3D oxygen vacancy distribution and defect-property relations in an oxide heterostructure.

Oxide heterostructures exhibit a vast variety of unique physical properties. Examples are unconventional superconductivity in layered nickelates and topological polar order in (PbTiO3)n/(SrTiO3)n superlattices. Although it is clear that variations in oxygen content are crucial for the electronic correlation phenomena in oxides, it remains a major challenge to quantify their impact. Here, we measure the chemical composition in multiferroic (LuFeO3)9/(LuFe2O4)1 superlattices, mapping correlations between the distribution of oxygen vacancies and the electric and magnetic properties. Using atom probe tomography, we observe oxygen vacancies arranging in a layered three-dimensional structure with a local density on the order of 1014 cm-2, congruent with the formula-unit-thick ferrimagnetic LuFe2O4 layers. The vacancy order is promoted by the locally reduced formation energy and plays a key role in stabilizing the ferroelectric domains and ferrimagnetism in the LuFeO3 and LuFe2O4 layers, respectively. The results demonstrate pronounced interactions between oxygen vacancies and the multiferroic order in this system and establish an approach for quantifying the oxygen defects with atomic-scale precision in 3D, giving new opportunities for deterministic defect-enabled property control in oxide heterostructures.

Lipid-derived electrophiles inhibit the function of membrane channels during ferroptosis.

The therapeutic targeting of ferroptosis requires full understanding of the molecular mechanism of this regulated cell death pathway. While lipid-derived electrophiles (LDEs), including 4-hydroxy-2-nonenal (4-HNE), are important biomarkers of ferroptosis, a functional role for these highly reactive species in ferroptotic cell death execution has not been established. Here, through mechanistic characterization of LDE-detoxification impairment, we demonstrate that LDEs mediate altered protein function during ferroptosis. Applying live cell fluorescence imaging, we first identified that export of glutathione-LDE-adducts through multidrug resistance-associated protein (MRP) channels is inhibited following exposure to a panel of ferroptosis inducers (FINs) with different modes of action (type I-IV FINs erastin, RSL3, FIN56, and FINO2). This channel inhibition was recreated by both initiation of lipid peroxidation and treatment with 4-HNE. Importantly, treatment with radical-trapping antioxidants prevented impaired LDE-adduct export when working with both FINs and lipid peroxidation initiators but not 4-HNE, pinpointing LDEs as the cause of this inhibited MRP activity observed during ferroptosis. Our findings, when combined with reports of widespread LDE alkylation of key proteins following ferroptosis induction, including MRP1, set a precedent for LDEs as critical mediators of ferroptotic cell damage. Lipid hydroperoxide breakdown to form truncated phospholipids and LDEs may fully explain membrane permeabilization and modified protein function downstream of lipid peroxidation, offering a unified explanation of the molecular cell death mechanism of ferroptosis.

Clinical Validation of a Capillary Blood Home-Based Self-Sampling Technique for Monitoring of Infliximab, Vedolizumab, and C-Reactive Protein Concentrations in Patients With Inflammatory Bowel Disease.

BACKGROUND: Therapeutic drug monitoring provides important guidance for treatment of patients with inflammatory bowel disease (IBD) and could help to early identify treatment failure. This study aimed to validate a finger prick-based capillary blood sampling technique to measure biological trough levels and C-reactive protein (CRP) and evaluate patient performance and -support. METHODS: In this prospective cohort study, patients with IBD receiving infliximab (IFX) or vedolizumab (VEDO) therapy performed finger prick-based capillary blood sampling at home. Additionally, blood was collected through routinely performed in-hospital venepuncture prior to biological infusion. IFX, VEDO, and CRP concentrations were measured by enzyme-linked immunosorbent assay. The concordance between methods was statistically evaluated and a survey was conducted to assess practicality and patient support. RESULTS: In total, 81 patients (46 IFX, 35 VEDO) were enrolled. Mean differences between both methods were 0.42 (95% confidence interval, -1.74 to 2.58) µg/mL for IFX and 0.72 (95% confidence interval, -5.50 to 6.94) µg/mL for VEDO. Passing-Bablok regressions demonstrated no evidence for systematic or proportional biases. Venous and capillary IFX (ρ = 0.96, P < .001) and VEDO (ρ = 0.97, P < .001) levels strongly correlated and showed high intermethod agreement (Cohen's kappa: IFX = 0.82; VEDO = 0.94). Similarly, venous and capillary CRP levels were strongly correlated (ρ = 0.99, P < .001). Most patients (>95%) were able to successfully perform the self-sampling at home without prior instructions. CONCLUSIONS: This study clinically validated a finger prick-based capillary blood self-sampling technique allowing concomitant home monitoring of biological levels and CRP for patients with IBD, who reported substantial support, tolerability, and practicality.

Central-line-associated bloodstream infection burden among Dutch neonatal intensive care units.

BACKGROUND: The establishment of an epidemiological overview provides valuable insights needed for the (future) dissemination of infection-prevention initiatives. AIM: To describe the nationwide epidemiology of central-line-associated bloodstream infections (CLABSI) among Dutch Neonatal Intensive Care Units (NICUs). METHODS: Data from 2935 neonates born at <32 weeks' gestation and/or with a birth weight <1500 g admitted to all nine Dutch NICUs over a two-year surveillance period (2019-2020) were analysed. Variations in baseline characteristics, CLABSI incidence per 1000 central-line days, pathogen distribution and CLABSI care bundles were evaluated. Multi-variable logistic mixed-modelling was used to identify significant predictors for CLABSI. RESULTS: A total of 1699 (58%) neonates received a central line, in which 160 CLABSI episodes were recorded. Coagulase-negative staphylococci were the most common infecting organisms of all CLABSI episodes (N=100, 63%). An almost six-fold difference in the CLABSI incidence between participating units was found (2.91-16.14 per 1000 line-days). Logistic mixed-modelling revealed longer central line dwell-time (adjusted odds ratio (aOR):1.08, P<0.001), umbilical lines (aOR:1.85, P=0.03) and single rooms (aOR:3.63, P=0.02) to be significant predictors of CLABSI. Variations in bundle elements included intravenous tubing care and antibiotic prophylaxis. CONCLUSIONS: CLABSI remains a common problem in preterm infants in The Netherlands, with substantial variation in incidence between centres. Being the largest collection of data on the burden of neonatal CLABSI in The Netherlands, this epidemiological overview provides a solid foundation for the development of a collaborative platform for continuous surveillance, ideally leading to refinement of national evidence-based guidelines. Future efforts should focus on ensuring availability and extraction of routine patient data in aggregated formats.

Quantitative Mapping of Chemical Defects at Charged Grain Boundaries in a Ferroelectric Oxide.

Polar discontinuities, as well as compositional and structural changes at oxide interfaces can give rise to a large variety of electronic and ionic phenomena. In contrast to earlier work focused on domain walls and epitaxial systems, this work investigates the relation between polar discontinuities and the local chemistry at grain boundaries in polycrystalline ferroelectric ErMnO3 . Using orientation mapping and scanning probe microscopy (SPM) techniques, the polycrystalline material is demonstrated to develop charged grain boundaries with enhanced electronic conductance. By performing atom probe tomography (APT) measurements, an enrichment of erbium and a depletion of oxygen at all grain boundaries are found. The observed compositional changes translate into a charge that exceeds possible polarization-driven effects, demonstrating that structural phenomena rather than electrostatics determine the local chemical composition and related changes in the electronic transport behavior. The study shows that the charged grain boundaries behave distinctly different from charged domain walls, giving additional opportunities for property engineering at polar oxide interfaces.

Capsules with Ileocolonic-Targeted Release of Vitamin B2, B3, and C (ColoVit) Intended for Optimization of Gut Health: Development and Validation of the Production Process.

The ileocolonic-targeted delivery of vitamins can establish beneficial alterations in gut microbial composition. Here, we describe the development of capsules containing riboflavin, nicotinic acid, and ascorbic acid covered with a pH-sensitive coating (ColoVit) to establish site-specific release in the ileocolon. Ingredient properties (particle size distribution, morphology) relevant for formulation and product quality were determined. Capsule content and the in vitro release behaviour were determined using a HPLC-method. Uncoated and coated validation batches were produced. Release characteristics were evaluated using a gastro-intestinal simulation system. All capsules met the required specifications. The contents of the ingredients were in the 90.0-120.0% range, and uniformity requirements were met. In the dissolution test a lag-time in drug release of 277-283 min was found, which meets requirements for ileocolonic release. The release itself is immediate as shown by dissolution of the vitamins of more than 75% in 1 h. The production process of the ColoVit formulation was validated and reproducible, it was shown that the vitamin blend was stable during the production process and in the finished coated product. The ColoVit is intended as an innovative treatment approach for beneficial microbiome modulation and optimization of gut health.

Focused ion beam lithography for position-controlled nanowire growth.

To exploit the promising properties of semiconductor nanowires and ensure the uniformity required to achieve device integration, their position on the growth substrate must be controlled. This work demonstrates the direct patterning of a SiO2/Si substrate using focused ion beam (FIB) patterning to control self-catalyzed GaAsSb nanowire growth in molecular beam epitaxy (MBE). Besides position control, FIB patterning parameters influence nanowire yield, composition and structure. Total ion dose per hole is found to be the most important parameter. Yield of single nanowires ranges from ≈34% to ≈83%, with larger holes dominated by multiple nanowires per hole. Areas exposed to low ion beam doses are selectively etched by routine pre-MBE HF cleaning, enabling patterning and nanowire nucleation with minimal damage to the Si substrate. The optical and electronic properties of nanowires are found to depend on the ion dose used during patterning, indicating the potential for FIB patterning to tune nanowire properties. These findings demonstrate the possibility for a FIB lithography protocol which could provide a rapid and direct patterning process for flexible controlled nanowire growth.

Temporary diverting stoma in therapy-refractory luminal colonic Crohn's disease: an alternative to immediate colorectal resection?

AIM: Creation of a diverting stoma in patients with Crohn's disease (CD) can counteract luminal inflammation. The clinical utility of a diverting stoma with the prospect of restoration of gastrointestinal continuity warrants further investigation. The aim of this work was to evaluate the long-term effects of creation of a diverting stoma on the disease course in patients with luminal colonic CD. METHOD: In this retrospective, multicentre cohort study we investigated the disease course of patients who received a diverting stoma in the biological era. Clinical characteristics, medication use and surgical course were assessed at the time of creation of the diverting stoma and during follow-up. The primary outcome was the rate of successful and lasting reestablishment of gastrointestinal continuity. RESULTS: Thirty six patients with refractory luminal CD from four institutions underwent creation of a diverting stoma. Of the overall cohort, 20 (56%) patients had their gastrointestinal continuity reestablished after initial stoma creation and 14 (39%) who had their stoma reversed remained stoma-free during a median of 3.3 years follow-up (interquartile range 2.1-6.1 years). Absence of stoma reversal was associated with the presence of proctitis (p = 0.02). Colorectal resection after creation of a diverting stoma was performed in 28 (78%) patients, with 7 (19%) having a less extensive resection and 6 (17%) having a more extensive resection compared with the surgical plan before stoma creation. CONCLUSION: A diverting stoma could potentially be an alternative to immediate definitive stoma placement in specific populations consisting of patients with luminal colonic CD, especially in the absence of proctitis.

Creation and preclinical evaluation of genetically attenuated malaria parasites arresting growth late in the liver.

Whole-sporozoite (WSp) malaria vaccines induce protective immune responses in animal malaria models and in humans. A recent clinical trial with a WSp vaccine comprising genetically attenuated parasites (GAP) which arrest growth early in the liver (PfSPZ-GA1), showed that GAPs can be safely administered to humans and immunogenicity is comparable to radiation-attenuated PfSPZ Vaccine. GAPs that arrest late in the liver stage (LA-GAP) have potential for increased potency as shown in rodent malaria models. Here we describe the generation of four putative P. falciparum LA-GAPs, generated by CRISPR/Cas9-mediated gene deletion. One out of four gene-deletion mutants produced sporozoites in sufficient numbers for further preclinical evaluation. This mutant, PfΔmei2, lacking the mei2-like RNA gene, showed late liver growth arrest in human liver-chimeric mice with human erythrocytes, absence of unwanted genetic alterations and sensitivity to antimalarial drugs. These features of PfΔmei2 make it a promising vaccine candidate, supporting further clinical evaluation. PfΔmei2 (GA2) has passed regulatory approval for safety and efficacy testing in humans based on the findings reported in this study.

Live-cell imaging reveals impaired detoxification of lipid-derived electrophiles is a hallmark of ferroptosis.

The central mechanism in ferroptosis linking lipid hydroperoxide accumulation with cell death remains poorly understood. Although lipid hydroperoxides are known to break down to reactive lipid-derived electrophiles (LDEs), the ability of cells to detoxify increasing LDE levels during ferroptosis has not been studied. Here, we developed an assay (ElectrophileQ) correlating the cellular retention vs. excretion of a fluorogenic lipophilic electrophile (AcroB) that enables live-cell assessment of the glutathione-mediated LDE conjugation and adduct export steps of the LDE detoxification pathway. This method revealed that during ferroptosis, LDE detoxification failure occurs through decreased conjugation or export impairment, amplifying cellular electrophile accumulation. Notably, ferroptosis susceptibility was increased following exacerbation of LDE-adduct export impairment through export channel inhibition. Our results expand understanding of the ferroptosis molecular cell death mechanism to position the LDE detoxification pathway as a ferroptosis-relevant therapeutic target. We envision the ElectrophileQ assay becoming an invaluable tool for studying ferroptosis and cellular health.

The effect of riboflavin supplementation on the systemic redox status in healthy volunteers: A post-hoc analysis of the RIBOGUT trial.

BACKGROUND: Riboflavin is a redox-active vitamin that plays a pivotal role in human energy metabolism. Riboflavin may have beneficial health effects by increasing extracellular antioxidant capacity, thereby alleviating oxidative stress. Reduced levels of free thiols in blood reflect systemic oxidative stress, since they are readily oxidized by reactive species. In this study, we aimed to study the potential of riboflavin supplementation to improve the systemic redox status in healthy volunteers. METHODS: This study was a post-hoc analysis of the RIBOGUT study, a randomized, double-blind, placebo-controlled human intervention trial that investigated the effect of riboflavin supplements on the gut microbiota composition of healthy individuals. Serum free thiols were quantified before and after intervention and adjusted to serum albumin levels. Changes in albumin-adjusted free thiols were analyzed, as well as potential associations with routine laboratory parameters and faecal bacterial quantification by fluorescence in-situ hybridization (FISH). RESULTS: Participants were randomized to either placebo (n = 34), riboflavin 50 mg daily (n = 32), or riboflavin 100 mg daily (n = 33). At baseline, no significant differences in albumin-adjusted serum free thiols were observed. After intervention with either placebo or riboflavin, albumin-adjusted serum free thiols did not significantly change (P > 0.05), however, observed changes were inversely associated with changes in C-reactive protein (CRP) levels (r = -0.22, P < 0.05). At baseline, albumin-adjusted serum free thiols were positively associated with faecal relative abundances of Faecalibacterium prausnitzii (P < 0.01). CONCLUSION: Riboflavin did not change the systemic redox status in healthy individuals as reflected by serum free thiols, but observed changes in albumin-adjusted free thiol levels were negatively associated with changes in CRP levels. Strikingly, albumin-adjusted free thiols were independently associated with relative abundances of faecal F. prausnitzii, which may suggest a potential host redox-microbiota interaction.