Self-Maintaining Gut Macrophages Are Essential for Intestinal Homeostasis.

Macrophages are highly heterogeneous tissue-resident immune cells that perform a variety of tissue-supportive functions. The current paradigm dictates that intestinal macrophages are continuously replaced by incoming monocytes that acquire a pro-inflammatory or tissue-protective signature. Here, we identify a self-maintaining population of macrophages that arise from both embryonic precursors and adult bone marrow-derived monocytes and persists throughout adulthood. Gene expression and imaging studies of self-maintaining macrophages revealed distinct transcriptional profiles that reflect their unique localization (i.e., closely positioned to blood vessels, submucosal and myenteric plexus, Paneth cells, and Peyer's patches). Depletion of self-maintaining macrophages resulted in morphological abnormalities in the submucosal vasculature and loss of enteric neurons, leading to vascular leakage, impaired secretion, and reduced intestinal motility. These results provide critical insights in intestinal macrophage heterogeneity and demonstrate the strategic role of self-maintaining macrophages in gut homeostasis and intestinal physiology.

Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition.

The safety and immunogenicity of a bivalent conjugate vaccine against Salmonella enterica Typhi and Paratyphi A in healthy Indian adults: a phase 1, randomised, active-controlled, double-blind trial.

BACKGROUND: Enteric fever caused by Salmonella enterica Typhi and Salmonella Paratyphi A is an important public health problem, especially in low-income and middle-income countries with limited access to safe water and sanitation. We present results from, to our knowledge, the first ever human study of a bivalent paratyphoid A-typhoid conjugate vaccine (Sii-PTCV). METHODS: In this double-blind phase 1 study, 60 healthy Indian adults were randomly assigned (1:1) to receive a single intramuscular dose of either Sii-PTCV or typhoid conjugate vaccine (Typbar-TCV). Safety was assessed by observing solicited adverse events for 1 week, unsolicited events for 1 month, and serious adverse events (SAEs) over 6 months. Immunogenicity at 1 month and 6 months was assessed by measuring anti-capsular polysaccharide antigen Vi (anti-Vi) IgG and IgA against Salmonella Typhi and anti-lipopolysaccharide (LPS) IgG against Salmonella Paratyphi A by ELISA, and functional antibodies using serum bactericidal assay (SBA) against Salmonella Paratyphi A. This study is registered with Clinical Trial Registry-India (CTRI/2022/06/043608) and is completed. FINDINGS: 60 participants were enrolled. Of these 60 participants, 57 (95%) participants were male and three (5%) participants were female. Solicited adverse events were observed in 27 (90%) of 30 participants who received Sii-PTCV and 26 (87%) of 30 participants who received Typbar-TCV. The most common local solicited event was pain in 27 (90%) participants who received Sii-PTCV and in 23 (77%) participants who received Typbar-TCV. The most common solicited systemic event was myalgia in five (17%) participants who received Sii-PTCV, whereas four (13%) participants who received Typbar-TCV had myalgia and four (13%) had headache. No vaccine-related unsolicited adverse events or SAEs were reported. The seroconversion rates on day 29 were 96·7% (95% CI 82·8-99·9) with Sii-PTCV and 100·0% (88·4-100·0) with Typbar-TCV for anti-Vi IgG; 93·3% (77·9-99·2) with Sii-PTCV and 100·0% (88·4-100·0) with Typbar-TCV for anti-Vi IgA; 100·0% (88·4-100·0) with Sii-PTCV and 3·3% (0·1-17·2) with Typbar-TCV for anti-LPS (paratyphoid); and 93·3% (77·9-99·2) with Sii-PTCV and 0% (0·0-11·6) with Typbar-TCV for SBA titres (paratyphoid). Paratyphoid anti-LPS immune responses were sustained at day 181. INTERPRETATION: Sii-PTCV was safe and immunogenic for both typhoid and paratyphoid antigens indicating its potential for providing comprehensive protection against enteric fever. FUNDING: Serum Institute of India.

A timeline study on vascular co-morbidity induced cerebral endothelial dysfunction assessed by perfusion MRI.

Endothelial dysfunction is considered a key element in the early pathogenesis of neurodegenerative disorders. Dysfunction of the cerebral endothelial cells can result in dysregulation of cerebral perfusion and disruption of the Blood Brain Barrier (BBB), leading to brain damage, neurodegeneration and cognitive decline. It has been shown that the presence of modifiable risk factors exacerbates endothelial dysfunction. This study primarily aimed to identify which among various perfusion MRI methodologies could be effectively utilized to non-invasively identify early pathological alterations as a result of endothelial dysfunction. We compared these perfusion MRI measurements to invasive immunohistochemistry to detect early pathological alterations in the cerebral vasculature of a rat model of multiple cardiovascular co-morbidities (the ZSF1 Obese rat) at several stages of the cerebrovascular pathology. We observed cerebral hyperperfusion, expressed by increased Cerebral Blood Flow (CBF) and increased BBB permeability in the ZSF1 Obese rats, at an early stage of disease development. The increase in CBF observed with Arterial Spin Labeling (ASL) was lost during later stages of disease progression. These findings are in line with recent clinical findings in early stages of Alzheimer's disease (AD), that also show early increases in CBF.

Triple challenges - Small sample size in both exposure and control groups to scan rare maternal outcomes in a signal identification approach: A simulation study.

There is a dearth of safety data on maternal outcomes after perinatal medication exposure. Data-mining for unexpected adverse event occurrence in existing datasets is a potentially useful approach. One method, the Poisson tree-based scan statistic (TBSS), assumes that the expected outcome counts, based on incidence of outcomes in the control group, are estimated without error. This assumption may be difficult to satisfy with a small control group. Our simulation study evaluated the effect of imprecise incidence proportions from the control group on TBSS' ability to identify maternal outcomes in pregnancy research. We simulated base case analyses with "true" expected incidence proportions and compared these to imprecise incidence proportions derived from sparse control samples. We varied parameters impacting Type I error and statistical power (exposure group size, outcome's incidence proportion, and effect size). We found that imprecise incidence proportions generated by a small control group resulted in inaccurate alerting, inflation of Type I error, and removal of very rare outcomes for TBSS analysis due to "zero" background counts. Ideally, the control size should be at least several times larger than the exposure size to limit the number of false positive alerts and retain statistical power for true alerts.

Intravoxel incoherent motion as a surrogate marker of perfused vascular density in rat brain.

Intravoxel incoherent motion (IVIM) MRI has emerged as a valuable technique for the assessment of tissue characteristics and perfusion. However, there is limited knowledge about the relationship between IVIM-derived measures and changes at the level of the vascular network. In this study, we investigated the potential use of IVIM MRI as a noninvasive tool for measuring changes in cerebral vascular density. Variations in quantitative immunohistochemical measurements of the vascular density across different regions in the rat brain (cortex, corpus callosum, hippocampus, thalamus, and hypothalamus) were related to the pseudo-diffusion coefficient D* and the flowing blood fraction f in healthy Wistar rats. We assessed whether region-wise differences in the vascular density are reflected by variations in the IVIM measurements and found a significant positive relationship with the pseudo-diffusion coefficient (p < 0.05, ß = 0.24). The effect of cerebrovascular alterations, such as blood-brain barrier (BBB) disruption on the perfusion-related IVIM parameters, is not well understood. Therefore, we investigated the effect of BBB disruption on the IVIM measures in a rat model of metabolic and vascular comorbidities (ZSF1 obese rat) and assessed whether this affects the relationship between the cerebral vascular density and the noninvasive IVIM measurements. We observed increased vascular permeability without detecting any differences in diffusivity, suggesting that BBB leakage is present before changes in the tissue integrity. We observed no significant difference in the relationship between cerebral vascular density and the IVIM measurements in our model of comorbidities compared with healthy normotensive rats.

Non-Invasive Tumor Grade Evaluation in Von Hippel-Lindau-Associated Clear Cell Renal Cell Carcinoma: A Magnetic Resonance Imaging-Based Study.

BACKGROUND: Pathology grading is an essential step for the treatment and evaluation of the prognosis in patients with clear cell renal cell carcinoma (ccRCC). PURPOSE: To investigate the utility of texture analysis in evaluating Fuhrman grades of renal tumors in patients with Von Hippel-Lindau (VHL)-associated ccRCC, aiming to improve non-invasive diagnosis and personalized treatment. STUDY TYPE: Retrospective analysis of a prospectively maintained cohort. POPULATION: One hundred and thirty-six patients, 84 (61%) males and 52 (39%) females with pathology-proven ccRCC with a mean age of 52.8 ± 12.7 from 2010 to 2023. FIELD STRENGTH AND SEQUENCES: 1.5 and 3 T MRIs. Segmentations were performed on the T1-weighted 3-minute delayed sequence and then registered on pre-contrast, T1-weighted arterial and venous sequences. ASSESSMENT: A total of 404 lesions, 345 low-grade tumors, and 59 high-grade tumors were segmented using ITK-SNAP on a T1-weighted 3-minute delayed sequence of MRI. Radiomics features were extracted from pre-contrast, T1-weighted arterial, venous, and delayed post-contrast sequences. Preprocessing techniques were employed to address class imbalances. Features were then rescaled to normalize the numeric values. We developed a stacked model combining random forest and XGBoost to assess tumor grades using radiomics signatures. STATISTICAL TESTS: The model's performance was evaluated using positive predictive value (PPV), sensitivity, F1 score, area under the curve of receiver operating characteristic curve, and Matthews correlation coefficient. Using Monte Carlo technique, the average performance of 100 benchmarks of 85% train and 15% test was reported. RESULTS: The best model displayed an accuracy of 0.79. For low-grade tumor detection, a sensitivity of 0.79, a PPV of 0.95, and an F1 score of 0.86 were obtained. For high-grade tumor detection, a sensitivity of 0.78, PPV of 0.39, and F1 score of 0.52 were reported. DATA CONCLUSION: Radiomics analysis shows promise in classifying pathology grades non-invasively for patients with VHL-associated ccRCC, potentially leading to better diagnosis and personalized treatment. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

Vasa previa in singleton pregnancies: diagnosis and clinical management based on an international expert consensus.

BACKGROUND: There are limited data to guide the diagnosis and management of vasa previa. Currently, what is known is largely based on case reports or series and cohort studies. OBJECTIVE: This study aimed to systematically collect and classify expert opinions and achieve consensus on the diagnosis and clinical management of vasa previa using focus group discussions and a Delphi technique. STUDY DESIGN: A 4-round focus group discussion and a 3-round Delphi survey of an international panel of experts on vasa previa were conducted. Experts were selected on the basis of their publication record on vasa previa. First, we convened a focus group discussion panel of 20 experts and agreed on which issues were unresolved in the diagnosis and management of vasa previa. A 3-round anonymous electronic survey was then sent to the full expert panel. Survey questions were presented on the diagnosis and management of vasa previa, which the experts were asked to rate on a 5-point Likert scale (from "strongly disagree"=1 to "strongly agree"=5). Consensus was defined as a median score of 5. Following responses to each round, any statements that had median scores of ≤3 were deemed to have had no consensus and were excluded. Statements with a median score of 4 were revised and re-presented to the experts in the next round. Consensus and nonconsensus statements were then aggregated. RESULTS: A total of 68 international experts were invited to participate in the study, of which 57 participated. Experts were from 13 countries on 5 continents and have contributed to >80% of published cohort studies on vasa previa, as well as national and international society guidelines. Completion rates were 84%, 93%, and 91% for the first, second, and third rounds, respectively, and 71% completed all 3 rounds. The panel reached a consensus on 26 statements regarding the diagnosis and key points of management of vasa previa, including the following: (1) although there is no agreement on the distance between the fetal vessels and the cervical internal os to define vasa previa, the definition should not be limited to a 2-cm distance; (2) all pregnancies should be screened for vasa previa with routine examination for placental cord insertion and a color Doppler sweep of the region over the cervix at the second-trimester anatomy scan; (3) when a low-lying placenta or placenta previa is found in the second trimester, a transvaginal ultrasound with Doppler should be performed at approximately 32 weeks to rule out vasa previa; (4) outpatient management of asymptomatic patients without risk factors for preterm birth is reasonable; (5) asymptomatic patients with vasa previa should be delivered by scheduled cesarean delivery between 35 and 37 weeks of gestation; and (6) there was no agreement on routine hospitalization, avoidance of intercourse, or use of 3-dimensional ultrasound for diagnosis of vasa previa. CONCLUSION: Through focus group discussion and a Delphi process, an international expert panel reached consensus on the definition, screening, clinical management, and timing of delivery in vasa previa, which could inform the development of new clinical guidelines.

Technology Characterization Through Diverse Evaluation Methodologies: Application to Thoracic Imaging in Photon-Counting Computed Tomography.

OBJECTIVE: Different methods can be used to condition imaging systems for clinical use. The purpose of this study was to assess how these methods complement one another in evaluating a system for clinical integration of an emerging technology, photon-counting computed tomography (PCCT), for thoracic imaging. METHODS: Four methods were used to assess a clinical PCCT system (NAEOTOM Alpha; Siemens Healthineers, Forchheim, Germany) across 3 reconstruction kernels (Br40f, Br48f, and Br56f). First, a phantom evaluation was performed using a computed tomography quality control phantom to characterize noise magnitude, spatial resolution, and detectability. Second, clinical images acquired using conventional and PCCT systems were used for a multi-institutional reader study where readers from 2 institutions were asked to rank their preference of images. Third, the clinical images were assessed in terms of in vivo image quality characterization of global noise index and detectability. Fourth, a virtual imaging trial was conducted using a validated simulation platform (DukeSim) that models PCCT and a virtual patient model (XCAT) with embedded lung lesions imaged under differing conditions of respiratory phase and positional displacement. Using known ground truth of the patient model, images were evaluated for quantitative biomarkers of lung intensity histograms and lesion morphology metrics. RESULTS: For the physical phantom study, the Br56f kernel was shown to have the highest resolution despite having the highest noise and lowest detectability. Readers across both institutions preferred the Br56f kernel (71% first rank) with a high interclass correlation (0.990). In vivo assessments found superior detectability for PCCT compared with conventional computed tomography but higher noise and reduced detectability with increased kernel sharpness. For the virtual imaging trial, Br40f was shown to have the best performance for histogram measures, whereas Br56f was shown to have the most precise and accurate morphology metrics. CONCLUSION: The 4 evaluation methods each have their strengths and limitations and bring complementary insight to the evaluation of PCCT. Although no method offers a complete answer, concordant findings between methods offer affirmatory confidence in a decision, whereas discordant ones offer insight for added perspective. Aggregating our findings, we concluded the Br56f kernel best for high-resolution tasks and Br40f for contrast-dependent tasks.

Incorporation of vasa previa screening into a routine anomaly scan: A single center cohort study.

INTRODUCTION: Vasa previa (VP), defined as unprotected fetal vessels traversing the membranes over the cervix, is associated with a high perinatal mortality when undiagnosed prenatally. Conversely, prenatal diagnosis with ultrasound and cesarean delivery before the membranes rupture is associated with excellent outcomes. However, controversy exists regarding screening for VP. In the UK, routine screening for VP is not recommended. The objective of this study was to report the incidence of VP and our experience in the detection of VP with a universal screening protocol at the time of the second-trimester fetal anomaly scan with third-trimester confirmation in an unselected population of pregnancies. MATERIAL AND METHODS: We performed a single-center historical cohort study of all pregnant women who underwent routine second-trimester anomaly screening scans at West Middlesex University Hospital, London, UK, between 2012 and 2016. Over 5 years, every patient undergoing routine anomaly screening was evaluated for VP using a systematic protocol during their 20-week anomaly scan. Suspected cases of VP were rescanned in the third trimester by specialist sonographers with an interest in VP. The primary outcomes were the incidence and detection of VP. RESULTS: During the study period, 24 690 anatomy scans were performed. A total of 64 patients were identified as having potential VP at the second-trimester anomaly screening scan, of which 19 were confirmed by the specialist sonographer in the third trimester and at delivery. The screen positive rate was 0.26% (95% confidence interval [CI] 0.20%-0.32%). VP at birth was found in 19/24690 births (1:1299 [95% CI: 1:832-1:2030] births). Universal screening for VP using our protocol had a sensitivity of 100% and a specificity of 99.78% (95% CI: 99.72%-99.84%). The false-positive rate of the second-trimester screen was 0.18% (95% CI: 0.13-0.24). There were no false positives or false negatives at delivery. Of the 19 patients with confirmed VP, 17 had scheduled cesarean deliveries, and two required emergency deliveries due to antepartum hemorrhage. One baby died, giving a perinatal mortality of 5%. CONCLUSIONS: VP complicates approximately 1:1300 pregnancies. Routine screening for VP yielded a 100% detection rate. We suggest the inclusion of structured VP assessment in standard fetal anomaly screening programs.

Guided recall of positive autobiographical memories increases anticipated pleasure and psychological resources, and reduces depressive symptoms: a replication and extension of a randomised controlled trial of brief positive cognitive-reminiscence therapy.

Reminiscence-based interventions focus on recalling autobiographical memories and reflective reasoning to develop a healthy and adaptive view of oneself and one's life. This study aimed to replicate the effects of a three-session, group-based, positive-memory version of cognitive-reminiscence therapy (CRT) on psychological resources and mental well-being and extend the findings to anticipated pleasure. The participants (N = 75, Mage = 43.7 (SD = 16.7), 60% females) were randomised to CRT or control group. Anticipated pleasure, psychological resources (schemas of positive self-esteem, self-efficacy, meaning in life, optimism), mental well-being (depression, anxiety, and stress symptoms) and theorised change processes (automatic negative thoughts, awareness of narrative identity) were assessed. Relative to the control group, the CRT group reported significantly higher anticipated pleasure (d = 0.76-0.93) and psychological resources of self-esteem, self-efficacy, and optimism (d's = 0.58-0.99) at post-CRT and follow-up, and lower depressive symptoms post-CRT and at follow-up (d = 0.56-0.67). Findings on meaning in life and negative automatic thinking were partially replicated. This study replicates findings of the effectiveness of this intervention for improving psychological resources such as self-worth, confidence and optimism and depressive symptoms, and indicates additional effects on anticipated pleasure. CRT may serve as a standalone intervention, or as an adjunct "memory booster" for interventions focused on future thinking and related anticipated reward.

The application of communication accommodation theory to understand receiver reactions in healthcare speaking up interactions.

Speaking up for patient safety is a well-documented, complex communication interaction, which is challenging both to teach and to implement into practice. In this study we used Communication Accommodation Theory to explore receivers' perceptions and their self-reported behaviors during an actual speaking up interaction in a health context. Intergroup dynamics were evident across interactions. Where seniority of the participants was salient, the within-profession interactions had more influence on the receiver's initial reactions and overall evaluation of the message, compared to the between profession interactions. Most of the seniority salient interactions occurred down the hierarchy, where a more senior professional ingroup member delivered the speaking up message to a more junior receiver. These senior speaker interactions elicited fear and impeded the receiver's voice. We found that nurses/midwives and allied health clinicians reported using different communication behaviors in speaking up interactions. We propose that the term "speaking up" be changed, to emphasize receivers' reactions when they are spoken up to, to help receivers engage in more mutually beneficial communication strategies.

Interactions between Brainstem Neurons That Regulate the Motility to the Stomach.

Activity in the dorsal vagal complex (DVC) is essential to gastric motility regulation. We and others have previously shown that this activity is greatly influenced by local GABAergic signaling, primarily because of somatostatin (SST)-expressing GABAergic neurons. To further understand the network dynamics associated with gastric motility control in the DVC, we focused on another neuron prominently distributed in this complex, neuropeptide-Y (NPY) neurons. However, the effect of these neurons on gastric motility remains unknown. Here, we investigate the anatomic and functional characteristics of the NPY neurons in the nucleus tractus solitarius (NTS) and their interactions with SST neurons using transgenic mice of both sexes. We sought to determine whether NPY neurons influence the activity of gastric-projecting neurons, synaptically interact with SST neurons, and affect end-organ function. Our results using combined neuroanatomy and optogenetic in vitro and in vivo show that NPY neurons are part of the gastric vagal circuit as they are trans-synaptically labeled by a viral tracer from the gastric antrum, are primarily excitatory as optogenetic activation of these neurons evoke EPSCs in gastric-antrum-projecting neurons, are functionally coupled to each other and reciprocally connected to SST neurons, whose stimulation has a potent inhibitory effect on the action potential firing of the NPY neurons, and affect gastric tone and motility as reflected by their robust optogenetic response in vivo. These findings indicate that interacting NPY and SST neurons are integral to the network that controls vagal transmission to the stomach.SIGNIFICANCE STATEMENT The brainstem neurons in the dorsal nuclear complex are essential for regulating vagus nerve activity that affects the stomach via tone and motility. Two distinct nonoverlapping populations of predominantly excitatory NPY neurons and predominantly inhibitory SST neurons form reciprocal connections with each other in the NTS and with premotor neurons in the dorsal motor nucleus of the vagus to control gastric mechanics. Light activation and inhibition of NTS NPY neurons increased and decreased gastric motility, respectively, whereas both activation and inhibition of NTS SST neurons enhanced gastric motility.

Early transcriptional responses to human enteric fever challenge.

Enteric fever, caused by oral infection with typhoidal Salmonella serovars, presents as a non-specific febrile illness preceded by an incubation period of 5 days or more. The enteric fever human challenge model provides a unique opportunity to investigate the innate immune response during this incubation period, and how this response is altered by vaccination with the Vi polysaccharide or conjugate vaccine. We find that on the same day as ingestion of typhoidal Salmonella, there is already evidence of an immune response, with 199 genes upregulated in the peripheral blood transcriptome 12 hours post-challenge (false discovery rate <0.05). Gene sets relating to neutrophils, monocytes, and innate immunity were over-represented (false discovery rate <0.05). Estimating cell proportions from gene expression data suggested a possible increase in activated monocytes 12 hours post-challenge (P = 0.036, paired Wilcoxon signed-rank test). Furthermore, plasma TNF-α rose following exposure (P = 0.011, paired Wilcoxon signed-rank test). There were no significant differences in gene expression (false discovery rate <0.05) in the 12 hours response between those who did and did not subsequently develop clinical or blood culture confirmed enteric fever or between vaccination groups. Together, these results demonstrate early perturbation of the peripheral blood transcriptome after enteric fever challenge and provide initial insight into early mechanisms of protection.

Revealing the Role of CO during CO2 Hydrogenation on Cu Surfaces with In Situ Soft X-Ray Spectroscopy.

The reactions of H2, CO2, and CO gas mixtures on the surface of Cu at 200 °C, relevant for industrial methanol synthesis, are investigated using a combination of ambient pressure X-ray photoelectron spectroscopy (AP-XPS) and atmospheric-pressure near edge X-ray absorption fine structure (AtmP-NEXAFS) spectroscopy bridging pressures from 0.1 mbar to 1 bar. We find that the order of gas dosing can critically affect the catalyst chemical state, with the Cu catalyst maintained in a metallic state when H2 is introduced prior to the addition of CO2. Only on increasing the CO2 partial pressure is CuO formation observed that coexists with metallic Cu. When only CO2 is present, the surface oxidizes to Cu2O and CuO, and the subsequent addition of H2 partially reduces the surface to Cu2O without recovering metallic Cu, consistent with a high kinetic barrier to H2 dissociation on Cu2O. The addition of CO to the gas mixture is found to play a key role in removing adsorbed oxygen that otherwise passivates the Cu surface, making metallic Cu surface sites available for CO2 activation and subsequent conversion to CH3OH. These findings are corroborated by mass spectrometry measurements, which show increased H2O formation when H2 is dosed before rather than after CO2. The importance of maintaining metallic Cu sites during the methanol synthesis reaction is thereby highlighted, with the inclusion of CO in the gas feed helping to achieve this even in the absence of ZnO as the catalyst support.

Fluid flow as a driver of embryonic morphogenesis.

Fluid flow is a powerful morphogenic force during embryonic development. The physical forces created by flowing fluids can either create morphogen gradients or be translated by mechanosensitive cells into biological changes in gene expression. In this Primer, we describe how fluid flow is created in different systems and highlight the important mechanosensitive signalling pathways involved for sensing and transducing flow during embryogenesis. Specifically, we describe how fluid flow helps establish left-right asymmetry in the early embryo and discuss the role of flow of blood, lymph and cerebrospinal fluid in sculpting the embryonic cardiovascular and nervous system.

Evidence and recommendation for mucopolysaccharidosis type II newborn screening in the United States.

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is an X-linked condition caused by pathogenic variants in the iduronate-2-sulfatase gene. The resulting reduced activity of the enzyme iduronate-2-sulfatase leads to accumulation of glycosaminoglycans that can progressively affect multiple organ systems and impair neurologic development. In 2006, the US Food and Drug Administration approved idursulfase for intravenous enzyme replacement therapy for MPS II. After the data suggesting that early treatment is beneficial became available, 2 states, Illinois and Missouri, implemented MPS II newborn screening. Following a recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children in February 2022, in August 2022, the US Secretary of Health and Human Services added MPS II to the Recommended Uniform Screening Panel, a list of conditions recommended for newborn screening. MPS II was added to the Recommended Uniform Screening Panel after a systematic evidence review reported the accuracy of screening, the benefit of presymptomatic treatment compared with usual case detection, and the feasibility of implementing MPS II newborn screening. This manuscript summarizes the findings of the evidence review that informed the Advisory Committee's decision.

Prdm16 Supports Arterial Flow Recovery by Maintaining Endothelial Function.

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Atrial Tachyarrhythmias and Stroke: Temporal Relationship and Stroke Subtypes.

BACKGROUND AND PURPOSE: Research into the temporal relationship between atrial tachyarrhythmias (atrial tachycardia [AT] and atrial fibrillation [AF]) and stroke has produced conflicting findings. Systematic categorization of stroke subtypes may help clarify the discussion. OBJECTIVES: The objective of the study was to examine the presence and timing of AT/AF in relation to ischemic stroke subtypes, categorized as either cardioembolic (CE) or non-CE. METHODS: Consecutive patients presenting to the Austin Hospital with acute stroke from 2012 to 2019 and a cardiac implantable electronic device (CIED) were identified. Using a case-control design, the temporal proximity of AT/AF episodes in the 90 days prior to stroke was compared in the CE and non-CE stroke groups. RESULTS: 5,591 patients presented to the Austin Hospital with acute stroke from 2012 to 2019, of whom 31 patients with an ischemic stroke and a CIED with ≥90 days of monitoring were identified. Twelve strokes were adjudicated as CE and 19 as non-CE by a stroke neurologist. Six of the 12 CE stroke patients (50%) experienced AT/AF within 30 days preceding their stroke, while none of the 19 non-CE stroke patients recorded any AT/AF in the same period (p = 0.001). Four CE stroke patients (33%) had no AT/AF preceding their strokes at any time. The odds ratio for CE stroke was highest (39; 95% confidence interval [CI]: 1.92-791.5) when AT/AF occurred in the 30 days prior, declining to 20.65 (95% CI: 1.00-427.66) and 6.07 (95% CI: 0.94-39.04) in the subsequent 31-60- and 61-90-day windows, respectively. CONCLUSIONS: CE strokes were associated with a significantly higher proportion of preceding AT/AF compared with non-CE strokes. These findings support a potential temporal relationship between AT/AF and CE stroke and demonstrate that stroke subtyping can better characterize the relationship between AF and ischemic stroke. However, this study's findings are limited by its sample size and small number of informative cases.