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Background and Objectives: Genome-wide association studies (GWASs) have only 2 loci associated with spontaneous intracerebral hemorrhage (ICH): APOE for lobar and 1q22 for nonlobar ICH. We aimed to discover new loci through an analysis that combines correlated traits (multi-trait analysis of GWAS [MTAG]) and explore a gene-based analysis, transcriptome-wide association study (TWAS), and proteome-wide association study (PWAS) to understand the biological mechanisms of spontaneous ICH providing potential therapeutic targets., Methods: We use the published MTAG of ICH (patients with spontaneous intraparenchymal bleeding) and small-vessel ischemic stroke. For all ICH, lobar ICH, and nonlobar ICH, a pairwise MTAG combined ICH with traits related to cardiovascular risk factors, cerebrovascular diseases, or Alzheimer disease (AD). For the analysis, we assembled those traits with a genetic correlation ≥0.3. A new MTAG combining multiple traits was performed with those traits whose pairwise MTAG yielded new GWAS-significant single nucleotide polymorphisms (SNPs), with a posterior-probability of model 3 (GWAS-pairwise) ≥0.6. We perform TWAS and PWAS that correlate the genetic component of expression or protein levels with the genetic component of a trait. We use the ICH cohort from UK Biobank as replication., Results: For all ICH (1,543 ICH, 1,711 controls), the mean age was 72 ± 2 in cases and 70 ± 2 in controls, and half of them were women. Replication cohort: 700 ICH and 399,717 controls. Novel loci were found only for all ICH (the trait containing lobar and nonlobar ICH), combining data of ICH and small vessel stroke, white matter hyperintensities volume, fractional anisotropy, mean diffusivity, and AD. We replicated 6 SNPs belonging to 2q33.2 ( ICA1L , β = 0.20, SE = 0.03, p value = 8.91 × 10 -12 ), 10q24.33 ( OBFC1 , β = -0.12, SE = 0.02, p value = 1.67 × 10 -8 ), 13q34 ( COL4A2 , β = 0.02, SE = 0.02, p value = 2.34 × 10 -11 ), and 19q13.32 ( APOC1 , β = -0.19, SE = 0.03, p value = 1.38 × 10 -12 ; APOE , β = 0.21, SE = 0.03, p value = 2.70 × 10 -11 ; PVRL2:CTB-129P6.4 , β = 0.15, SE = 0.03, p value = 1.38 × 10 -8 ); 2 genes ( SH3PXD2A , Z -score = 4.83, p value = 6.67 × 10 -7 ; and APOC1 , Z -score: = 5.11, p value = 1.60 × 10 -7 ); and ICA1L transcript ( Z -score = 6.8, p value = 9.1 × 10 -12 ) and protein levels ( Z -score = -5.8, p value = 6.7 × 10 -9 )., Discussion: Our results reinforce the role of APOE in ICH risk, replicate previous ICH-associated loci (2q33 and 13q34), and point to new ICH associations with OBFC1 , PVRL2:CTB-129P6.4 , APOC1 , and SH3PXD2A . Our study used data from European subjects, our main limitation. These molecules could be potential targets for future studies for modulating ICH risk.

Grain boundaries in noble metal catalysts have been identified as critical sites for enhancing catalytic activity in electrochemical reactions such as the oxygen reduction reaction. However, conventional methods to modify grain boundary density often alter particle size, shape, and morphology, obscuring the specific role of grain boundaries in catalytic performance. This study addresses these challenges by employing gold nanoparticle assemblies to control grain boundary density through the manipulation of nanoparticle collision frequency during synthesis. We demonstrate a direct correlation between increased grain boundary density and enhanced two-electron oxygen reduction reaction activity, achieving a significant improvement in both specific and mass activity. Additionally, the gold nanoparticle assemblies with high grain boundary density exhibit remarkable electrochemical stability, attributed to boron segregation at the grain boundaries, which prevents structural degradation. This work provides a promising strategy for optimizing the activity, selectivity, and stability of noble metal catalysts through precise grain boundary engineering., (© 2024. The Author(s).)

Anticancer drugs inhibit DNA replication by intercalating between DNA base pairs, forming covalent bonds with nucleotide bases, or binding to the DNA groove. To develop safer drugs, novel molecular structures with alternative binding mechanisms are essential. Stable boron hydrides offer a promising alternative for cancer therapy, opening up additional options like boron neutron capture therapy based on 10 B and thermal neutron beams or proton boron fusion therapy using 11 B and proton beams. These therapies are more efficient when the boron compound is ideally located inside cancer cells, particularly in the nucleus. Current cancer treatments often utilize small, polycyclic, aromatic, planar molecules that intercalate between ds-DNA base pairs, requiring only a spacing of approximately 0.34 nm. In this paper, we demonstrate another type of intercalation. Notably, [3,3'-Fe(1,2-C 2 B 9 H 11 ) 2 ] - , ([ o -FESAN] - ), a compact 3D molecule measuring 1.1 nm × 0.6 nm, can as well intercalate by strong non-bonding interactions preferentially with guanine. Unlike known intercalators, which are positive or neutral, [ o -FESAN] - is a negative species and when an [ o -FESAN] - molecule approaches the negatively charged DNA phosphate chain an anion-anion interaction consistently anti-electrostatic via C cluster -H⋯O-P bonds occurs. Then, when more molecules approach, an elongated outstandingly self-assembled structure of [ o -FESAN] - -[ o -FESAN] - forms moving anions towards the interthread region to interact with base pairs and form aggregates of four [ o -FESAN] - anions per base pair. These aggregates, in this environment, are generated by C cluster -H⋯O-C, N-H⋯H-B and C cluster -H⋯H-B interactions. The ferrabis(dicarbollide) boron-rich small molecules not only effectively penetrate the nucleus but also intercalate with ds-DNA, making them promising for cancer treatment. This amphiphilic anionic molecule, used as a carrier-free drug, can enhance radiotherapy in a multimodal perspective, providing healthcare professionals with improved tools for cancer treatment. This work demonstrates these findings with a plethora of techniques.

Background: Ischemic stroke (IS) represents a significant health burden globally, necessitating a better understanding of its genetic underpinnings to improve prevention and treatment strategies. Despite advances in IS genetics, studies focusing on the Spanish population and sex-stratified analyses are lacking., Methods: A case-control genome-wide association study was conducted with 9081 individuals (3493 IS cases and 5588 healthy controls). IS subtypes using Trial of ORG 10172 in Acute Stroke Treatment criteria were explored in a sex-stratified approach. Replication efforts involved the MEGASTROKE, GIGASTROKE, and the UK Biobank international cohorts. Post-genome-wide association study analysis included: in silico proteomic analysis, gene-based analysis, quantitative trait loci annotation, transcriptome-wide association analysis, and bioinformatic analysis using chromatin accessibility data., Results: Identified as associated with IS and its subtypes were 4 significant and independent loci. Replication confirmed 5p15.2 as a new locus associated with small-vessel occlusion stroke, with rs59970332-T as the lead variant (beta [SE], 0.13 [0.02]; P =4.34×10 -8 ). Functional analyses revealed CTNND2 given proximity and its implication in pathways involved in vascular integrity and angiogenesis. Integration of Hi-C data identified additional potentially modulated genes, and in silico proteomic analysis suggested a distinctive blood proteome profile associated with the lead variant. Gene-set enrichment analyses highlighted pathways consistent with small-vessel disease pathogenesis. Gene-based associations with known stroke-related genes such as F2 and FGG were also observed, reinforcing the relevance of our findings., Conclusions: We found CTNND2 as a potential key molecule in small-vessel occlusion stroke risk, and predominantly in males. This study sheds light on the genetic architecture of IS in the Spanish population, providing novel insights into sex-specific associations and potential molecular mechanisms. Further research, including replication in larger cohorts, is essential for a comprehensive understanding of these findings and for their translation to clinical practice., Competing Interests: Dr Arenillas reports compensation from Medtronic, Daiichi Sankyo, Boehringer Ingelheim, and Pfizer for consultant services; grants from AstraZeneca, Instituto de Salud Carlos III, European Commission and Gerencia de Salud Castilla y León; compensation from Philips for data and safety monitoring services; travel support from Daiichi Sankyo Company. Dr Ribo reports stock holdings in Methinks, Nora, and Ancaonda Biomed; compensation from Cerenovus, Vesalio, Stryker Corporation, Philips, Rapid Pulse, AptaTargets, and Medtronic MiniMed Inc for consultant services; compensation from Sensome for data and safety monitoring services. Dr Heitsch reports employment by Washington University School of Medicine in St. Louis; reports funding from National Institutes of Health and American Heart Association. Dr Dhar reports grants from National Institute of Neurological Disorders and Stroke. The other authors report no conflicts.

Direct-acting antivirals ledipasvir (LDV) and daclatasvir (DCV) are widely used as part of combination therapies to treat Hepatitis C infections. Here we show that these compounds inhibit the proliferation, invasion, and colony formation of triple-negative MDA-MB-231 breast cancer cells, SRC-transduced SW620 colon cancer cells and SRC- transduced NIH3T3 fibroblasts. DCV also inhibits the expression of PDL-1, which is responsible for resistance to immunotherapy in breast cancer cells. The demonstrated low toxicity in many Hepatitis C patients suggests LDV and DCV could be used in combination therapies for cancer patients. At the molecular level, these direct-acting antivirals inhibit the phosphorylation of Akt and the ephrin type A receptor 2 (EPHA2) by destabilizing a Src-EPHA2 complex, although they do not affect the general kinase activity of Src. Thus, LDV and DCV could be effective drugs for Src-associated cancers without the inherent toxicity of classical Src inhibitors., 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 © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Since 2021 the use of G-CSF was implemented in allo-HCT with PTCY-based prophylaxis with the aim of shortening the aplastic phase and reducing infectious complications. This study investigates the effectiveness of this change in protocol performed at our institution. One-hundred forty-six adults undergoing allo-HCT with PTCY-based prophylaxis were included, and among them, 58 (40%) received G-CSF. The median of days to neutrophil engraftment was shorter in the G-CSF group (15 vs. 20 days, p < 0.001). Patients receiving G-CSF had a lower incidence of day +30 bacterial bloodstream infections (BSI) than the rest (20.7% vs. 47.7%, p < 0.001). GVHD, SOS, and TA-TMA incidences were comparable between groups, and using G-CSF did not impact on survival. Endothelial activation was investigated using EASIX and by the measurement of soluble biomarkers in cryopreserved plasma samples obtained on days 0, +7, +14 and +21 of 39 consecutive patients (10 received G-CSF) included in the study. EASIX, VWF:Ag, sVCAM-1, sTNFRI, ST2, REG3α, TM and NETs medians values were comparable in patients receiving G-CSF and those who did not. Compared with allo-HCT performed without G-CSF, the addition of G-CSF to PTCY-based allo-HCT accelerated neutrophil engraftment contributing on decreasing BSI incidence, and without inducing additional endothelial activation., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Cyanobacterial harmful algal blooms can pose risks to ecosystems and human health worldwide due to their capacity to produce natural toxins. The potential dangers associated with numerous metabolites produced by cyanobacteria remain unknown. Only select classes of cyanopeptides have been extensively studied with the aim of yielding substantial evidence regarding their toxicity, resulting in their inclusion in risk management and water quality regulations. Information about exposure concentrations, co-occurrence, and toxic impacts of several cyanopeptides remains largely unexplored. We used liquid chromatography-mass spectrometry (LC-MS)-based metabolomic methods associated with chemometric tools (NP Analyst and Data Fusion-based Discovery), as well as an acute toxicity essay, in an innovative approach to evaluate the association of spectral signatures and biological activity from natural cyanobacterial biomass collected in a eutrophic reservoir in southeastern Brazil. Four classes of cyanopeptides were revealed through metabolomics: microcystins, microginins, aeruginosins, and cyanopeptolins. The bioinformatics tools showed high bioactivity correlation scores for compounds of the cyanopeptolin class (0.54), in addition to microcystins (0.54-0.58). These results emphasize the pressing need for a comprehensive evaluation of the (eco)toxicological risks associated with different cyanopeptides, considering their potential for exposure. Our study also demonstrated that the combined use of LC-MS/MS-based metabolomics and chemometric techniques for ecotoxicological research can offer a time-efficient strategy for mapping compounds with potential toxicological risk. Environ Toxicol Chem 2024;43:2222-2231. © 2024 SETAC., (© 2024 SETAC.)

Purpose: To identify risk factors predisposing patients to poor outcomes after fixation of periprosthetic hip fractures around femoral stems., Methods: Prospective multicentre cohort study of fractures around a hip replacement stem managed by internal fixation. The primary outcome was one-year mortality, while secondary outcomes were local complications and healthcare burden-related outcomes (nursing facility utilization and hospital length of stay)., Results: One-year mortality was 16.2%. Age-adjusted Charlson Comorbidity Index score (OR=1.17; 95%CI=1.03-1.33)), Pfeiffer Short Portable Mental Status Questionnaire (SPMSQ) score (OR=1.16; 1.06-1.28), prosthetic dysfunction (OR=1.90; 1.00-3.61), and postoperative medical complications (OR=1.97; 1.06-3.68) were predictors of mortality. Patients with prior prosthetic dysfunction, lower Pfeiffer SPMSQ scores, Vancouver A fractures, and fractures fixed only using cerclages were at higher risk of local complications, which occurred in 9.3% of cases. Medical (OR=1.81; 1.05-3.13) and local complications (OR=5.56; 2.42-3.13) emerged as consistent risk factors for new institutionalization. Average hospitalization time was 13.9±9.2 days. Each day of fixation delay led to an average 1.4-day increase in total hospitalization., Conclusion: Frail periprosthetic hip-fracture patients with poorer functional status, dysfunctional replacements, and postoperative complications are at increased risk of mortality. Postoperative complications are more common in patients with dysfunctional arthroplasties, Vancouver A fractures, and fixation using cerclages alone. Postoperative complications were the most consistent predictor of higher healthcare resource utilization., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hector J Aguado reports financial support was provided by AO Foundation. Hector J Aguado reports financial support was provided by Government of Castile and Leon Ministry of Health. If there are other authors, they 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 © 2024. Published by Elsevier Ltd.)

Halogenation of aliphatic C-H bonds is a chemical transformation performed in nature by mononuclear nonheme iron dependent halogenases. The mechanism involves the formation of an iron(IV)-oxo-chloride species that abstracts the hydrogen atom from the reactive C-H bond to form a carbon-centered radical that selectively reacts with the bound chloride ligand, a process commonly referred to as halide rebound. The factors that determine the halide rebound, as opposed to the reaction with the incipient hydroxide ligand, are not clearly understood and examples of well-defined iron(IV)-oxo-halide compounds competent in C-H halogenation are scarce. In this work we have studied the reactivity of three well-defined iron(IV)-oxo complexes containing variants of the tetradentate 1-(2-pyridylmethyl)-1,4,7-triazacyclononane ligand (Pytacn). Interestingly, these compounds exhibit a change in their chemoselectivity towards the functionalization of C-H bonds under certain conditions: their reaction towards C-H bonds in the presence of a halide anionleads to exclusive oxygenation, while the addition of a superacid results in halogenation. Almost quantitative halogenation of ethylbenzene is observed when using the two systems with more sterically congested ligands and even the chlorination of strong C-H bonds such as those of cyclohexane is performed when a methyl group is present in the sixth position of the pyridine ring of the ligand. Mechanistic studies suggest that both reactions, oxygenation and halogenation, proceed through a common rate determining hydrogen atom transfer step and the presence of the acid dictates the fate of the resulting alkyl radical towards preferential halogenation over oxygenation., 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 © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Controlling lake eutrophication is a challenge. A case-specific diagnostics driven approach is recommended that will guide to a suite of measures most promising in restoration of eutrophic lakes as exemplified by the case of the shallow lake Groote Melanen, The Netherlands. A lake system analysis identified external and internal nutrient load as main reasons for poor water quality and reoccurring cyanobacterial blooms in the lake. Based on this analysis, a package of restoration measures was implemented between January 2015 and May 2016. These measures included fish removal, dredging, capping of peat rich sediment with sand and an active barrier (lanthanum-modified bentonite), diversion of two inlet streams, reconstruction of banks, and planting macrophytes. Dredging and sand capping caused temporarily elevated turbidity and suspended solids concentrations, while addition of the lanthanum-modified clay caused a temporary exceedance of the Dutch La standard for freshwaters. Diversion of inflow streams caused 35 % less water inflow and larger water level fluctuations, but the lake remained water transporting with strongly improved water quality as was revealed by comparing five years pre-intervention water quality data with five years' post-intervention data. Total phosphorus concentration in the water column was reduced by 93 % from 0.47 mg P l -1 before the intervention to 0.03 mg P l -1 after the intervention, total nitrogen by 66 % from 1.27 to 0.21 mg N l -1 , total chlorophyll-a by 75 % from 68 to 16 µg l -1 , cyanobacteria chlorophyll-a by 88 % from 32 to 4 µg l -1 . Turbidity had declined by 58 % from 23.5 FTU to on average 9.9 FTU. No cyanobacteria blooms were recorded over the entire post-intervention monitoring period (2016-2021). Submerged macrophytes increased from complete absence before intervention to around 10 %-15 % coverage after intervention. Repeated fish removal lowered the fish stock to below 100 kg ha -1 with 12 % of bream and carp remaining. Hence, the package of cohesive measures that was based on a thorough diagnosis resulted in rapidly, strongly and enduringly improved water quality. This case provides evidence for the power of combining measures in restoring eutrophic lakes., 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 © 2024. Published by Elsevier Ltd.)

Background: To establish the feasibility and safety of multimodal prehabilitation (MP), and to obtain pilot data on the change in quality of life, functional walking capacity, and the need for surgery for a full-scale trial., Methods: Pilot randomized controlled trial that included patients older than 50 years old suffering from moderate to severe intermittent claudication and who were candidates for endovascular revascularization (ER). Participants were excluded if they presented with ischemic rest pain, gangrene or ulceration of the index leg, significant lesions in the iliac vessels, planned surgical bypass, comorbidities in which exercise was contraindicated or if they were unable to speak English or French. Participants were randomized in a 1:1 ratio to 12 weeks of MP or institutional standard of care (unsupervised walking advice). MP consisted of i)1 weekly supervised exercise session; ii) home-based exercise prescription; iii) nutritional counseling and supplementation; iv) smoking cessation therapy; and v) psychosocial support. Feasibility and safety were measured with recruitment and retention rates, as well as the occurrence of any adverse events. In addition, barriers to attend supervised sessions and compliance to each component were assessed. Change in functional walking capacity, health-related quality of life, and the rates of patients deciding not to undergo ER were collected and analyzed throughout the follow-up period of 12 months., Results: Of the 37 patients referred for eligibility, 27 (73%) accepted to participate in the trial and were randomized. Of the 27 patients included, 24 completed the 12-week program. Adherence to each prehabilitation component was 83% interquartile range [72,93] for supervised exercise, 90% [83,96] for home-based exercise and 69% [45,93] for nutritional sessions. Fifty percent of patients were referred for and underwent psychosocial intervention and 40% of the active smokers enrolled in the smoking cessation program. No adverse events were observed during the program. The 2 main barriers for not fully adhering to the intervention were excessive pain while performing the exercises and the difficulty to keep up with the prescribed exercises. A statistically significant mean change (standard deviation (SD)) was seen in the MP group versus standard of care for functional capacity, mean (SD) 6 Min Walk Test 60 (74) vs. -11 (40) meters P < 0.05, and quality of life mean (SD) VascuQol 1.15 (0.54) vs. -0.3 (1.09) points P < 0.05. There was no statistically significant difference between groups in the rates of patients deciding to undergo ER during the 1-year follow-up period., Conclusions: The results of this pilot trial demonstrate that MP is safe and feasible. A 12-week MP program seems to improve quality of life and functional walking capacity to a greater extent than unsupervised walking advice. There is a need for a large-scale trial to investigate the effectiveness of MP at improving quality of life and assessing its impact on the rates of patients deciding not to undergo or delay ER. The long-term functional and quality of life outcomes of the patients deciding to undergo ER after prehabilitation also need to be assessed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Moisture activated dry granulation (MADG) is an attractive granulation process. However, only a few works have explored modified drug release achieved by MADG, and to the best of the authors knowledge, none of them have explored gastroretention. The aim of this study was to explore the applicability of MADG process for developing gastroretentive placebo tablets, aided by SeDeM diagram. Floating and swelling capacities have been identified as critical quality attributes (CQAs). After a formulation screening step, the type and concentration of floating matrix formers and of binders were identified as the most relevant critical material attributes (CMAs) to investigate in ten formulations. A multiple linear regression analysis (MLRA) was applied against the factors that were varied to find the design space. An optimized product based on principal component analysis (PCA) results and MLRA was prepared and characterized. The granulate was also assessed by SeDeM. In conclusion, granulates lead to floating tablets with short floating lag time (<2 min), long floating duration (>4 h), and showing good swelling characteristics. The results obtained so far are promising enough to consider MADG as an advantageous granulation method to obtain gastroretentive tablets or even other controlled delivery systems requiring a relatively high content of absorbent materials in their composition., 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 © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Patients with depressive disorders are especially prone to suicide risk. Among the clinical predictors of suicidality, those specifically related to depressive disorders have not been accurately detailed. Our aim was to conduct a systematic review and meta-analysis of studies reporting longitudinal predictors of suicidal ideation, suicide attempts and suicide death within depression, including diagnostic subtypes, symptoms, clinical course, and assessment scales. A systematic search of the literature between 2001 and 2022 identified 4422 references, among which 19 studies providing 45 different predictors of suicidality met the inclusion criteria. Random effects meta-analyses were performed for 22 predictors, three for suicidal ideation, eleven for suicide attempts and eight for suicide death. Heterogeneity and publication bias were inspected through I 2 tests and Egger's tests respectively. Meta-analysis results showed that severity of hopelessness predicted suicidal ideation and suicide attempts. History of suicide attempts, suicidal ideation, severe depression, and psychotic symptoms predicted subsequent suicide attempts and suicide death. Time to full remission and sleep disturbances were also found as relevant predictors of future suicide behaviours. This review specifies which predictors of suicidality within the clinical features of depression will help clinicians and policy makers to better prevent suicide risk in patients with depressive disorders. Further longitudinal studies are needed to reliably assess the predictive ability of our results and to analyse other possible clinical predictors to prevent suicidality, especially with regard to suicidal ideation., (© 2023. The Author(s).)

Candida infections can be serious in intensive care unit (ICU) patients, as Candida is an organism that specially colonizes the digestive system. In immunocompromised patients, treatment is protocolized, but in non-neutropenic patients, it is not well established. On the other hand, the treatment of this type of infection is not absent of adverse effects. The prevalence of fungal infections, especially candidiasis, and its mortality in the ICU is high, mainly due to the lack of diagnosis and absence of treatment criteria, because they are often detected in the disseminated candidiasis phase, such as candidemia. One of the indicators of the progression of the disease is the presence of Candida in more than two different foci, named Candida multifocality, within the concept of invasive candidiasis. In fact, the invasive fungal diseases in adult patients i intensive care unit (FUNDICU) project was created to optimize the management of candidiasis. The management of candidiasis in ICU patients first requires the identification of patients at high risk of candidiasis, which must be performed based on the evidence of immune dysregulation, higher severity index (acute physiologic assessment and chronic health evaluation and multiple organ dysfunction syndrome), long ICU stays or other factors such as mechanical ventilation or us of broad-spectrum antibiotics. To increase detection and dispense the appropriate antifungal at an early stage, it is necessary to include the concept of multifocality in invasive candidiasis with screening of different foci. Antifungal treatment reduces mortality both overall and attributable to Candida. Detecting a high invasive candidiasis risk is a patient safety concept and should be treated as such. Identifying patients (critically non-neutropenic adult patients with severe multiple organ dysfunction syndrome and the first isolation of Candida spp. in a study sample of possible secondary infection) and demonstrating invasive candidiasis (multifocal or disseminated) require urgent initiation of antifungal treatment to minimize mortality attributable to invasive candidiasis in the ICU and eliminate mortality rates above 50%., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Major Depressive Disorder (MDD) is one of the most disabling mental health problems worldwide. The Recovery Model emphasizes peer support to empower individuals with MDD, improve self-management, and patients' quality of life. Despite the demonstrated efficacy of peer-led interventions, further research is needed due to methodological limitations and variability in interventions across studies. Therefore, the objective of this trial is to evaluate the effectiveness of an adjuvant peer-led intervention for the reduction of depressive symptoms in individuals diagnosed with MDD attended in primary care mental health units., Methods: A controlled, parallel, randomized clinical trial will be conducted. The intervention group (n = 35) will receive 6 weeks of peer-led sessions based on a peer support program drive whilst supervised by nurses, while the control group (n = 35) will use a mobile Health (mHealth) application for emotional wellness based on CBT for 6 weeks. Measurements will be collected at baseline, at 6 weeks, at 6 and 12 months after the intervention to evaluate post-intervention effects. The primary outcome is the reduction of depressive symptoms through the Beck Depression Inventory (BDI-II) after the intervention. Secondary outcomes will involve measures such as adherence to psychiatric treatment, quality of life, adherence to mediterranean diet, alcohol consumption and physical activity., Discussion: We hypothesize that this peer-led intervention, in contrast to the mHealth, will show improvement in BDI-II score reduction of 6 points after six weeks, 6 and 12 months. Standardized peer-led programs can benefit patients and professionals in terms of efficacy and feasibility of clinical treatment of depression, healthy habits, self-care and quality of life. In addition, they can provide recovery and relapse reduction, improved psychosocial support, minimization of intensive care use, and support for patient autonomy through self-management., Trial Registration: The trial protocol is prospectively registered with ClinicalTrials.gov under protocol registration number NCT06398561. Date of registration: May 01, 2024. Recruitment is ongoing., (© 2024. The Author(s).)

Context: The field of chemistry has significantly evolved, with catalysis playing a crucial role in transforming chemical processes. From Valerius' use of sulfuric acid in the sixteenth century to modern advancements, catalysis has driven innovations across various industries. The introduction of gold as a catalyst marked a pivotal shift, expanding its applications beyond ornamentation to homogeneous catalysis. Gold's unique properties, such as its electrophilic nature and flexibility, have enabled its use in synthesizing complex molecules, including those in nanomedicine and sustainable chemical processes. The development of gold-based complexes, particularly in hydroalkoxylation and hydroamination reactions, showcases their efficiency in forming carbon-oxygen bonds under mild conditions. Recent studies on dual gold catalysis and heterobimetallic complexes further highlight gold's versatility in achieving high turnover rates and selectivity. This evolution underscores the potential of gold catalysis in advancing environmentally sustainable methodologies and enhancing the scope of modern synthetic chemistry. The debate about the nature of monogold and dual-gold catalysis is open., Methods: DFT calculations have played a key role in promoting the activation of alkynes, in particular the hydrophenoxylation of alkynes by metal-based catalysts. They not only help identify the most efficient and selective catalysts but also aid in screening for those capable of performing a dual metal catalytic mechanism. The most commonly used functionals are BP86 and B3LYP, with the SVP and 6-31G(d) basis sets employed for geometry optimizations, and M06 with TZVP or 6-311G(d,p) basis sets used for single-point energy calculations in a solvent. Grimme dispersion correction has been explicitly added either in the solvent single point energy calculations or in the gas phase geometry optimizations or in both. To point out that M06 implicitly includes part of this dispersion scheme., (© 2024. The Author(s).)

The development of novel synthetic methods has greatly expanded the toolbox available to chemists for engineering porphyrin and phthalocyanine derivatives with precise electronic and optical properties. In this study, we focus on the UV-vis absorption characteristics of substituted phthalocyanines and their contracted analogs, subphthalocyanines, which feature nonplanar, bowl-shaped geometries. These macrocycles, which are central to numerous applications in materials science and catalysis, possess extensive π-conjugated systems that drive their unique electronic properties. We explore how the change from a metalloid (B) to a metal (Zn) and the resulting coordination environments influence the aromaticity and, consequently, the spectroscopic features of these systems. A combined computational and experimental approach reveals a direct correlation between the aromaticity of the external conjugated pathways and the Q bands in the UV-vis spectra. Our findings highlight key structural modifications that can be leveraged to fine-tune the optical properties of porphyrinoid systems, offering new pathways for the design of advanced materials and catalysts with tailored functionalities.

Objectives: Assessing occupational exposure to radiofrequency electromagnetic fields (RF-EMF) presents significant challenges due to the considerable variability in exposure levels within and between occupations. This spatial and temporal variability complicates the reliable evaluation of potential health risks associated with RF-EMF exposure in the workplace. Accurate assessment methods are crucial to understand the extent of exposure and to evaluate potential health risks, especially given the potential for higher exposures in occupational settings compared to the general population. This study compares the historical RF-EMF exposure estimates in the INTEROCC RF-EMF job-exposure matrix (RF-JEM) with recent personal measurement data collected in 2 countries as part of the OccRF-Health study, to assess the broader applicability of the RF-JEM., Methods: Weighted kappa (k  w) coefficients and Spearman rank correlation tests were performed to assess the alignment between RF-JEM estimates and measurements for 8 h time-weighted average exposure intensity and prevalence estimates across various occupations. The comparisons were mainly based on 22 jobs having ≥5 measured workers in the OccRF-Health study., Results: Poor agreement was found for both exposure prevalence and intensity between both methods (k  w < 0.1). RF-JEM values likely overestimated exposure levels for both electric (E) and magnetic (H) fields (mean percentage difference >194%) compared to current personal measurements., Conclusions: Findings suggest that the INTEROCC-JEM likely overestimates current exposure intensity levels in the measured jobs. Adopting a semiquantitative JEM could also mitigate misclassification errors due to exposure variability, improving accuracy in exposure assessment. These findings indicate the need for more targeted personal measurements, including among highly exposed workers, and for potentially considering new exposure metrics to more accurately assess occupational RF-EMF exposures in occupational epidemiological research., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Occupational Hygiene Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Breweŕs spent grain (BSG) is the main by-product of the brewing industry, and due to its rapid decomposition, it generates serious environmental problems such as malodors and greenhouse gases emissions. On the other hand, this lignocellulosic compound contains a large number of antioxidants, being ferulic acid (FA) the most abundant. FA is a powerful antioxidant molecule that has demonstrated significant protective effects on key components of the skin, including keratinocytes, fibroblasts, collagen, and elastin. FA inhibits melanogenesis, promotes angiogenesis and accelerates the wound healing although its use is limited by its rapid oxidation. In this study, different hydrolysis treatments (chemical, enzymatic and hydrothermal) were performed on BSG to obtain FA. Herein FA-loaded ultradeformable liposomes (ULs) were designed to improve their stability and in vivo performance. These nanosystems allow FA permeability through human skin, as proven by an ex vivo skin permeability assay using Franz diffusion cells. The toxicity and anti-inflammatory activity of the formulation has been investigated. The free form and 100 nm FA&#95;ULs were evaluated. Cell viability was dose-dependent and provided optimal results for the treatment of inflammatory skin conditions in an in vivo Oxazolone-induced Delayed Type Hypersensitivity model using Swiss CD1 mice, demonstrated by the reduction of the inflammatory cytokines expression, ear thickness, bioluminescence and histological evaluation. These results pave the way for FA-based treatments of skin and inflammatory conditions., 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 © 2024. Published by Elsevier B.V.)

The emergence of cellular immunotherapy treatments is introducing more efficient strategies to combat cancer as well as autoimmune and infectious diseases. However, the cellular manufacturing procedures associated with these therapies remain costly and time-consuming, thus limiting their applicability. Recently, lymph-node-inspired PEG-heparin hydrogels have been demonstrated to improve primary human T cell culture at the laboratory scale. To go one step further in their clinical applicability, we assessed their scalability, which was successfully achieved by 3D printing. Thus, we were able to improve primary human T cell infiltration in the biohybrid PEG-heparin hydrogels, as well as increase nutrient, waste, and gas transport, resulting in higher primary human T cell proliferation rates while maintaining the phenotype. Thus, we moved one step further toward meeting the requirements needed to improve the manufacture of the cellular products used in cellular immunotherapies.

Purpose: PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells., Methods: Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells., Results: Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization., Conclusion: By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The value of adding fusion to decompression surgery for lumbar degenerative spondylolisthesis and spinal canal stenosis remains debated. Therefore, the comparative effectiveness and selected healthcare resource utilization of patients undergoing decompression with or without fusion surgery at 3 years follow-up was assessed., Methods: Using observational data from the Lumbar Stenosis Outcome Study and a target trial emulation with index trial benchmarking approach, our study assessed the comparative effectiveness of the two main surgical interventions for lumbar degenerative spondylolisthesis-fusion and decompression alone in patients with lumbar degenerative spondylolisthesis and spinal canal stenosis. The primary outcome-measure was change in health-related quality of life (EuroQol Health Related Quality of Life 5-Dimension 3-Level questionnaire [EQ-5D-3L]); secondary outcome measures were change in back/leg pain intensity (Numeric Rating Scale), change in satisfaction (Spinal Stenosis Measure satisfaction subscale), physical therapy and oral analgesic use (healthcare utilization)., Results: 153 patients underwent decompression alone and 62 had decompression plus fusion. After inverse probability weighting, 137 patients were included in the decompression alone group (mean age, 73.9 [7.5] years; 77 female [56%]) and 36 in the decompression plus fusion group (mean age, 70.1 [6.7] years; 18 female [50%]). Our findings were compatible with no standardized mean differences in EQ-5D-3L summary index change score at 3 years (EQ-5D-3L German: 0.07 [95% confidence interval (CI), - 0.25 to 0.39]; EQ-5D-3L French: 0.18 [95% CI, - 0.14 to 0.50]). No between-group differences in change in back/leg pain intensity or satisfaction were found. Decompression plus fusion was associated with greater physical therapy utilization at 3 years follow-up., Conclusion: Decompression alone should be considered the primary option for patients with lumbar degenerative spondylolisthesis and spinal stenosis., (© 2024. The Author(s).)

Inflammatory diseases of the skin have a considerable high prevalence worldwide and negatively impact the patients' quality of life. First-line standard therapies for these conditions inherently entail important side effects when used long-term, particularly complicating the management of chronic cases. Therefore, there is a need to develop novel therapeutic strategies to offer reliable alternative treatments. Abnormally high reactive oxygen species (ROS) levels are characteristic of this kind of illnesses, and therefore a reasonable therapeutic goal. Cyanocobalamin, also known as Vitamin B 12 , possesses notable antioxidant and ROS-scavenging properties which could make it a possible therapeutic alternative. However, its considerable molecular weight restricts passive diffusion through the skin and forces the use of an advanced transdermal delivery system. Here, we present several prototypes of Cyanocobalamin-loaded Dissolving Microarray Patches (B 12 @DMAPs) with adequate mechanical properties to effectively penetrate the stratum corneum barrier, allowing drug deposition into the skin structure. Ex vivo penetration and permeability studies noted an effective drug presence within the dermal skin layers; in vitro compatibility studies in representative cell skin cell lines such as L929 fibroblasts and HaCaT keratinocytes ensured their safe use. The in vivo efficacy of the selected prototype was tested in a delayed-type hypersensitivity murine model that mimics an inflammatory skin process. Several findings such as a reduction of MPO-related photon emission in a bioluminescence study, protection against histological damage, and decrease of inflammatory cytokines levels point out the effectivity of B 12 @DMAPs to downregulate the skin inflammatory environment. Overall, B 12 @DMAPs offer a cost-effective translational alternative for improving patients' skin healthcare., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Background and Objective: Computational models of hemodynamics can contribute to optimizing surgical plans, and improve our understanding of cardiovascular diseases. Recently, machine learning methods have become essential to reduce the computational cost of these models. In this study, we propose a method that integrates 1-D blood flow equations with Physics-Informed Graph Neural Networks (PIGNNs) to estimate the propagation of blood flow velocity and lumen area pulse waves along arteries., Methods: Our methodology involves the creation of a graph based on arterial topology, where each 1-D line represents edges and nodes in the blood flow analysis. The innovation lies in decoding the mathematical data connecting the nodes, where each node has velocity and lumen area pulse waveform outputs. The training protocol for PIGNNs involves measurement data, specifically velocity waves measured from inlet and outlet vessels and diastolic lumen area measurements from each vessel. To optimize the learning process, our approach incorporates fundamental physical principles directly into the loss function. This comprehensive training strategy not only harnesses the power of machine learning but also ensures that PIGNNs respect fundamental laws governing fluid dynamics., Results: The accuracy was validated in silico with different arterial networks, where PIGNNs achieved a coefficient of determination (R 2 ) consistently above 0.99, comparable to numerical methods like the discontinuous Galerkin scheme. Moreover, with in vivo data, the prediction reached R 2 values greater than 0.80, demonstrating the method's effectiveness in predicting flow and lumen dynamics using minimal data., Conclusions: This study showcased the ability to calculate lumen area and blood flow rate in blood vessels within a given topology by seamlessly integrating 1-D blood flow with PIGNNs, using only blood flow velocity measurements. Moreover, this study is the first to compare the PIGNNs method with other classic Physics-Informed Neural Network (PINNs) approaches for blood flow simulation. Our findings highlight the potential to use this cost-effective and proficient tool to estimate real-time arterial pulse waves., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Radiofrequency electromagnetic fields (RF-EMF, 100 kHz to 300 GHz) are classified by IARC as possibly carcinogenic to humans (Group 2B). This study evaluates the potential association between occupational RF-EMF exposure and brain tumor risk, utilizing for the first time, a RF-EMF job-exposure matrix (RF-JEM) developed in the multi-country INTEROCC case-control study. Cumulative and time-weighted average (TWA) occupational RF-EMF exposures were estimated for study participants based on lifetime job histories linked to the RF-JEM using three different methods: (1) by considering RF-EMF intensity among all exposed jobs, (2) by considering RF-EMF intensity among jobs with an exposure prevalence ≥ the median exposure prevalence of all exposed jobs, and (3) by considering RF-EMF intensity of jobs of participants who reported RF-EMF source use. Stratified conditional logistic regression models were used, considering various lag periods and exposure time windows defined a priori. Generally, no clear associations were found for glioma or meningioma risk. However, some statistically significant positive associations were observed including in the highest exposure categories for glioma for cumulative and TWA exposure in the 1- to 4-year time window for electric fields (E) in the first JEM application method (odds ratios [ORs] = 1.36, 95% confidence interval [95% CI] 1.08, 1.72 and 1.27, 95% CI 1.01, 1.59, respectively), as well as for meningioma for cumulative exposure in the 5- to 9-year time window for electric fields (E) in the third JEM application method (OR = 2.30, 95% CI 1.11, 4.78). We did not identify convincing associations between occupational RF-EMF exposure and risk of glioma or meningioma., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Elucidating the factors affecting the transfer of naturally occurring radionuclides (NOR) between environmental compartments is a key part of the assessment of ecosystem's exposure to naturally occurring radionuclide materials (NORM). For that, the sorption and desorption solid-liquid distribution coefficients (K d ) of radium (Ra) were quantified in a collection of 31 soil samples with contrasting edaphic properties under controlled conditions in laboratory batch experiments. Ra sorption was demonstrated to be moderate to high, with K d (Ra) values ranging from 10 2 to 10 3  L kg -1 . Ra sorbed was mostly irreversible, as evidenced by desorption percentages lower than 2 %. An exploratory analysis with partial least squares (PLS) regression identified the soil properties that correlated with K d (Ra) and discarded those that were not relevant for describing K d variability. A dataset of the sorption K d (Ra) values and associated soil properties was built from our own data and from the literature after performing an in-depth review of similar Ra sorption studies. For the first time, K d (Ra) parametric prediction models were constructed using univariate linear regression (ULR) and multivariate linear regression (MLR). Ra sorption in soils was mostly explained by the soil properties directly or indirectly related to the available exchange sites, such as the levels of water-soluble and exchangeable Ca and Mg as well as the pH of the contact solution. The most promising models explained around 80 % of the K d (Ra) data variance, only needing K d (Ca + Mg) or additional soil descriptors such as pH, Mn content, and the specific surface area. The validation of the proposed models confirmed that K d (Ra) can be predicted with only a few soil properties that can be characterised in routine analysis. Thus, the proposed models could be used to estimate the interaction of Ra in soils in risk assessment., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The planarian Schmidtea mediterranea is being studied as a model species for regeneration, but the assembly of planarian genomes remains challenging. Here, we report a high-quality haplotype-phased, chromosome-scale genome assembly of the sexual S2 strain of S. mediterranea and high-quality chromosome-scale assemblies of its three close relatives, S. polychroa, S. nova, and S. lugubris. Using hybrid gene annotations and optimized ATAC-seq and ChIP-seq protocols for regulatory element annotation, we provide valuable genome resources for the planarian research community and a first comparative perspective on planarian genome evolution. Our analyses reveal substantial divergence in protein-coding sequences and regulatory regions but considerable conservation within promoter and enhancer annotations. We also find frequent retrotransposon-associated chromosomal inversions and interchromosomal translocations within the genus Schmidtea and, remarkably, independent and nearly complete losses of ancestral metazoan synteny in Schmidtea and two other flatworm groups. Overall, our results suggest that platyhelminth genomes can evolve without syntenic constraints., (© 2024. The Author(s).)

Background: Topical imiquimod has been shown to be an effective treatment for extramammary Paget disease (EMPD), although available evidence supporting its use is based on case reports and small series of patients., Objectives: To investigate the therapeutic outcomes and analyse potential clinicopathological factors associated with the imiquimod response in a large cohort of patients with EMPD., Methods: Retrospective chart review of 125 patients with EMPD treated with imiquimod at 20 Spanish tertiary-care hospitals., Results: During the study period, patients received 134 treatment regimens with imiquimod, with 70 (52.2%) treatments achieving a complete response (CR), 41 (30.6%) a partial response and 23 (17.2%) no response. The cumulative CR rates at 24 and 48 weeks of treatment were 46.3% and 71.8%, respectively, without significant differences between first-time and previously treated EMPD. Larger lesions (≥ 6 cm; P = 0.04) and EMPD affecting > 1 anatomical site (P = 0.002) were significantly associated with a worse treatment response. However, the CR rate did not differ significantly by the number of treatment applications (≤ 4 vs. > 4 times per week; P = 0.112). Among patients who achieved CR, 30 of 69 (43%) treatments resulted in local recurrences during a mean follow-up period of 36 months, with an estimated 3- and 5-year recurrence-free survival of 55.7% and 36.4%, respectively., Conclusions: Imiquimod appears as an effective therapeutic alternative for both first-line and previously treated EMPD lesions. However, a less favourable therapeutic response could be expected in larger lesions and those affecting > 1 anatomical site. Based on our results, a three to four times weekly regimen of imiquimod with a treatment duration of at least 6 months could be considered an appropriate therapeutic strategy for patients with EMPD., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The oxygen reduction reaction (ORR) is a critical process that limits the efficiency of fuel cells and metal-air batteries due to its slow kinetics, even when catalyzed by platinum (Pt). To reduce Pt usage, enhancing both the specific activity and electrochemically active surface area (ECSA) of Pt catalysts is essential. Here, ultrafine, grain boundary (GB)-rich Pt nanoparticle assemblies are proposed as efficient ORR catalysts. These nanowires offer a large ECSA and a high density of concave GB sites, which improve specific activity. Atoms at these GB sites exhibit increased coordination and lattice distortion, leading to a favorable reduction in oxygen binding energy and enhanced ORR performance. Furthermore, boron segregation stabilizes these GBs, preserving active sites during catalysis. The resulting boron-stabilized Pt nanoassemblies demonstrate ORR specific and mass activities of 9.18 mA cm -2 and 6.40 A mg -1 Pt (at 0.9 V vs. RHE), surpassing commercial Pt/C catalysts by over 35-fold, with minimal degradation after 60 000 potential cycles. This approach offers a versatile platform for optimizing the catalytic performance of a wide range of nanoparticle systems., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 17 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment including SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, CRTC3, AP001453 . 3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, DPH1, GSDMB, MED24 and THRA in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance of BD polygenic risk scores across diverse populations, and present a high-throughput fine-mapping pipeline ( https://github.com/mkoromina/SAFFARI ).

A bandwidth-efficient coherent analog IFoF approach is proposed, employing a twin optical sideband (twin-OSSB) modulation of intermediate frequency-over-fiber (IFoF) signals in a dually modulated electroabsorption modulated laser (EML), demonstrating stable modulations without complex bias drifts and polarization control. The receiver (Rx) utilizes heterodyne detection with phase noise canceling (PNC) techniques for channel recovery. Successful demonstrations include an 8 Gbps aggregated twin-OSSB of two QPSK channels, with measurements covering optical back-to-back (btb) and 25 km of a standard single-mode fiber (SSMF), revealing sensitivities of -30 dBm and -25 dBm for QPSK-twin-OSSB and 16-QAM single user, respectively.

Emerging pollutants, such as pharmaceuticals and microplastics have become a pressing concern due to their widespread presence and potential impacts on ecological systems. To assess the ecosystem-level effects of these pollutants within a multi-stressor context, we simulated real-world conditions by exposing a near-natural multi-trophic aquatic food web to a gradient of environmentally relevant concentrations of fluoxetine and microplastics in large mesocosms over a period of more than three months. We measured the biomass and abundance of different trophic groups, as well as ecological functions such as nutrient availability and decomposition rate. To explore the mechanisms underlying potential community and ecosystem-level effects, we also performed behavioral assays focusing on locomotion parameters as a response variable in three species: Daphnia magna (zooplankton prey), Chaoborus flavicans larvae (invertebrate pelagic predator of zooplankton) and Asellus aquaticus (benthic macroinvertebrate), using water from the mesocosms. Our mesocosm results demonstrate that presence of microplastics governs the response in phytoplankton biomass, with a weak non-monotonic dose-response relationship due to the interaction between microplastics and fluoxetine. However, exposure to fluoxetine evoked a strong non-monotonic dose-response in zooplankton abundance and microbial decomposition rate of plant material. In the behavioral assays, the locomotion of zooplankton prey D. magna showed a similar non-monotonic response primarily induced by fluoxetine. Its predator C. flavicans, however, showed a significant non-monotonic response governed by both microplastics and fluoxetine. The behavior of the decomposer A. aquaticus significantly decreased at higher fluoxetine concentrations, potentially leading to reduced decomposition rates near the sediment. Our study demonstrates that effects observed upon short-term exposure result in more pronounced ecosystem-level effects following chronic exposure., 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 © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The study of beach morphology holds significant importance in coastal management, offering insights into coastal and environmental processes. It involves analyzing physical characteristics and beach features such as profile shape, slope, sediment composition, and grain size, as well as changes in elevation due to both erosion and accretion over time. Furthermore, studying changes in beach morphology is essential in predicting and monitoring coastal inundation events, especially in the context of rising sea levels and subsidence in some areas. However, having access to high-frequency oblique imagery and beach elevation datasets to document and confirm coastal forcing events and understand their impact on beach morphology is a notable challenge. This paper describes a one-year dataset comprising bi-monthly topographic surveys and imagery collected daily at 30 min increments at the beach adjacent to Horace Caldwell Pier in Port Aransas, Texas. The data collection started in February 2023 and ended in January 2024. The dataset includes 18 topographic surveys, 6879 beach images, and ocean/wave videos that can be combined with colocated National Oceanic and Atmospheric Administration metocean measurements. The one-year temporal span of the dataset allows for the observation and analysis of seasonal variations, contributing to a deeper understanding of coastal dynamics in the study area. Furthermore, a study that combines survey measurements with camera imagery is rare and provides valuable information on conditions before, after, and between surveys and periods of inundation. The imagery enables monitoring of inundation events, while the topographic surveys facilitate the analysis of their impact on beach morphology, including beach erosion and accretion. Various products, including beach profiles, contours, slope maps, triangular irregular networks, and digital elevation models, were derived from the topographic dataset, allowing in depth analysis of beach morphology. Additionally, the dataset contains a time series of four wet/dry shoreline delineations per day and their corresponding elevation extracted by combining the imagery with the digital elevation models. Thus, this paper provides a high-frequency morphological dataset and a machine learning-ready dataset suitable for predicting coastal inundation., (© 2024 The Author(s).)

Colloidal metal nanoparticles exhibit interesting catalytic properties for the hydrogenation of (hetero)arenes. Catalysts based on precious metals, such as Ru and Rh, proceed efficiently under mild reaction conditions. In contrast, heterogeneous catalysts based on earth-abundant metals can selectively hydrogenate (hetero)arenes but require harsher reaction conditions. Bimetallic catalysts that combine precious and earth-abundant metals are interesting materials to mitigate the drawbacks of each component. To this end, RuNi nanoparticles bearing a phosphine ligand were prepared through the decomposition of [Ru(η4-C8H12)(η6-C8H10)] and [Ni(η4-C8H12)2] by H2 at 85°C. Wide angle X-ray scattering confirmed a bimetallic segregated structure, with Ni predominantly on the surface. Spectroscopic analyses revealed that the phosphine ligand coordinated to the surface of both metals, suggesting, as well, a partial Ni shell covering the Ru core. The RuNi-based nanomaterials were used as catalysts in the hydrogenation of quinoline to assess the impact of the metallic composition and of the stabilizing agent on their catalytic performance., (© 2024 Wiley‐VCH GmbH.)

The Blood-Brain Barrier (BBB) significantly impedes drug delivery to the central nervous system. Nanotechnology, especially surface-functionalized lipid nanoparticles, offers innovative approaches to overcome this barrier. However, choosing an effective functionalization strategy is challenging due to the lack of detailed comparative analysis in current literature. Our systematic review examined various functionalization strategies and their impact on BBB permeability from 2041 identified articles, of which 80 were included for data extraction. Peptides were the most common modification (18) followed by mixed strategies (12) proteins (9), antibodies (7), and other strategies (8). Interestingly, 26 studies showed BBB penetration with unmodified or modified nanoparticles using commonly applied strategies such as PEGylation or surfactant addition. Statistical analysis across 42 studies showed correlation between higher in vivo permeation improvements and nanoparticle type, size, and functionalization category. The highest ratios were found for nanostructured lipid carriers or biomimetic systems, in studies with particle sizes under 150 nm, and in those applying mixed functionalization strategies. The interstudy heterogeneity we observed highlights the importance of adopting standardized evaluation protocols to enhance comparability. Our systematic review aims to provide a comparative insight and identify future research directions in the development of more effective lipid nanoparticle systems for drug delivery to the brain to help improve the treatment of neurological and psychiatric disorders and brain tumours., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The incidence of mental health issues in children is increasing worldwide. In Chile, a recent surge in reports of deteriorating mental health among school populations and an increase in complaints related to poor school climate have been observed. Physical activity, specifically active breaks in the classroom, has shown positive effects on children's health. However, evidence regarding its impact on mental health and school climate in children is limited., Objective: This work outlines the design, measurements, intervention program, and potential efficacy of the "Active Classes + School Climate and Mental Health" project. This project will assess a 12-week program of active breaks through guided videos with curricular content in the school classroom, and its effects on mental health and school climate as its primary indicators. Additionally, it will measure physical activity, physical fitness, motor competence, and academic performance in students aged 6-10 years in the Biobío province, Chile, as secondary indicators. Methodology: A multicenter randomized controlled trial involving 823 students from 1st to 4th grade (6-10 years old), six schools (three intervention and three control) will be conducted in the Biobío region, Chile. Participants belonging to the intervention group will implement video-guided active breaks through the "Active Classes" web platform, featuring curricular content, lasting 5-10 min and of moderate to vigorous intensity physical activity, twice a day, Monday to Friday, over a span of 12 weeks. Expected Results/Discussion: To our knowledge, this will be the first study in Chile to evaluate the effects of incorporating video-guided active breaks with curricular content on mental health variables and school climate in schoolchildren. Thus, this study contributes to the scarce evidence on the effects of video-guided active breaks on mental health variables and school climate in schoolchildren worldwide. Additionally, it will provide crucial information about active teaching methodologies that have the potential to positively contribute to the wellbeing of students, thus addressing the problems of mental health and climate in Chilean schools. ClinicalTrials.gov ID NCT06423404., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zapata-Lamana, Robles-Campos, Reyes-Molina, Rojas-Bravo, Salcedo Lagos, Chávez-Castillo, Gajardo-Aguayo, Villalobos, Arias, Sanhueza-Campos, Ibarra Mora, Reyes-Amigo, Cristi-Montero, Sánchez-Oliva, Ruiz-Hermosa, Sánchez-López, Poblete-Valderrama, Celis-Morales, Martorell, Carrasco-Marín, Albornoz-Guerrero, Parra-Rizo and Cigarroa.)

High-valent oxoiron species have been invoked as oxidizing agents in a variety of iron-dependent oxygenases. Taking inspiration from nature, selected nonheme iron complexes have been developed as catalysts to elicit C-H oxidation through the mediation of putative oxoiron(V) species, akin to those proposed for Rieske oxygenases. The addition of carboxylic acids in these iron-catalyzed C-H oxidations has proved highly beneficial in terms of product yields and selectivities, suggesting the direct involvement of iron(V)-oxo-carboxylato species. When the carboxylic acid functionality is present in the alkane substrate, it acts as a directing group, enabling the selective intramolecular γ-C-H hydroxylation that eventually affords γ-lactones. While this mechanistic frame is solidly supported by previous mechanistic studies, direct spectroscopic detection of the key iron(V)-oxo-carboxylato intermediate and its competence for engaging in the selective γ-C-H oxidation leading to lactonization have not been accomplished. In this work, we generate a series of well-defined iron(V)-oxo-carboxylato species ( 2c - 2f ) differing in the nature of the bound carboxylate ligand. Species 2c - 2f are characterized by a set of spectroscopic techniques, including UV-vis spectroscopy, cold-spray ionization mass spectrometry (CSI-MS), and, in selected cases, EPR and Mössbauer spectroscopies. We demonstrate that 2c - 2f undergo site-selective γ-lactonization of the carboxylate ligand in a stereoretentive manner, thus unequivocally identifying metal-oxo-carboxylato species as the powerful yet selective C-H cleaving species in catalytic γ-lactonization reactions of carboxylic acids. Reactivity experiments confirm that the intramolecular formation of γ-lactones is in competition with the intermolecular oxidation of external alkanes and olefins. Finally, mechanistic studies, together with DFT calculations, support a mechanism involving a site-selective C-H cleavage in the γ-position of the carboxylate ligand by the oxo moiety, followed by a fast carboxylate rebound, eventually leading to the selective formation of γ-lactones., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Heteropolycyclic molecular systems, which are essential components in the fields of materials and pharmacology, frequently consist of 2D extended organic aromatic rings. Here, we introduce a type of inorganic-organic hybrid 3D conjugates by merging an aromatic boron cluster with a phosphine and a π-conjugated unit. To achieve this, a couple-close synthetic strategy via B-H activation of nido-carboranes with alkynes has been developed, which leads to diverse boron cluster-extended phosphoniums in a twisted structure with high yields under mild conditions. Experimental and theoretical results reveal that the fusion between the boron cluster and the formed borophosphonium heterocycle facilitates electron delocalization throughout the structure. The unusual framework demonstrates distinct properties from bare boron clusters and pure aromatic ring-extended counterparts, such as improved thermal/chemical stability and photophysical properties. Thus, the boron cluster-based 3D conjugates expand the library of aromatic-based heterocyclics, showcasing great potential in functional materials., (© 2024. The Author(s).)

Artificial enzymes are valuable biocatalysts able to perform new-to-nature transformations with the precision and (enantio-)selectivity of natural enzymes. Although they are highly engineered biocatalysts, they often cannot reach catalytic rates akin those of their natural counterparts, slowing down their application in real-world industrial processes. Typically, their designs only optimise the chemistry inside the active site, while overlooking the role of protein dynamics on catalysis. In this work, we show how the catalytic performance of an already engineered artificial enzyme can be further improved by distal mutations that affect the conformational equilibrium of the protein. To this end, we subjected a specialised artificial enzyme based on the lactococcal multidrug resistance regulator (LmrR) to an innovative algorithm that quickly inspects the whole protein sequence space for hotpots which affect the protein dynamics. From an initial predicted selection of 73 variants, two variants with mutations distant by more than 11 Å from the catalytic pAF residue showed increased catalytic activity towards the new-to-nature hydrazone formation reaction. Their recombination displayed a 66% higher turnover number and 14 °C higher thermostability. Microsecond time scale molecular dynamics simulations evidenced a shift in the distribution of productive enzyme conformations, which are the result of a cascade of interactions initiated by the introduced mutations.

Gold nanoparticles (AuNP) are known to aggregate on the surface of lipid vesicles, yet the molecular mechanism behind this phenomenom remains unclear. In this work, we have investigated the binding behaviour of AuNPs, synthesized with pulsed laser ablation, to phospholipid vesicles under varying conditions of ionic strength (KCl concentration) and NP to vesicle ratios. Our observations reveal a strong influence of electrolyte concentration on AuNP aggregation mediated by vesicles. Notably, cluster formation is observed even at less than one AuNP per vesicle ratio at low enough ionic strengths. These results evidence a binding mechanism governed by electrostatic attraction with a distinct cooperative behaviour at very low salt concentrations, resulting in a significant increase in nanoparticle clustering. This behaviour is quantitatively analysed through a model that incorporates the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory, considering the electrical double layer attraction between dissimilar, non-oppositely charged objects. This study not only provides insight into the fundamental understanding of nanoparticle-vesicle interactions but also suggests potential strategies for controlling nanoparticle assembly in biological and synthetic systems by tuning the ionic strength.

Importance: Ambient air pollution and antimicrobial resistance pose significant global public health challenges. It is not known whether ambient air pollution is associated with increased consumption of antimicrobials., Objective: To assess whether a short-term association exists between ambient air pollution levels and antimicrobial consumption among the general population seeking primary care consultations for acute respiratory symptoms., Design, Setting, and Participants: This 2-stage cross-sectional ecological time series analysis study using data on daily ambient air pollution and antimicrobial consumption was conducted in the 11 largest cities in Catalonia, Spain, from June 23, 2012, to December 31, 2019, among all inhabitants aged 12 years or older. Statistical analysis was performed from November 2022 to December 2023., Exposures: Daily ambient air pollution (particulate matter of 10 μg/m3 [PM10], particulate matter of 2.5 μg/m3 [PM2.5], and nitrogen dioxide [NO2])., Main Outcomes and Measures: The main outcome was antimicrobial consumption associated with primary care consultations for acute respiratory symptoms in the 30 days before and after the dispensing of the antimicrobial. Antimicrobial consumption was measured as defined daily doses (DDDs) per 1000 inhabitants per day., Results: Among 1 938 333 inhabitants (median age, 48 years [IQR, 34-65 years]; 55% female participants), there were 8 421 404 antimicrobial dispensations, with a median of 12.26 DDDs per 1000 inhabitants per day (IQR, 6.03-15.32 DDDs per 1000 inhabitants per day). The median adjusted morbidity score was 2.0 (IQR, 1.0-5.0). For the 1 924 814 antimicrobial dispensations associated with primary care consultations for acute respiratory symptoms, there was a significant correlation between increases of 10 μg/m3 in the concentration of the 3 pollutants studied and heightened antimicrobial consumption at day 0 (PM10: relative risk [RR], 1.01 [95% CI, 1.01-1.02]; PM2.5: RR, 1.03 [95% CI, 1.01-1.04]; NO2: RR, 1.04 [95% CI, 1.03-1.05]). A delayed association emerged between increases in PM2.5 concentration and antimicrobial consumption between day 7 (RR, 1.00 [95% CI, 1.00-1.01]) and day 10 (RR, 1.00 [95% CI, 1.00-1.01]) after exposure., Conclusions and Relevance: In this 2-stage cross-sectional study using ecological time series analysis, short-term exposure to air pollution was associated with increased antimicrobial use associated with primary care consultations for acute respiratory symptoms in the general population. This finding could contribute to informing policy decisions aimed at reducing air pollution and its associated risks, thereby promoting respiratory health and reducing antimicrobial use.

Competing Interests: Disclosures: Disclosures are available with the article online.

Objectives: Escherichia coli can cause infections in the urinary tract and in normally sterile body sites leading to invasive E. coli disease (IED), including bacteraemia and sepsis, with older populations at increased risk. We aimed to estimate the theoretical coverage rate by the ExPEC4V and 9V vaccine candidates. In addition, we aimed at better understanding the diversity of E. coli isolates, including their genetic and phenotypic antimicrobial resistance (AMR), sequence types (STs), O-serotypes and the bacterial population structure., Methods: Blood and urine culture E. coli isolates (n = 304) were collected from hospitalized patients ≥60 years (n = 238) with IED during a multicentric, observational study across three continents. All isolates were tested for antimicrobial susceptibility, O-serotyped, whole-genome sequenced and bioinformatically analysed., Results: A large diversity of STs and of O-serotypes were identified across all centres, with O25b-ST131, O6-ST73 and O1-ST95 being the most prevalent types. A total of 45.4% and 64.7% of all isolates were found to have an O-serotype covered by the ExPEC4V and ExPEC9V vaccine candidates, respectively. The overall frequency of MDR was 37.4% and ST131 was predominant among MDR isolates. Low in-patient genetic variability was observed in cases where multiple isolates were collected from the same patient., Conclusions: Our results highlight the predominance of MDR O25b-ST131 E. coli isolates across diverse geographic areas. These findings provide further baseline data on the theoretical coverage of novel vaccines targeting E. coli associated with IED in older adults and their associated AMR levels., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

There is an increase in the worldwide prevalence of congenital abdominal wall defects (CAWD), with gastroschisis (GS) and omphalocele (OC) being the most common. It is widely accepted that folic acid supplementation (FAS) in the maternal diet decreases the incidence of anomalies such as neural tube defects, but there is controversy regarding the possible beneficial role for other congenital malformations. Several epidemiological studies raise controversy regarding a possible relationship between vitamin supplementation with the occurrence of abdominal wall malformations. The aim of the present study is to obtain an updated review of the global frequency of CAWD in neonates and the relationship with FAS in the mothers. For this we have carried out a systematic search of epidemiological studies in different article databases between 2011 and 2022. The analysis of 25 studies conducted in different countries where cases of OC and/or GS are registered directly or together with other congenital defects shows that 60% inquire into the relationship of FAS with the incidence of CAWD. Half of them proposes a beneficial effect of FAS and the other half find no association, concluding that there is no unanimous evidence that FAS in the maternal diet decreases the incidence of CAWD. However, it seems that an influential factor to take into account is the nutritional habits of the mothers., (© 2024 The Author(s). Congenital Anomalies published by John Wiley & Sons Australia, Ltd on behalf of Japanese Teratology Society.)

To inform the clinical practice guidelines' recommendations developed by the European Academy of Allergy and Clinical Immunology systematic reviews (SR) assessed using GRADE on the impact of environmental tobacco smoke (ETS) and active smoking on the risk of new-onset asthma/recurrent wheezing (RW)/low lung function (LF), and on asthma-related outcomes. Only longitudinal studies were included, almost all on combustion cigarettes, only one assessing e-cigarettes and LF. According to the first SR (67 studies), prenatal ETS increases the risk of RW (moderate certainty evidence) and may increase the risk of new-onset asthma and of low LF (low certainty evidence). Postnatal ETS increases the risk of new-onset asthma and of RW (moderate certainty evidence) and may impact LF (low certainty evidence). Combined in utero and postnatal ETS may increase the risk of new-onset asthma (low certainty evidence) and increases the risk of RW (moderate certainty evidence). According to the second SR (24 studies), ETS increases the risk of severe asthma exacerbations and impairs asthma control and LF (moderate certainty evidence). According to the third SR (25 studies), active smoking increases the risk of severe asthma exacerbations and of suboptimal asthma control (moderate certainty evidence) and may impact asthma-related quality-of-life and LF (low certainty evidence)., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Extracorporeal photopheresis (ECP) is a therapy that combines the collection of mononuclear cells by apheresis, the addition of a photosensitizer (8-methoxisoralen), the illumination of the product with ultraviolet A light, and the immediate infusion of the product to the patient. Initially developed and approved to treat T-cell cutaneous lymphomas, soon started to be used to treat graft versus host disease (GvHD) developed after allogeneic hematopoietic-cell transplantation. The high response rate of ECP in skin, ocular, oral, pulmonary, and liver forms of chronic GvHD, the steroid-sparing effect, and the improved overall survival of treated patients, made ECP one of the second-line treatments used to treat steroid-resistant acute and chronic GVHD. Recently, the development of new drugs for treating GVHD has changed the position of ECP in the therapy of GVHD and has started to be used in combination with drugs for increasing the response rate to the treatment in severe or resistant forms of acute and chronic GVHD. ECP remains an essential therapeutic resource in the management of patients with refractory acute and chronic GVHD., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Voice outcome after carbon dioxide transoral laser microsurgery (CO 2 TOLMS) for glottic cancer is of prime importance. However, a comprehensive overview according to the European Laryngological Society (ELS) classification of cordectomies is still lacking. The aim of this systematic review is to summarize data on voice outcome associated with individual types of ELS glottic cordectomy after CO 2 TOLMS., Materials and Methods: A systematic review of the literature was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. The initial search identified 936 records of which 25 publications were then included. Voice outcome data (Voice Handicap Index [VHI] version 30, grade of dysphonia [G] and maximum phonation time [MPT]) were extracted per resection type. Weighted averages were calculated., Results: Data show a gradual increase in the VHI scores although they were still similar for all cordectomy types (range 14.2 to 21.5). The grade of dysphonia showed a gradual increase with increasing resection depth (range 1.0 to 1.9). There was a gradual decrease in the MPT (range 15.2 to 7.2)., Conclusion: Voice outcome is related to cordectomy type with mild dysphonia characterizing ELS type I, II and III cordectomies, while more extended cordectomies (ELS type IV, V and VI) result in moderate dysphonia and shortness of breath during phonation. The voice handicap experienced by patients is limited even in the more extended cordectomies., (Copyright © 2022. Published by Elsevier Inc.)