies combining the triangulation of data sources may help to improve the identification of people with asthma. We aimed to combine information from the self-reporting of asthma, medication use and symptoms to identify asthma patterns in the users of an mHealth app., Methods: We studied MASK-air® users who reported their daily asthma symptoms (assessed by a 0-100 visual analogue scale - "VAS Asthma") at least three times (either in three different months or in any period). K-means cluster analysis methods were applied to identify asthma patterns based on: (i) whether the user self-reported asthma; (ii) whether the user reported asthma medication use and (iii) VAS asthma. Clusters were compared by the number of medications used, VAS asthma levels and Control of Asthma and Allergic Rhinitis Test (CARAT) levels., Findings: We assessed a total of 8,075 MASK-air® users. The main clustering approach resulted in the identification of seven groups. These groups were interpreted as probable: (i) severe/uncontrolled asthma despite treatment (11.9-16.1% of MASK-air® users); (ii) treated and partly-controlled asthma (6.3-9.7%); (iii) treated and controlled asthma (4.6-5.5%); (iv) untreated uncontrolled asthma (18.2-20.5%); (v) untreated partly-controlled asthma (10.1-10.7%); (vi) untreated controlled asthma (6.7-8.5%) and (vii) no evidence of asthma (33.0-40.2%). This classification was validated in a study of 192 patients enrolled by physicians., Interpretation: We identified seven profiles based on the probability of having asthma and on its level of control. mHealth tools are hypothesis-generating and complement classical epidemiological approaches in identifying patients with asthma., (Copyright © 2022 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Background and Aims: Lipoprotein(a) is a recognized independent cardiovascular risk factor and apolipoprotein B (apoB) level better reflects the risk than LDL-cholesterol. Despite this cardiovascular prediction mostly relies on traditional risk factors. We evaluated the association between Lp(a) and lipid biomarkers of cardiovascular risk in relation to age and sex in apparently healthy individuals., Methods and Results: 422 presumably healthy subjects aged 19-84 were included. Lipid profile, Lp(a), apoB and small dense low-density lipoprotein cholesterol (sdLDL-C) were assayed. Subjects were divided at desirable cut-points of apoB and LDL-C. A group with elevated apoB (≥100 mg/dL) at low LDL-C (≤115 mg/dL) was appointed as high-risk and a group with low apoB but elevated LDL-C as low-risk. Significantly elevated triglycerides, TG/HDL-C and sdLDL-C were found in high risk group, but Lp(a) levels were comparable. TG/HDL-C was the best predictor of high risk with a very good diagnostic accuracy (AUC = 0.85), whereas Lp(a) had no discriminatory power. Women aged ≤40 with low LDL-C ≤ 100 mg/dL and elevated Lp(a) ≥ 40 mg/dL had higher levels of apoB and sdLDL-C (p = 0.002; p = 0.07) than those with Lp(a) < 40 mg/dL, which was not observed in men. In young females increase of LDL-C and apoB significantly raised the risk of elevated Lp(a)., Conclusions: Women younger than 40 with low LDL-C may be at increased cardiovascular risk associated with elevated Lp(a) and apolipoprotein B levels. Inclusion of Lp(a) and apoB in the routine lipid testing providing information on an individual level may improve the prediction of cardiovascular risk in primary prevention., 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 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Introduction: The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain., Methods: We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD)., Results: We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration., Discussion: AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation., Highlights: APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. β-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Genetic studies of Alzheimer disease (AD) have prioritized variants in genes related to the amyloid cascade, lipid metabolism, and neuroimmune modulation. However, the cell-specific effect of variants in these genes is not fully understood. Here, we perform single-nucleus RNA-sequencing (snRNA-seq) on nearly 300,000 nuclei from the parietal cortex of AD autosomal dominant (APP and PSEN1) and risk-modifying variant (APOE, TREM2 and MS4A) carriers. Within individual cell types, we capture genes commonly dysregulated across variant groups. However, specific transcriptional states are more prevalent within variant carriers. TREM2 oligodendrocytes show a dysregulated autophagy-lysosomal pathway, MS4A microglia have dysregulated complement cascade genes, and APOEε4 inhibitory neurons display signs of ferroptosis. All cell types have enriched states in autosomal dominant carriers. We leverage differential expression and single-nucleus ATAC-seq to map GWAS signals to effector cell types including the NCK2 signal to neurons in addition to the initially proposed microglia. Overall, our results provide insights into the transcriptional diversity resulting from AD genetic architecture and cellular heterogeneity. The data can be explored on the online browser ( http://web.hararilab.org/SNARE/ )., (© 2023. The Author(s).)

To assess the determinants of lipid parameters in primary care patients without diagnosed cardiovascular disease (CVD), a cross-sectional study was conducted during 2018-2019 with a total of 200 patients. The following lipid parameters were measured: total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), small, dense LDL (sdLDL-C), and lipoprotein (a) (Lp(a)). Predictors of elevated and adequately controlled lipid parameters were assessed with logistic regression analysis. Older age was related to higher risk of TC ≥ 6.2 mmol/L [OR 1.03 (95% CI 1.0-1.05)], sdLDL-C ≥ 1.0 mmol/L [OR 1.05 (95% CI 1.0-1.1)], and decreased risk of Lp(a) ≥ 50 mg/dL [OR 0.97 (95% CI 0.94-0.99)]. Patients with diabetes mellitus (DM) had increased probability of TG ≥ 2.25 mmol/L [OR 3.77 (95% CI 1.34-10.6)] and Lp(a) ≥ 50 mg/dL [OR 2.97 (1.34-6.10)] as well as adequate control of TG and Lp(a). Higher material status was related to lower risk of TC ≥ 6.2 mmol/L [OR 0.19 (95% CI 0.04-0.82)] and LDL-C ≥ 3.6 mmol/L [OR 0.33 (95% CI 0.12-0.92)]. High BMI was related to increased [OR 1.14 (95% CI 1.02-1.29)], and female gender [OR 0.33 (95% CI 0.12-0.96)] and hypertension [OR 0.29 (95% CI 0.1-0.87)] to decreased risk of TG ≥ 2.25 mmol/L [OR 1.14 (95% CI 1.02-1.29)]. Taking lipid-lowering drugs (LLD) was associated with LDL-C < 2.6 mmol/L [OR 2.1 (95% CI 1.05-4.19)] and Lp(a) < 30 mg/dL [OR 0.48 (95% CI 0.25-0.93)]. Physical activity was related to LDL-C < 2.6 mmol/L [OR 2.02 (95% CI 1.02-3.98)]. Higher abdominal circumference was associated with decreased risk of TG < 1.7 mmol/L [OR 0.96 (95% CI 0.93-0.99)]. Elevated lipid parameters were related to age, gender, material status, BMI, history of DM, and hypertension. Adequate control was associated with age, education, physical activity, LLD, history of DM, and abdominal circumference.

Magnet/superconductor hybrids (MSHs) hold the promise to host emergent topological superconducting phases. Both one-dimensional (1D) and two-dimensional (2D) magnetic systems in proximity to s-wave superconductors have shown evidence of gapped topological superconductivity with zero-energy end states and chiral edge modes. Recently, it was proposed that the bulk transition-metal dichalcogenide 4Hb-TaS 2 is a gapless topological nodal-point superconductor (TNPSC). However, there has been no experimental realization of a TNPSC in a MSH system yet. Here we present the discovery of TNPSC in antiferromagnetic (AFM) monolayers on top of an s-wave superconductor. Our calculations show that the topological phase is driven by the AFM order, resulting in the emergence of a gapless time-reversal invariant topological superconducting state. Using low-temperature scanning tunneling microscopy we observe a low-energy edge mode, which separates the topological phase from the trivial one, at the boundaries of antiferromagnetic islands. As predicted by the calculations, we find that the relative spectral weight of the edge mode depends on the edge's atomic configuration. Our results establish the combination of antiferromagnetism and superconductivity as a novel route to design 2D topological quantum phases., (© 2023. The Author(s).)

Planarized emitters exhibiting thermally activated delayed fluorescence (TADF) have attracted attention due to their narrow emission spectra, improved photostability, and high quantum yields, but with large singlet-triplet energy gaps (Δ E ST ) and no heavy atoms, the origin of their TADF remains a subject of debate. Here we prepare two isomeric, coplanar donor-acceptor compounds, with HMAT-2PYM performing dual TADF and room-temperature phosphorescence but with HMAT-4PYM exhibiting only prompt fluorescence. Although conventional TADF design principles suggest that neither isomer should exhibit TADF, we reveal differences in the excited state potential energy surfaces that enable spin-flip processes in only one isomer. We also find that hydrogen bonding is absent between the planar units of these emitters, despite earlier claims of intramolecular hydrogen bonding in similar compounds. Overall, this work demonstrates that potential energy surface analysis is a practical strategy for designing coplanar TADF materials that might otherwise be overlooked by conventional TADF design metrics.

Elevated liver enzyme activity may be associated with metabolic syndrome (MetS); however, it is not included in the MetS definition for children. Postprandial changes in the levels of biochemistry tests are related to manifestations of metabolic abnormalities. We assessed the association between fasting and postprandial liver enzymes levels with MetS and elevated hemoglobin A1c (HbA1c) in children aged 9-11. The study included 51 girls and 48 boys, all presumably healthy. In all participants' anthropometric indices, fasting glucose, insulin, lipid profile and HbA1c were measured. Enzymes, including alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), were assayed in fasting and postprandial states. Individuals were divided into subgroups: with (MetS(+): n = 26); without MetS (MetS(-): n = 73); with HbA1c levels ≤ 5.3% (n = 39); and ≥5.7% (n = 11). Elevated fasting GGT levels were found in 23% of MetS(+) children and rarely in MetS(-) children; increased postprandial GGT was noted in 35% of MetS(+) individuals. Postprandial GGT changes tend to predict MetS (OR = 1.16; p = 0.092). Increased fasting ALT was found rarely in MetS(+) children, but did not occur in MetS(-) children. HbA1c ≥ 5.7% occurred rarely and neither fasting ALT nor GGT were related to elevated HbA1c. However, postprandial change of ALT was a good positive predictor of increased HbA1c (OR = 1.33; p = 0.021). Postprandial GGT performs better as an indicator of metabolic syndrome occurrence, and instead postprandial ALT may predict prediabetes in prepubertal children.

The morphology and composition of clasts have the potential to reveal the nature and extent of erosional processes acting in a region. Dense accumulations of granule- to pebble-sized clasts covering the ground throughout the Glen Torridon region of Gale crater on Mars were studied using data acquired by the Mars Science Laboratory Curiosity rover between sols 2300 and 2593. In this study, measurements of shape, size, texture, and elemental abundance of unconsolidated granules and pebbles within northern Glen Torridon were compiled. Nine primary clast types were identified through stepwise hierarchical clustering, all of which are sedimentary and can be compositionally linked to local bedrock, suggesting relatively short transport distances. Several clast types display features associated with fragmentation along bedding planes and existing cracks in bedrock. These results indicate that Glen Torridon clasts are primarily the product of in-situ physical weathering of local bedrock., (© 2022 Jet Propulsion Laboratory. California Institute of Technology. Government sponsorship acknowledged.)

Complex magnetic order arises due to the competition of different interactions between the magnetic moments. Recently, there has been an increased interest in such states not only to unravel the fundamental physics involved, but also with regards to applications exploiting their unique interplay with moving electrons. Whereas it is the Dzyaloshinskii-Moriya interaction (DMI) that has attracted much attention because of its nature to induce non-collinear magnetic order including magnetic-field stabilized skyrmions, it is the frustration of exchange interactions that can drive magnetic order down to the nano-scale. On top of that, interactions between multiple spins can stabilize two-dimensional magnetic textures as zero-field ground states, known as multi-Q states. Here, we introduce a two-dimensional itinerant magnet with various competing atomic-scale magnetic phases. Using spin-polarized scanning tunneling microscopy we observe several zero-field uniaxial or hexagonal nano-scale magnetic states. First-principles calculations together with an atomistic spin model reveal that these states are stabilized by the interplay of frustrated exchange and higher-order interactions while the DMI is weak. Unexpectedly, it is found that not only non-collinear magnetic states arise, but that higher-order interactions can also lead to collinear nano-scale multi-Q states., (© 2022. The Author(s).)

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Angiopoietin-like proteins ANGPTL3 and ANGPTL8 have been shown to inhibit lipoprotein lipase, and thus regulate triglyceride level in the circulation. Whether the regulation of lipid metabolism by ANGPTLs is affected by the menopausal status remains unclear. We aimed to assess the relationships between serum ANGPTL3 and ANGPTL8 and atherogenic biomarkers in presumably healthy women during ageing. The study group included 94 women of whom 31 were premenopausal (PRE ≤ 40 years) and 37 were postmenopausal (POST ≥ 52 years). Atherogenic lipid and non-lipid biomarkers and ANGPTLs (ANGPTL3, ANGPTL8) were assayed in serum samples. TG/HDL-C index, non-HDL-cholesterol, remnant cholesterol concentrations, and BMI were calculated. Median levels of ANGPTL3 and concentrations of lipid biomarkers were significantly higher in POST comparing to PRE but ANGPTL8 levels were not different. In PRE, ANGPTL8 levels correlated significantly with TG and TG/HDL-C index while there were no correlations between ANGPTL3 and these biomarkers. In POST both ANGPTLs correlated with TG, sdLDL-C, and TG/HDL-C. ANGPTL8 and sd-LDL-C were the most significant predictors of early triglyceride elevation > 100 mg/dL (1.13 mmol/L) in the whole group and POST whereas the prediction power of ANGPTL3 was negligible in the whole group and non-significant in the subgroups. We demonstrated a significant positive correlation of ANGPTL3 with age category which predisposes to postmenopause. Despite the increase in ANGPTL3 level with ageing the ANGPTL3/ANGPL8 ratio was maintained. In conclusion, ANGPTL8 predicts the early triglyceride elevation better than ANGPTL3, especially in postmenopausal women. The association of ANGPTL3 with triglyceride levels is weaker than ANGPTL8 and depends on menopausal status. We suggest that the choice for the best efficient treatment of dyslipidemia with new inhibitors of angiopoietin-like proteins may depend on the menopausal status.

The associations between individual components of metabolic syndrome (MetS) and bone health in children are complex, and data on this topic are sparse and inconsistent. We assessed the relationship between bone turnover markers and markers of the processes underlying MetS (insulin resistance and inflammation) in a group of presumably healthy children aged 9-11 years: 89 (51 girls, 38 boys) presenting without any features of MetS and 26 (10 girls, 16 boys) with central obesity and two features of MetS. Concentrations of glucose, triglycerides (TG), HDL cholesterol (HDL-C), C-reactive protein (CRP), HbA1c, total 25-hydroxyvitamin D (25(OH)D), intact-P1NP (N-terminal propeptide of type I procollagen), CTX-1 (C-terminal telopeptide of type I collagen) were assayed and insulin resistance was assessed (HOMA-IR). BMI centile, waist circumference (WC) and blood pressure were measured. The presence of MetS in girls resulted in significantly lower concentrations of CTX-1 and a trend to lower CTX-1 in boys. The concentrations of bone formation marker i-P1NP were not affected. Among the features associated with MetS, HOMA-IR appeared as the best positive predictor of MetS in girls, whereas CRP was the best positive predictor in boys. A significant influence of HOMA-IR on the decrease in CTX-1 in girls was independent of BMI centile and WC, and the OR of having CTX-1 below the median was 2.8-fold higher/1SD increased in HOMA-IR ( p = 0.003). A weak relationship between CTX-1 and CRP was demonstrated in girls (r = -0.233; p = 0.070). Although TG, as a MetS component, was the best significant predictor of MetS in both sexes, there were no correlations between bone markers and TG. We suggest that dyslipidemia is not associated with the levels of bone markers in prepubertal children whereas CRP is weakly related to bone resorption in girls. In prepubertal girls, insulin resistance exerts a dominant negative impact on bone resorption, independent of BMI centile and waist circumference.

Background: Autosomal-dominant Alzheimer's disease (ADAD) is caused by pathogenic mutations in APP, PSEN1, and PSEN2, which usually lead to an early age at onset (< 65). Circular RNAs are a family of non-coding RNAs highly expressed in the nervous system and especially in synapses. We aimed to investigate differences in brain gene expression of linear and circular transcripts from the three ADAD genes in controls, sporadic AD, and ADAD., Methods: We obtained and sequenced RNA from brain cortex using standard protocols. Linear counts were obtained using the TOPMed pipeline; circular counts, using python package DCC. After stringent quality control (QC), we obtained the counts for PSEN1, PSEN2 and APP genes. Only circPSEN1 passed QC. We used DESeq2 to compare the counts across groups, correcting for biological and technical variables. Finally, we performed in-silico functional analyses using the Circular RNA interactome website and DIANA mirPath software., Results: Our results show significant differences in gene counts of circPSEN1 in ADAD individuals, when compared to sporadic AD and controls (ADAD = 21, AD = 253, Controls = 23-ADADvsCO: log 2 FC = 0.794, p = 1.63 × 10 -04 , ADADvsAD: log 2 FC = 0.602, p = 8.22 × 10 -04 ). The high gene counts are contributed by two circPSEN1 species (hsa&#95;circ&#95;0008521 and hsa&#95;circ&#95;0003848). No significant differences were observed in linear PSEN1 gene expression between cases and controls, indicating that this finding is specific to the circular forms. In addition, the high circPSEN1 levels do not seem to be specific to PSEN1 mutation carriers; the counts are also elevated in APP and PSEN2 mutation carriers. In-silico functional analyses suggest that circPSEN1 is involved in several pathways such as axon guidance (p = 3.39 × 10 -07 ), hippo signaling pathway (p = 7.38 × 10 -07 ), lysine degradation (p = 2.48 × 10 -05 ) or Wnt signaling pathway (p = 5.58 × 10 -04 ) among other KEGG pathways. Additionally, circPSEN1 counts were able to discriminate ADAD from sporadic AD and controls with an AUC above 0.70., Conclusions: Our findings show the differential expression of circPSEN1 is increased in ADAD. Given the biological function previously ascribed to circular RNAs and the results of our in-silico analyses, we hypothesize that this finding might be related to neuroinflammatory events that lead or that are caused by the accumulation of amyloid-beta., (© 2022. The Author(s).)

Competing Interests: L. Klimek berichtet über Zuschüsse und/oder Honorare von Allergopharma, MEDA/Mylan, HAL Allergie, ALK Abelló, LETI Pharma, Stallergenes, Quintiles, Sanofi, ASIT biotech, Lofarma, Allergy Therapeut., AstraZeneca, GSK, Inmunotk, Cassella med, außerhalb der eingereichten Arbeit; und folgende Mitgliedschaften: AeDA, DGHNO, Deutsche Akademie für Allergologie und klinische Immunolgie, HNO-BV, GPA, EAACI;Ch. Bergmann berichtet über Referentenhonorare von Sanofi Genzyme;S. Becker gibt folgende potenziellen Interessenkonflikte an: Wissenschaftliche Beratung: Novartis, Sanofi-Genzyme, Bencard Allergie; Vortragshonorare: Novartis, Sanofi-Genzyme, Bencard Allergie, HAL-Allergie, MSD, AstraZeneca; Studien: Otonomy, Regeneron, Sensorien, AstraZeneca, Auris medical;M. Cuevas berichtet über Honorare von AstraZeneca, GSK, Sanofi und Novartis;P. V. Tomazic, C. A. Hintschich, F. Klimek, U. Förster-Rurmann, I. Casper, H. J. Welkoborsky, J. Hagemann, K.-Ch. Bergmann, T. Huppertz hat keine Interessenkonflikte im Zusammenhang mit dieser Publikation.

Aim: Dual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR-324 belongs to the DENKI pharmacological class. This first-in-human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324 in healthy male participants., Methods: This was a randomised, double-blind, placebo-controlled ascending dosing study in two parts: in part 1, 30 participants received 0.004-11.475 mg h -1 of STR-324 or placebo (ratio 4:1) by 4 h intravenous infusion in a two-group, partial crossover design with four treatment periods separated by 1 month wash-out, and in part 2, 48 participants divided into three groups received either the active drug (1.25-11.25 mg h -1 ) or placebo (ratio 3:1) by 48 h intravenous infusion. Safety and tolerability parameters, pharmacokinetics and pharmacodynamic effects on neurocognitive and neurophysiological tasks and on a nociceptive test battery were evaluated., Results: No clinically relevant changes in safety parameters were observed. All treatment-emergent adverse events were mild and transient. The pharmacokinetics of STR-324 could not be determined due to most concentrations being below quantifiable limits. STR-324 metabolite concentrations were measurable, showing dose proportionality of C max and AUC inf with an estimated t 1/2 of 0.2-0.5 h. Significant changes in pharmacodynamic parameters were observed, but these were not consistent or dose-dependent., Conclusion: STR-324 displayed favourable safety and tolerability profiles at all doses up to 11.475 mg h -1 . Although pharmacokinetic characterisation of STR-324 was limited, dose proportionality could be assumed based on major metabolite data assayed as proxy. No clear effects on nociceptive thresholds or other pharmacodynamic measures were observed., Trial Registry: EudraCT (2014-002402-21) and toetsingonline.nl (63085)., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Abstract: Point-of-care ultrasound (POCUS) has been described as a useful tool for identification of coronavirus disease 2019 (COVID-19) in adults and children. Although several case reports describe POCUS findings in children with COVID-19, to our knowledge, there have been no published multicenter case series describing the large heterogeneity in lung POCUS findings in pediatric COVID-19. This series includes 7 symptomatic patients with COVID-19 who had a lung POCUS performed at 6 institutions by pediatric emergency attendings and fellows. The findings were variable, ranging from no findings to the appearance of B-lines, pleural abnormalities, consolidations, and a pleural effusion. Further studies are needed to improve our understanding, characterization, and prognostic correlation of POCUS findings in this novel disease in children., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: M. Wagenmann hat innerhalb der vergangenen 3 Jahre Honorare für Beratung, Vorträge oder Forschungsunterstützung von folgenden Firmen erhalten: ALK-Abelló, Allergopharma, AstraZeneca, Bencard Allergie, Genzyme, HAL Allergie, Infectopharm, LETI Pharma, MEDA Pharma, Novartis, Sanofi Aventis, Stallergenes, Teva – außerhalb der vorliegenden Arbeit.B. Wollenberg hat Honorare und/oder Forschungsgelder von MSD, Sanofi, Astra Zeneca, Novartis, BMS Adboard außerhalb der vorliegenden Arbeit erhalten.J. Hagemann gibt an, Zuwendungen der Fa. Novartis Pharma GmbH für Vorträge erhalten zu haben.C. Bachert erhielt Honorare und/oder Forschungsgelder von Sanofi, Novartis, GSL, Astra-Zeneca außerhalb der vorliegenden Arbeit.A. Chaker führt über die Technische Universität München Beratungsleistungen (z. B. Advisory Boards, DSMBs), Vorträge oder weitere Aktivitäten für Allergopharma, ALK-Abello, Astra Zeneca, GSK, HAL Allergy, Mundipharma, Nexter, Immunotek, Lofarma, SanofiGenzyme und Regeneron durch; hat klinische Studien oder Forschungsgelder über die Technische Universität München erhalten von ALK, Allergopharma, Astra Zeneca, Bencard/Allergen Therapeutics, ASIT Biotech, GSK, Novartis, Roche, und Zeller AG, ferner Forschungsmittel erhalten vom Umweltbundesamt der Bundesrepublik Deutschland, EIT Health und DZL (BMBF). AMC hat ferner Honorare und Reisekostenerstattungen erhalten vom Bayerischen Ärzteblatt, der Deutschen Gesellschaft für Allergologie und klinische Immunologie (DGAKI) und der European Academy of Allergy and Clinical Immunology.H. Olze erhielt Honorare und/oder Forschungsgelder von F. Hoffmann- La Roche Ltd, Sanofi-Aventis Deutschland GmbH, AstraZeneca GmbH, GlaxoSmithKline GmbH & Co. KG.L. Klimek berichtet über Zuschüsse und/oder Honorare von Allergopharma, MEDA/Mylan, HAL Allergie, ALK Abelló, LETI Pharma, Stallergenes, Quintiles, Sanofi, ASIT Biotech, Lofarma, Allergy Therapeut., AstraZeneca, GSK, Inmunotk, außerhalb der eingereichten Arbeit; und Mitgliedschaft bei folgenden Organisationen: AeDA, DGHNO, Deutsche Akademie für Allergologie und klinische Immunologie, HNO-BV GPA, EAACI.U. Förster-Ruhrmann erhielt Honorare für Vorträge von Novartis, AstraZeneca, Sanofi und GSK außerhalb der vorliegenden Arbeit. C. Bousquet berichtet über Zuschüsse und/oder Honorare von Chiesi, Cipla, Hikma, Menarini, Mundipharma, Mylan, Novartis, Purina, Sanofi- Aventis, Takeda, Teva, Uriach, other from KYomed-Innov, außerhalb der vorliegenden Arbeit.W. Schlenter, S. Becker, A. G. Beule, T. Deitmer, H. J. Welkoborsky, S. Dazert, C. Rudack, T. Huppertz, T.K. Hoffmann, H. Wrede, I. Casper, A. Sperl, A. Dietz, T. Zuberbier, K. C. Bergmann, A. Bedbrook und C. Bergmann haben keine Interessenkonflikte im Zusammenhang mit der vorliegenden Arbeit.

In this study, the photosensitive nature of reactive enamine and polyenamine intermediates is investigated to improve our understanding of light-mediated aminocatalytic reactions. Experimental optical absorption data and TD-DFT calculations reveal that these intermediates are excited directly from the HOMO on the enamine moiety to low-lying unoccupied orbitals localized on the catalyst scaffold. This indicates that the photophysical properties of enamine intermediates can be tuned for visible light-mediated reactions by modifications to the aminocatalyst.

Purpose: The recent repurposing of ketamine as treatment for pain and depression has increased the need for accurate population pharmacokinetic (PK) models to inform the design of new clinical trials. Therefore, the objectives of this study were to externally validate available PK models on (S)-(nor)ketamine concentrations with in-house data and to improve the best performing model when necessary., Methods: Based on predefined criteria, five models were selected from literature. Data of two previously performed clinical trials on (S)-ketamine administration in healthy volunteers were available for validation. The predictive performances of the selected models were compared through visual predictive checks (VPCs) and calculation of the (root) mean (square) prediction errors (ME and RMSE). The available data was used to adapt the best performing model through alterations to the model structure and re-estimation of inter-individual variability (IIV)., Results: The model developed by Fanta et al. (Eur J Clin Pharmacol 71:441-447, 2015) performed best at predicting the (S)-ketamine concentration over time, but failed to capture the (S)-norketamine C max correctly. Other models with similar population demographics and study designs had estimated relatively small distribution volumes of (S)-ketamine and thus overpredicted concentrations after start of infusion, most likely due to the influence of circulatory dynamics and sampling methodology. Model predictions were improved through a reduction in complexity of the (S)-(nor)ketamine model and re-estimation of IIV., Conclusion: The modified model resulted in accurate predictions of both (S)-ketamine and (S)-norketamine and thereby provides a solid foundation for future simulation studies of (S)-(nor)ketamine PK in healthy volunteers after (S)-ketamine infusion., (© 2021. The Author(s).)

Incontinentia pigmenti is an uncommon X-linked dominant neurocutaneous ectodermal dysplasia. The disorder is usually lethal in males in utero, although it may occasionally occur in males with somatic mosaicsism or Klinefelter syndrome. This is a case report of a rare case of incontinentia pigmenti in a newborn male who presented with characteristic skin eruptions following Blaschko's lines. Histopathology and genetic testing confirmed the diagnosis. The management of patients with incontinentia pigmenti may require a multidisciplinary approach, and early diagnosis is of great importance.

Antiferromagnets have recently moved into the focus of application-related research, with the perspective to use them in future spintronics devices. At the same time the experimental determination of the detailed spin texture remains challenging. Here we use spin-polarized scanning tunneling microscopy to investigate the spin structure of antiferromagnetic domain walls. Comparison with spin dynamics simulations allows the identification of a new type of domain wall, which is a superposition state of the adjacent domains. We determine the relevant magnetic interactions and derive analytical formulas. Our experiments show a pathway to control the number of domain walls by boundary effects, and demonstrate the possibility to change the position of domain walls by interaction with movable adsorbed atoms. The knowledge about the exact spin structure of the domain walls is crucial for an understanding and theoretical modelling of their properties regarding, for instance, dynamics, response in transport experiments, and manipulation.