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Bronchial hyperresponsiveness in mild to moderate asthma may result from airway smooth muscle cell proliferation or acquisition of a hypercontractile phenotype. Because these cells have not been well characterized in mild to moderate asthma, we examined the morphometric and gene expression characteristics of smooth muscle cells in this subgroup of patients with asthma. Using bronchial biopsies from 14 subjects with mild to moderate asthma and 15 control subjects, we quantified smooth muscle cell morphology by stereology and the expression of a panel of genes related to a hypercontractile phenotype of airway smooth muscle, using laser microdissection and two-step real-time polymerase chain reaction. We found that airway smooth muscle cell size was similar in both groups, but cell number was nearly twofold higher in subjects with asthma (p = 0.03), and the amount of smooth muscle in the submucosa was increased 50-83% (p < 0.005). Gene expression profiling in smooth muscle cells showed no difference in the expression of genes encoding phenotypic markers in cells from healthy subjects and subjects with asthma (all p > 0.1). We conclude that airway smooth muscle proliferation is a pathologic characteristic of subjects with mild to moderate asthma. However, smooth muscle cells in mild to moderate asthma do not show hypertrophy or gene expression changes of a hypercontractile phenotype observed in vitro. [ABSTRACT FROM AUTHOR]

Flaviviruses orchestrate a unique remodelling of the endoplasmic reticulum (ER) to facilitate translation and processing of their polyprotein, giving rise to virus replication compartments. While the signal recognition particle (SRP)-dependent pathway is the canonical route for ER-targeting of nascent cellular membrane proteins, it is unknown whether flaviviruses rely on this mechanism. Here we show that Zika virus bypasses the SRP receptor via extensive interactions between the viral non-structural proteins and the host translational machinery. Remarkably, Zika virus appears to maintain ER-localised translation via NS3-SRP54 interaction instead, unlike other viruses such as influenza. Viral proteins engage SRP54 and the translocon, selectively enriching for factors supporting membrane expansion and lipid metabolism while excluding RNA binding and antiviral stress granule proteins. Our findings reveal a sophisticated viral strategy to rewire host protein synthesis pathways and create a replication-favourable subcellular niche, providing insights into viral adaptation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Mucosal-associated invariant T cells (MAIT) are innate-like lymphocytes enriched in mucosal organs where they contribute to antimicrobial defense. APECED is an inborn error of immunity characterized by immune dysregulation and chronic mucocutaneous candidiasis. Reduction in the frequency of circulating MAITs has been reported in many inborn errors of immunity, but only in a few of them, the functional competence of MAITs has been assessed. Here, we show in a cohort of 24 patients with APECED, that the proportion of circulating MAITs was reduced compared with healthy age and sex-matched controls (1.1% vs. 2.6% of CD3 + T cells; p < 0.001) and the MAIT cell immunophenotype was more activated. Functionally the IFN-γ secretion of patient MAITs after stimulation was comparable to healthy controls. We observed in the patients elevated serum IFN-γ (46.0 vs. 21.1 pg/mL; p = 0.01) and IL-18 (42.6 vs. 13.7 pg/mL; p < 0.001) concentrations. Lower MAIT proportion did not associate with the levels of neutralizing anti-IL-22 or anti-IL-12/23 antibodies but had a clear negative correlation with serum concentrations of IFN-γ, IL-18, and protein C-reactive protein. Our data suggest that reduction of circulating MAITs in patients with APECED correlates with chronic type 1 inflammation but the remaining MAITs are functionally competent., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

People with severe-mental-illness (SMI), often defined as "schizophrenia-spectrum disorders and bipolar disorder", have increased premature mortality and elevated prevalence of diabetes compared with general population. Evidence indicated that one-third of their premature death was from cardiovascular diseases (CVD), with risk conferred by diabetes. Although earlier studies have examined SMI-associated diabetes-related outcomes, findings were inconsistent and not systematically evaluated. We systematically reviewed and quantitatively synthesized diabetes-related outcomes in patients with SMI (schizophrenia-spectrum disorders and bipolar disorder) by searching Embase, MEDLINE, PsycInfo, and Web-of-Science from inception to 31-March-2024, and included studies examining mortality and complication outcomes in SMI patients with co-occurring diabetes relative to patients with diabetes-only. Results were synthesized by random-effects models, with stratified-analyses by study-level characteristics. The study was registered with PROSPERO (CRD42023448490). Twenty-one studies involving 161,156 SMI patients with co-occurring diabetes were identified from ten regions. Regarding mortality risk, SMI-diabetes group exhibited increased risks of all-cause mortality (RR=1.77[95 % CI: 1.46-2.14]) and CVD-specific mortality (1.88[1.73-2.04]) relative to diabetes-only group. All-cause mortality risk was present in distinct regions and has persisted over time. Regarding complication risk, SMI-diabetes group showed higher risk of any complications (1.23[1.06-1.43]) than comparison, with stratified-analyses showing higher risk of metabolic-complications (1.84[1.58-2.15]), and lower likelihood of peripheral-vascular complications (0.91[0.84-0.99]), neuropathy (0.85[0.78-0.93]), and retinopathy (0.70[0.60-0.82]), albeit comparable cardiovascular-complications (1.04[0.89-1.22]), cerebrovascular-complications (1.07[0.86-1.33]), and nephropathy (0.92[0.72-1.17]). High heterogeneity was noted and could not be fully-explained by subgroup-analyses. Implementation of targeted interventions is needed to rectify their diabetes-related outcomes and mortality gap., Competing Interests: Declaration of competing interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper., (Copyright © 2024 Elsevier B.V. and ECNP. All rights reserved.)

Background: Sarcomas are diverse neoplasms with highly variable histological appearances in which diagnosis is often challenging and management options for metastatic/unresectable disease limited. Many sarcomas have distinctive molecular alterations, but the range of alterations is large, variable in type and rapidly increasing, meaning that testing by limited panels is unable to capture the broad spectrum of clinically pertinent genomic drivers required. Paired whole genome sequencing (WGS) in contrast allows comprehensive assessment of small variants, copy number and structural variants along with mutational signature analysis and germline testing., Methods: Introduction of WGS as a diagnostic standard for all eligible patients with known or suspected soft tissue sarcoma over a 2-year period at a soft tissue sarcoma treatment centre., Results: WGS resulted in a refinement in the diagnosis in 37% of cases, identification of a target for personalised therapy in 33% of cases, and a germline alteration in 4% of cases., Conclusion: Introduction of WGS poses logistical and training challenges, but offers significant benefits to this group of patients., (© 2024. Crown.)

Introduction: Trauma is the leading cause of paediatric mortality and morbidity. Stay-home regulations for coronavirus disease 2019 (COVID-19) reportedly changed trauma severity, yet data from Hong Kong were lacking. This study examined Hong Kong's spectrum of paediatric trauma and addressed knowledge gaps concerning epidemiological changes during COVID-19., Methods: Children with traumatic injuries who attended a tertiary trauma centre from January 2010 to March 2022 were included in this retrospective, cross-sectional study. We analysed demographic and clinical data and conducted unadjusted bivariate analyses of injury patterns before and after the pandemic., Results: In total, 725 children attended the Accident and Emergency Department due to trauma, 585 before and 140 during COVID-19. The male-to-female ratio was 1.84:1. The 90-day trauma-related mortality was 0.7%. The overall Injury Severity Score was 3.52 ± 5.95. The paediatric trauma incidence was similar before and after social-distancing policies (both 5.8 cases monthly). Gender, ISS distribution, intensive care unit stay length, and hospital stay length values were similar (p > 0.05). Trauma call activation (8.4% vs. 5.7%, p = 0.002) and road traffic accidents (10.6% vs. 5.7%, p = 0.009) significantly decreased, yet younger-patient injuries (< 10 years old; 85.7% vs. 71%, p < 0.001), burns (28% vs. 45.7%, p < 0.001), and domestic injuries (65.5% vs. 85.7%, p < 0.001) significantly increased. No significant self-harm, assault, or abuse increases were found., Conclusions: The paediatric trauma incidences were similar before and during the pandemic. However, domestic and burn injuries significantly increased, highlighting the importance of injury prevention., (© 2024. The Author(s).)

Removable denture wearers are at an increased risk of developing periodontal diseases due to biofilm deposition and microbial colonization on the denture surface. This study aimed to characterize and compare the metagenomic composition of saliva in denture wearers with different periodontal statuses. Twenty-four community-dwelling elders were recruited and grouped into denture wearers with active periodontitis (APD), non-denture wearers with active periodontitis (APXD), denture wearers with stable periodontal health conditions (SPCD), and non-denture wearers with stable periodontal health conditions (SPCXD). Saliva samples were collected and underwent Type IIB restriction-site-associated DNA for microbiome (2bRAD-M) metagenomic sequencing to characterize the species-resolved microbial composition. Alpha diversity analysis based on the Shannon index revealed no significant difference between groups. Beta diversity analysis using the Jaccard distance matrix was nearly significantly different between denture-wearing and non-denture-wearing groups ( p = 0.075). Some respiratory pathogens, including Streptococcus agalactiae and Streptococcus pneumoniae , were detected as the top 30 species in saliva samples. Additionally, LEfSe analysis revealed a substantial presence of pathogenic bacteria in denture groups. In the cohort of saliva samples collected from community-dwelling elders, a remarkable abundance of certain opportunistic pathogens was detected in the microbial community.

Joint injury is associated with risk for development of osteoarthritis (OA). Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis. However, the role of the fibrinolytic pathway is not well understood. Here, we showed that the fibrinolytic pathway, which includes plasminogen/plasmin, tissue plasminogen activator, urokinase plasminogen activator (uPA), and the uPA receptor (uPAR), was dysregulated in human OA joints. Pharmacological inhibition of plasmin attenuated OA progression after a destabilization of the medial meniscus in a mouse model whereas genetic deficiency of plasmin activator inhibitor, or injection of plasmin, exacerbated OA. We detected increased uptake of uPA/uPAR in mouse OA joints by microPET/CT imaging. In vitro studies identified that plasmin promotes OA development through multiple mechanisms, including the degradation of lubricin and cartilage proteoglycans and induction of inflammatory and degradative mediators. We showed that uPA and uPAR produced inflammatory and degradative mediators by activating the PI3K, 3'-phosphoinositide-dependent kinase-1, AKT, and ERK signaling cascades and activated matrix metalloproteinases to degrade proteoglycan. Together, we demonstrated that fibrinolysis contributes to the development of OA through multiple mechanisms and suggested that therapeutic targeting of the fibrinolysis pathway can prevent or slow development of OA.

Background: Radiation-induced angiosarcoma (RIA) is an uncommon but morbid complication after radiotherapy for breast cancer., Methods: Retrospective analysis of breast RIA patients at Cambridge University Hospital (CUH), a regional treatment centre in the East of England., Results: 22 patients were identified between 2010 and 2022. Median age of diagnosis was 65 years (range 41-78). Median time from breast radiotherapy to RIA diagnosis was 6.5 years (range 2.4-16.0)-this interval has decreased over the last 24 years (r 2  = 0.6601). 9% had metastasis at presentation. All patients underwent surgery (55% at CUH, 45% at local hospitals). 27% received peri-operative pegylated liposomal doxorubicin in the first-line setting. 62% relapsed following their primary curative-intent treatments after a median of 28 months. Metastases occurred in 36%, the commonest sites being lung (100%) and lymph node (50%). 2-year and 5-year overall survival (OS) rates for all patients were 73% and 60%, respectively. No correlation between progression-free survival (PFS) and OS was found with tumour size, margin, peri-operative chemotherapy, and whether surgery was performed at CUH. Patients with multifocal disease on their breasts had shorter PFS following surgery compared to single-lesion disease (median 10 vs 65 months; HR = 4.359 [95% CI 1.342-14.16]; P = 0.0143). Patients aged > 72 years had a median OS of 45 months vs 102 months for those ≤ 72 years (HR = 7.129 [95% CI 1.646-30.88]; P = 0.0086)., Conclusion: RIA has high rates of recurrence and mortality and appears to be occurring sooner after breast radiotherapy. Further studies on its pathogenesis and effective treatment are warranted., (© 2023. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Objective: Anti-citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA) and have long been regarded as pathogenic. Despite substantial in vitro evidence supporting this claim, reports investigating the proinflammatory effects of ACPAs in animal models of arthritis are rare and include mixed results. Here, we sequenced the plasmablast antibody repertoire of a patient with RA and functionally characterized the encoded ACPAs., Methods: We expressed ACPAs from the antibody repertoire of a patient with RA and characterized their autoantigen specificities on antigen arrays and enzyme-linked immunosorbent assays. Binding affinities were estimated by bio-layer interferometry. Select ACPAs (n = 9) were tested in the collagen antibody-induced arthritis (CAIA) mouse model to evaluate their effects on joint inflammation., Results: Recombinant ACPAs bound preferentially and with high affinity (nanomolar range) to citrullinated (cit) autoantigens (primarily histones and fibrinogen) and to auto-cit peptidylarginine deiminase 4 (PAD4). ACPAs were grouped for in vivo testing based on their predominant cit-antigen specificities. Unexpectedly, injections of recombinant ACPAs significantly reduced paw thickness and arthritis severity in CAIA mice as compared with isotype-matched control antibodies (P ≤ 0.001). Bone erosion, synovitis, and cartilage damage were also significantly reduced (P ≤ 0.01). This amelioration of CAIA was observed for all the ACPAs tested and was independent of cit-PAD4 and cit-fibrinogen specificities. Furthermore, disease amelioration was more prominent when ACPAs were injected at earlier stages of CAIA than at later phases of the model., Conclusion: Recombinant patient-derived ACPAs ameliorated CAIA. Their antiinflammatory effects were more preventive than therapeutic. This study highlights a potential protective role for ACPAs in arthritis., (© 2023 American College of Rheumatology.)

Neurotransmission in the brain is unreliable, suggesting that high-frequency spike bursts rather than individual spikes carry the neural code. For instance, cortical pyramidal neurons rely on bursts in memory formation. Protein synthesis is another key factor in long-term synaptic plasticity and learning but is widely considered unnecessary for synaptic transmission. Here, however, we show that burst neurotransmission at synapses between neocortical layer 5 pyramidal cells depends on axonal protein synthesis linked to presynaptic NMDA receptors and mTOR. We localized protein synthesis to axons with laser axotomy and puromycylation live imaging. We whole-cell recorded connected neurons to reveal how translation sustained readily releasable vesicle pool size and replenishment rate. We live imaged axons and found sparsely docked RNA granules, suggesting synapse-specific regulation. In agreement, translation boosted neurotransmission onto excitatory but not inhibitory basket or Martinotti cells. Local axonal mRNA translation is thus a hitherto unappreciated principle for sustaining burst coding at specific synapse types., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Reprogramming lipid metabolic pathways is a critical feature of activating immune responses to infection. However, how these reconfigurations occur is poorly understood. Our previous screen to identify cellular deubiquitylases (DUBs) activated during influenza virus infection revealed Usp25 as a prominent hit. Here, we show that Usp25-deleted human lung epithelial A549 cells display a >10-fold increase in pathogenic influenza virus production, which was rescued upon reconstitution with the wild type but not the catalytically deficient (C178S) variant. Proteomic analysis of Usp25 interactors revealed a strong association with Erlin1/2, which we confirmed as its substrate. Newly synthesized Erlin1/2 were degraded in Usp25 -/- or Usp25 C178S cells, activating Srebp2, with increased cholesterol flux and attenuated TLR3-dependent responses. Our study therefore defines the function of a deubiquitylase that serves to restrict a range of viruses by reprogramming lipid biosynthetic flux to install appropriate inflammatory responses., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Solar energy utilization is of great significance to current challenges of the energy crisis and environmental pollution, which benefit the development of the global community to achieve carbon neutrality goals. Hydrogen energy is also treated as a good candidate for future energy supply since its combustion not only supplies high-density energy but also shows no pollution gas. In particular, photocatalytic water splitting has attracted increasing research as a promising method for H 2 production. Recently, single-atom (SA) photocatalysts have been proposed as a potential solution to improve catalytic efficiency and lower the costs of photocatalytic water splitting for H 2 generation. Owing to the maximized atom utilization rate, abundant surface active sites, and tunable coordination environment, SA photocatalysts have achieved significant progress. This review reviews developments of advanced SA photocatalysts for H 2 generation regarding the different support materials. The recent progress of titanium dioxide, metal-organic frameworks, two-dimensional carbon materials, and red phosphorus supported SA photocatalysts are carefully discussed. In particular, the material designs, reaction mechanisms, modulation strategies, and perspectives are highlighted for realizing improved solar-to-energy efficiency and H 2 generation rate. This work will supply significant references for future design and synthesis of advanced SA photocatalysts., (© 2023 Wiley-VCH GmbH.)

Introduction: With persistent incidence, incomplete vaccination rates, confounding respiratory illnesses, and few therapeutic interventions available, COVID-19 continues to be a burden on the pediatric population. During a surge, it is difficult for hospitals to direct limited healthcare resources effectively. While the overwhelming majority of pediatric infections are mild, there have been life-threatening exceptions that illuminated the need to proactively identify pediatric patients at risk of severe COVID-19 and other respiratory infectious diseases. However, a nationwide capability for developing validated computational tools to identify pediatric patients at risk using real-world data does not exist., Methods: HHS ASPR BARDA sought, through the power of competition in a challenge, to create computational models to address two clinically important questions using the National COVID Cohort Collaborative: (1) Of pediatric patients who test positive for COVID-19 in an outpatient setting, who are at risk for hospitalization? (2) Of pediatric patients who test positive for COVID-19 and are hospitalized, who are at risk for needing mechanical ventilation or cardiovascular interventions?, Results: This challenge was the first, multi-agency, coordinated computational challenge carried out by the federal government as a response to a public health emergency. Fifty-five computational models were evaluated across both tasks and two winners and three honorable mentions were selected., Conclusion: This challenge serves as a framework for how the government, research communities, and large data repositories can be brought together to source solutions when resources are strapped during a pandemic., Competing Interests: The views expressed are solely those of the authors and do not necessarily represent those of the U.S. Department of Health and Human Services. Timothy Bergquist, Tellen Bennett, and Richard Moffitt disclosed that this work was performed by Sage Bionetworks and its subcontractors under a grant with the National Institute of Health (U24TR002306). Additional funding for Timothy Bergquist was provided through the Bill and Melinda Gates Foundation (INV- 018455). Marie Wax and Hui-Hsing Wong disclose that they are government support contractors employed by Aveshka Inc. and Tunnell Government Services Inc. respectively, which receives funds from the U.S. government under contract to provide technical and programmatic support for HHS-BARDA. Joy Alamgir discloses that he is a founder and a shareholder of ARIScience. Tellen Bennett has received funding from the National Institutes of Health – NCATS, Eunice Kennedy Shriver NICHD, and National Heart, Lung and Blood Institute (NHLBI)., (© The Author(s) 2023.)

Transition metal (TM) single atom catalysts (SACs) are of great potential for photocatalytic H 2 production because of their abundant catalytic active sites and cost-effectiveness. As a promising support material, red phosphorus (RP) based SACs are still rarely investigated. In this work, we have carried out systematic theoretical investigations by anchoring TM atoms (Fe, Co, Ni, Cu) on RP for efficient photocatalytic H 2 generation. Our density functional theory (DFT) calculations have revealed that 3d orbitals of TM locate close to the Fermi level to guarantee efficient electron transfer for photocatalytic performances. Compared with pristine RP, the introduction of single atom TM on the surface exhibit narrowed bandgaps, resulting in easier spatial separation for photon-generated charge carriers and an extended photocatalytic absorption window to the NIR range. Meanwhile, the H 2 O adsorptions are also highly preferred on the TM single atoms with strong electron exchange, which benefits the subsequent water-dissociation process. Due to the optimized electronic structure, the activation energy barrier of water-splitting has been remarkably reduced in RP-based SACs, revealing their promising potential for high-efficiency H 2 production. Our comprehensive explorations and screening of novel RP-based SACs will offer a good reference for further designing novel photocatalysts for high-efficiency H 2 generation., 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 © 2023 Lu, Sun, Wu, Lu, Chen, Chan, Wong and Huang.)

Background: Individuals with major depressive disorder have a cognitive bias toward emotional stimuli, which influences the quality and speed of emotional information processing. This study aimed to understand the factors underlying this bias by identifying when it occurs during information processing using an information processing model., Methods: A total of 57 participants-19 each [ (16 (84.21%) females and 3 (15.79%) males per group)], for the first-episode MDD (FMDD), recurrent episodes MDD (RMDD), and healthy controls (HCs) - matched for sex and hand preference, completed event-related potentials (ERP) to perform psychological function and a choice response time task., Results: Results revealed that recurrent episodes major depressive disorder participants had decreased N2b and P3b amplitudes but increased contingent negative variation during the processing of happy and neutral facial stimuli, relative to their counterparts. Both recurrent episodes major depressive disorder and first-episode major depressive disorder participants used a parallel information processing strategy for happy information at P3a latency, while healthy controls used a linear information processing strategy., Conclusion: The use of a parallel processing strategy among individuals with major depressive disorder may have led to impaired "happy" information processes, possibly explaining why individuals with major depressive disorder are less efficient than healthy controls. The results suggest the possibility that biases related to the processing of "happy" information among individuals with major depressive disorder may be related to a tendency for these individuals to engage in superficial decision-making. Future research is needed to examine the processes contributing to people with major depressive disorder having challenges with inhibition-facilitation of emotional stimuli., Competing Interests: Declaration of Interests: The authors have no conflict of interest to declare., (2023 authors.)

Infection by many (+)RNA viruses is accompanied by ER-expansion and membrane remodelling to form viral replication organelles, followed by assembly and secretion of viral progenies. We previously identified that virus-triggered lipophagy was critical for flaviviral assembly, and is driven by the lipid droplet associated protein Ancient ubiquitin protein 1 (Aup1). A ubiquitin conjugating protein Ube2g2 that functions as a co-factor for Aup1 was identified as a host dependency factor in our study. Here we characterized its function: Ube2g2-deficient cells displayed a dramatic reduction in virus production, which could be rescued by reconstituting the wild-type but not the catalytically deficient (C89K) mutant of Ube2g2, suggesting that its enzymatic activity is necessary. Ube2g2 deficiency did not affect entry of virus particles but resulted in a profound loss in formation of replication organelles, and production of infectious progenies. This phenomenon resulted from its dual activity in (i) triggering lipophagy in conjunction with Aup1, and (ii) degradation of ER chaperones such as Herpud1, SEL1L, Hrd1, along with Sec62 to restrict ER-phagy upon Xbp1-IRE1 triggered ER expansion. Our results therefore underscore an exquisite fine-tuning of selective autophagy by flaviviruses that drive host membrane reorganization during infection to enable biogenesis of viral replication organelles., (© 2023. The Author(s).)

Imbalance of collagen I expression results in severe pathologies. Apart from activation by the TGFβ-receptor/Smad pathway, control of collagen I expression remains poorly understood. Here, we used human dermal fibroblasts expressing a mCherry fluorescent protein driven by endogenous COL1A1 promoter to functionally screen the kinome and phosphatome. We identify 8 negative regulators, revealing that collagen is under tonic repression. The cell surface receptor BDKRB2 represses collagen I and other pro-fibrotic genes. Interestingly, it also promotes other basal membrane ECM genes. This function is independent of the natural ligand, bradykinin, and of SMAD2/3 factors, instead requiring constant ERK1/2 repression. TGFβ stimulation induces rapid BDKRB2 transcriptional downregulation. Human fibrotic fibroblasts have reduced BDKRB2 levels and enhancing its expression in keloid fibroblasts represses COL1A1. We propose that tonic signalling by BDKRB2 prevents collagen overproduction in skin fibroblasts., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Currently, scientists have devoted great efforts to finding effective treatments to combat COVID-19 infections. Although noble metal nanoparticles are able to realize protein modifications, their interactions with the protein are still unclear from the atomic perspective. To supply a general understanding, in this work, we have carried out theoretical calculations to investigate the interaction between protein segments (RBD1, RBD2, RBD3) of SARS-Cov-2 spike protein and a series of noble metal (Au, Ag, Cu, Pd, Pt) surfaces regarding the binding strength, protein orientations, and electronic modulations. In particular, the Au surface has shown the strongest binding preferences for the protein segments, which induces electron transfer between the Au and receptor-binding domain (RBD) segments. This further leads to the polarization of segments for virus denaturation. This work has offered a direct visualization of protein interactions with noble metal surfaces from the atomic level, which will benefit anti-virus material developments in the future., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Objective: Mast cells in the osteoarthritis (OA) synovium correlate with disease severity. This study aimed to further elucidate the role of mast cells in OA by RNA-Seq analysis and pharmacological blockade of the activity of histamine, a key mast cell mediator, in murine OA., Methods: We examined OA synovial tissues and fluids by flow cytometry, immunostaining, single-cell and bulk RNA-Seq, qPCR, and ELISA. Cetirizine, a histamine H1 receptor (H 1 R) antagonist, was used to treat the destabilization of the medial meniscus (DMM) mouse model of OA., Results: Flow cytometry and immunohistology analysis of OA synovial cells revealed KIT + FcεRI + and TPSAB1 + mast cells. Single-cell RNA-Seq of OA synovial cells identified the expression of prototypical mast cell markers KIT, TPSAB1, CPA3 and HDC, as well as distinctive markers HPGD, CAVIN2, IL1RL1, PRG2, and CKLF, confirmed by bulk RNA-Seq and qPCR. A mast cell prototypical marker expression score classified 40 OA patients into three synovial pathotypes: mast cell-high, -medium, and -low. Additionally, we detected mast cell mediators including histamine, tryptase AB1, CPA3, PRG2, CAVIN2, and CKLF in OA synovial fluids. Elevated H 1 R expression was detected in human OA synovium, and treatment of mice with the H 1 receptor antagonist cetirizine reduced the severity and OA-related mediators in DMM., Conclusion: Based on differential expression of prototypical and distinct mast cell markers, human OA joints can be stratified into mast cell-high, -medium, and -low synovial tissue pathotypes. Pharmacologic blockade of histamine activity holds the potential to improve OA disease outcome., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Background: Research in treatment of non-small cell lung cancer (NSCLC) has shown promising results with stereotactic ablative radiotherapy (SABR) of oligometastatic disease, wherein distant disease may be limited to one or a few distant organs by host factors. Traditionally, PET/CT has been used in detecting metastatic disease and avoiding futile surgical intervention, however, sensitivity and specificity is limited to only 81 and 79%, respectively. Mediastinal staging still identifies occult nodal disease in up to 20% of NSCLC patients initially thought to be operative candidates. Endobronchial ultrasound and transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive tool for the staging and diagnosis of thoracic malignancy. When EBUS is combined with endoscopic ultrasound using the same bronchoscope (EUS-B), the diagnostic sensitivity and negative predictive value increase to 84 and 97%, respectively. Endoscopic staging in patients with advanced disease has never been studied, but may inform treatment if a curative SABR approach is being taken., Methods: This is a multi-centre, prospective, cohort study with two-stage design. In the first stage, 10 patients with oligometastatic NSCLC (lung tumour ± hilar/mediastinal lymphadenopathy) with up to 5 synchronous metastases will be enrolled An additional 19 patients will be enrolled in the second stage if rate of treatment change is greater than 10% in the first stage. Patients will be subject to EBUS or combined modality EBUS/EUS-B to assess bilateral lymph node stations using a N3 to N2 to N1 progression. Primary endpoint is defined as the rate of change to treatment plan including change from SABR to conventional dose radiation, change in mediastinal radiation field, and change from curative to palliative intent treatment., Discussion: If a curative approach with SABR for oligometastatic disease is being explored, invasive mediastinal staging may guide treatment and prognosis. This study will provide insight into the use of endoscopic mediastinal staging in determining changes in treatment plan of NSCLC. Results will inform the design of future phase II trials., Trial Registration: Clinicaltrials.gov identifier NCT04852588. Date of registration: April 19, 2021., Protocol Version: 1.1 on December 9, 2021., (© 2022. The Author(s).)

Receipt of sufficient COPD medication has improved over time; however, recommended therapy continues to be underused, especially in patients at lower risk of COPD exacerbation https://bit.ly/3IhK5Y4., Competing Interests: Conflict of interest: M. Poon has nothing to disclose. Conflict of interest: P. Pequeno has nothing to disclose. Conflict of interest: S.D. Aaron reports personal fees from GSK, Sanofi and AstraZeneca, outside the submitted work. Conflict of interest: M.B. Stanbrook has nothing to disclose. Conflict of interest: H.H. Wong reports that Becton Dickinson provides funds that help support the advanced pulmonary procedures fellowship at his institution. Cook Medical provides support for simulation courses H.H. Wong runs for pulmonary trainees in Toronto. Conflict of interest: P. Cram has nothing to disclose. Conflict of interest: A.S. Gershon reports grants from Government of Ontario and the Canadian Respiratory Research Network during the conduct of the study., (Copyright ©The authors 2022.)

Background: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined., Objective: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD., Methods: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti-IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays., Results: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared with those of the controls., Conclusion: A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Rare earth (RE) based halide solid electrolytes (HEs) are recently considered as research hotspots in the field of all-solid-state batteries (ASSBs). The RE-based HEs possess high ionic conductivity, credible deformability, and good stability, which can bring excellent electrochemical performances for ASSBs. However, the conventional synthetic methods of RE HEs are a mechanochemical process and co-melting strategy, both approaches require expensive raw materials and sophisticated equipment. Therefore, a lot of research work is required to promote the preparation methods for these promising SSEs in ASSBs. Thus, a vacuum evaporation-assisted synthesis method is developed for the massive synthesis of HEs. The as-prepared Li 3 HoBr 6 (LHB) has a high lithium-ion conductivity close to the mS cm -1 level and the LHB-based Li-Se ASSBs can be assembled by cold pressing. Theoretical calculations have revealed that the Li migrations are highly preferred in Li 3 HoBr 6 owing to the low energy cost and high tolerance of stable structure. The tetrahedral and octahedral pathways are responsible for Li migrations in short and long ranges, respectively. The results show that the LHB-based Li-Se battery has good stability and rate performance, indicating that LHB has potential application in the field of ASSBs., (© 2021 Wiley-VCH GmbH.)

A woman in her 30s with underlying Graves' disease, who recently completed radioactive iodine treatment, presented with 2 weeks of acutely altered behaviour associated with auditory hallucinations and religious preoccupations. Laboratory investigation demonstrated elevated free thyroxine levels and suppressed thyroid-stimulating hormone levels. Additionally, there was a presence of antithyroid peroxidase antibodies consistent with autoimmune thyroid disease. She responded to antipsychotics and achieved biochemical euthyroidism. Subsequently, antipsychotic was tapered off during outpatient follow-up at the patient's own request, with supplement thyroxine continuing. After 1 week, acute hallucinations and religious preoccupations re-emerged, driving her to inflict self-injuries by swallowing coins and nails and banging her head against the wall, sustaining laceration wounds. Furthermore, she hammered a roofing nail into the external genitalia, embedded in the symphysis pubis. After supplemental thyroxine was stopped and olanzapine was started, she achieved biochemical euthyroid followed by remission of psychosis within 1 week. This case illustrates the importance of elucidating organic causes of psychosis as they are easily and swiftly reversible., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: This study aimed to examine the psychometric performance of the Recovering Quality of Life scale 10-item version (ReQoL-10) using a sample from a Singapore first-episode psychosis intervention program, to explore its clinical and sociodemographic correlates, and to discuss its utility as a patient-reported outcome measure (PROM)., Methods: Sociodemographic data, duration of untreated psychosis (DUP), and diagnosis were collected from 300 participants. Clinical data, which included baseline and current scores on the Patient Health Questionnaire 9-item version, EuroQoL-5 Dimension 3-level version, Positive and Negative Syndrome Scale, and Global Assessment of Functioning scale, were extracted. The ReQoL-10 was tested for structural validity, internal consistency, and construct validity, and a multiple linear regression determined if any of the baseline factors were statistically significant predictors of the total ReQoL-10 scores., Results: The mean (SD) total ReQoL-10 score of the sample was 27.8 (7.8). Confirmatory factor analysis confirmed the bifactor model structure of the ReQoL-10. The instrument demonstrated good internal consistency and adequate construct validity. Being older was associated with higher total ReQoL-10 scores, while being married, having a highest educational level of vocational/diploma, longer DUP, and a diagnosis of affective psychosis were associated with lower total ReQoL-10 scores., Conclusions: This study has validated the ReQoL-10 as suitable for routine use to measure recovery-specific quality of life in a psychiatric setting among patients with first-episode psychosis, and is a potential tool to initiate recovery conversations. As a PROM, it can facilitate shared decision making, in line with efforts to evaluate and improve quality of care., (© 2020 John Wiley & Sons Australia, Ltd.)

The canonical hippocampal NMDA memory receptor also controls the release of the transmitter glutamate and the growth factor BDNF., Competing Interests: HW, OC, PS No competing interests declared, (© 2021, Wong et al.)

In the textbook view, N-methyl-d-aspartate (NMDA) receptors are postsynaptically located detectors of coincident activity in Hebbian learning. However, controversial presynaptically located NMDA receptors (preNMDARs) have for decades been repeatedly reported in the literature. These preNMDARs have typically been implicated in the regulation of short-term and long-term plasticity, but precisely how they signal and what their functional roles are have been poorly understood. The functional roles of preNMDARs across several brain regions and different forms of plasticity can differ vastly, with recent discoveries showing key involvement of unusual subunit composition. Increasing evidence shows preNMDAR can signal through both ionotropic action by fluxing calcium and in metabotropic mode even in the presence of magnesium blockade. We argue that these unusual properties may explain why controversy has surrounded this receptor type. In addition, the expression of preNMDARs at some synapse types but not others can underlie synapse-type-specific plasticity. Last but not least, preNMDARs are emerging therapeutic targets in disease states such as neuropathic pain. We conclude that axonally located preNMDARs are required for specific purposes and do not end up there by accident., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

The adverse effects of depression on patients' life have been reported but information about its effects on the sequential organization of the information processing stages remains poorly understood as previous studies focused only on distinct stages. This study adds to existing knowledge by examining the effect of major depressive disorder (MDD) on the sequential organization of information processing, executive and community functioning. Fifty-seven participants with 19 participants each for first episode depression (FMDD), recurrent episodes depression (RMDD), and healthy controls (HCs) participated in this study. They completed assessments on executive and community functioning measures, and choice reaction time task (CRTT) for the event-related potential (ERP) data. Findings revealed no significant between-group difference in executive functioning but participants with depression (FMDD and RMDD) were found to be more depressed, with FMDD participants having worse community functioning skills compared with HCs. There was no significant between-group main effect on behavioral data. ERP data showed significantly less positive-going P3b among RMDD participants compared with HCs. FMDD participants used a different information processing strategy at P1, while HCs and RMDD participants used a different processing strategy at N2b compared with the other group(s), respectively. The results suggest the use of multifaceted assessment to get a holistic view of the health status of people with MDD in order to inform clinicians on the appropriate interventional strategies needed for the patient.

This paper describes the development and validation of the Case Management Quality Scale (CMQS) to measure the quality of care provided by case managers in an early intervention service for clients with first episode psychosis. A total of 300 client participants from the Singapore Early Psychosis Programme completed a self-administered survey comprising 52 items measuring case management, the Client Satisfaction Questionnaire 8-item version (CSQ-8), Recovery Self-Assessment - person in recovery version (RSA-R), and Working Alliance Inventory - long form client version (WAI-C), and Recovering Quality of Life 10-item version (ReQoL-10). Exploratory factor analysis was conducted on the 52-item scale and the items were reduced using criterion validity. Psychometric properties of the 25-item CMQS were tested using internal consistency and concurrent validity. A 2-factor structure of the CMQS was established comprising two subscales - Therapeutic alliance and Care and empowerment. The test of normality for CMQS and subscales was largely found to be within the acceptable range. The Cronbach's alpha for the CMQS scale was high (0.97) and in terms of convergent validity, the CMQS and the two subscales had a moderate correlation with the CSQ-8, RSA-R, and WAI-C (r ranging from 0.596-0.711) and a mild correlation with the ReQoL-10. In conclusion, the CMQS is a user-friendly, and psychometrically sound instrument that is potentially useful for measuring case manager-client therapeutic alliance, and the level of care and empowerment in a case management service., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Type I collagen is a key protein of most connective tissue and its up-regulation is required for wound healing but is also involved in fibrosis. Control of expression of this collagen remains poorly understood apart from Transforming Growth Factor beta (TGF-β1)-mediated induction. To generate a sensitive, practical, robust, image-based high-throughput-compatible reporter system, we genetically inserted a short-lived fluorescence reporter downstream of the endogenous type I collagen (COL1A1) promoter in skin fibroblasts. Using a variety of controls, we demonstrate that the cell line faithfully reports changes in type I collagen expression with at least threefold enhanced sensitivity compared to endogenous collagen monitoring. We use this assay to test the potency of anti-fibrotic compounds and screen siRNAs for regulators of TGF-β1-induced type I collagen expression. We propose our reporter cell line, Red-COLA1, as a new efficient tool to study type I collagen transcriptional regulation.

Inflammatory myofibroblastic tumour (IMT) is a rare malignancy with limited responses to corticosteroids and chemotherapy. About half of cases have activating rearrangements in the ALK gene which could be targeted with ALK inhibitors. A 40-year-old man presented with a large right lung mass and nodal, trapezius and cerebral metastases. Biopsy confirmed IMT with TPM4-ALK fusion. He was treated with prednisolone without clinical benefit. He received the Trk/ROS1/ALK inhibitor entrectinib in a clinical trial but his disease progressed in less than 3 months. Ifosfamide and etoposide in addition to radiotherapy to the brain and chest were administered. Transient improvement in the radiotherapy-treated areas was observed but his disease progressed shortly afterwards on all sites including the development of new adrenal metastasis. Compassionate use of the third-generation ALK inhibitor lorlatinib resulted in excellent partial response on all disease sites after 2 months, followed by a further 6 months of disease stabilisation. Repeat imaging showed slight increase in size of the cerebral metastasis but stable disease elsewhere, for which he was given stereotactic radiotherapy. His disease progressed 3 months later and lorlatinib was substituted with another ALK inhibitor brigatinib but he deteriorated and died shortly afterwards. Our patient tolerated lorlatinib well for 11 months with minimal toxicities, although he developed unilateral right-sided lung consolidation that was probably related to a combination of infection, radiotherapy and lorlatinib, which needed treatment with antibiotics and corticosteroids. This case demonstrates a role of lorlatinib in the treatment of TPM4-ALK-rearranged IMT despite failure of entrectinib.

Autophagy is an evolutionarily conserved process central to host metabolism. Among its major functions are conservation of energy during starvation, recycling organelles, and turnover of long-lived proteins. Besides, autophagy plays a critical role in removing intracellular pathogens and very likely represents a primordial intrinsic cellular defence mechanism. More recent findings indicate that it has not only retained its ability to degrade intracellular pathogens, but also functions to augment and fine tune antiviral immune responses. Interestingly, viruses have also co-evolved strategies to manipulate this pathway and use it to their advantage. Particularly intriguing is infection-dependent activation of autophagy with positive stranded (+)RNA virus infections, which benefit from the pathway without succumbing to lysosomal degradation. In this review we summarise recent data on viral manipulation of autophagy, with a particular emphasis on +RNA viruses and highlight key unanswered questions in the field that we believe merit further attention., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: The objective of this study was to quantify both the competitiveness of the EHR vendor market in the United States of America (US) and the degree of fragmentation of individual Medicare beneficiaries' medical records across the differing EHR vendors found in the US healthcare system., Methods and Materials: We determined the Part A and Part B Medicare-expenditure weighted market shares of EHR vendors and estimated the rate of attestation of meaningful use (MU) for EHRs among Medicare Part A & B providers from 2011 to 2016. Based on these data we calculated the annual Herfindahl-Hirschman Index to quantify the competitiveness of the EHR market as well as the number of vendors individual Medicare beneficiaries' medical records were stored in for the period 2014-2016., Results: We find that as of 2016 the EHR vendor environment was competitive but trending towards becoming highly concentrated soon. We also found that patient medical records were highly fragmented as only 4.5 % of expenditure-weighted individual Medicare beneficiaries had their MU medical records associated with a single vendor, while 19.8 % of expenditure-weighted beneficiaries had their MU medical records stored in 8 or more vendors., Discussion: These results indicate that there are tradeoffs between EHR market competition, and the challenges associated with achieving interoperability across numerous competing vendors., Conclusion: Uncertainty of interoperability among different EHR vendors may make transmission of medical records among different providers challenging, mitigating the benefit of vendor competition. This highlights the critical importance of current interoperability efforts moving forward., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Published by Elsevier B.V.)

Deubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, systematic analyses of DUBs that regulate this pathway have not been performed. Using a ubiquitin C-terminal electrophile, we profile DUBs that function during influenza A virus (IAV) infection and isolate OTUB1 as a key regulator of RIG-I-dependent antiviral responses. Upon infection, OTUB1 relocalizes from the nucleus to mitochondrial membranes together with RIG-I, viral PB2, and NS1. Its expression depends on competing effects of interferon stimulation and IAV-triggered degradation. OTUB1 activates RIG-I via a dual mechanism of K48 polyubiquitin hydrolysis and formation of an E2-repressive complex with UBCH5c. We reconstitute this mechanism in a cell-free system comprising [ 35 S]IRF3, purified RIG-I, mitochondrial membranes, and cytosol expressing OTUB1 variants. A range of IAV NS1 proteins trigger proteasomal degradation of OTUB1, antagonizing the RIG-I signaling cascade and antiviral responses., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ribosome assembly occurs mainly in the nucleolus, yet recent studies have revealed robust enrichment and translation of mRNAs encoding many ribosomal proteins (RPs) in axons, far away from neuronal cell bodies. Here, we report a physical and functional interaction between locally synthesized RPs and ribosomes in the axon. We show that axonal RP translation is regulated through a sequence motif, CUIC, that forms an RNA-loop structure in the region immediately upstream of the initiation codon. Using imaging and subcellular proteomics techniques, we show that RPs synthesized in axons join axonal ribosomes in a nucleolus-independent fashion. Inhibition of axonal CUIC-regulated RP translation decreases local translation activity and reduces axon branching in the developing brain, revealing the physiological relevance of axonal RP synthesis in vivo. These results suggest that axonal translation supplies cytoplasmic RPs to maintain/modify local ribosomal function far from the nucleolus in neurons., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: This qualitative study explored the perspectives of clients and caregivers on case management provided by the Singapore Early Psychosis Intervention Programme (EPIP), with the intent to understand the salient aspects of case management from their perspective., Methods: Clients and their caregivers were recruited from the EPIP outpatient clinics. Focus group discussions (FGDs) were conducted at a community centre outside the hospital with 47 clients and 19 caregivers. Facilitators were experienced researchers who were not involved in the care of the clients and trained in qualitative research methodologies. All FGDs were audio recorded and transcribed verbatim with all participants' identifiers omitted to protect confidentiality. Qualitative data analysis was conducted using thematic analysis., Results: There were 11 themes that emerged from the FGDs: therapeutic alliance, holistic monitoring, collaborative role with other care providers, counselling and guidance, crisis management, bridging role, client-centred care, client empowerment and strength building, psychoeducation/education on illness, support and problem solving. "Problem solving" surfaced only from the client FGDs; the remaining themes were common to both groups., Conclusions: The voices of clients and caregivers are important to EPIP case management service. This study has provided insights into their perspectives, understandings and lived experiences of case management and its impact on clients and caregivers., (© 2017 The Authors Early Intervention in Psychiatry Published by John Wiley & Sons Australia, Ltd.)

Osteoarthritis is characterized by articular cartilage breakdown, and emerging evidence suggests that dysregulated innate immunity is likely involved. Here, we performed proteomic, transcriptomic, and electron microscopic analyses to demonstrate that mast cells are aberrantly activated in human and murine osteoarthritic joint tissues. Using genetic models of mast cell deficiency, we demonstrate that lack of mast cells attenuates osteoarthritis in mice. Using genetic and pharmacologic approaches, we show that the IgE/FcεRI/Syk signaling axis is critical for the development of osteoarthritis. We find that mast cell-derived tryptase induces inflammation, chondrocyte apoptosis, and cartilage breakdown. Our findings demonstrate a central role for IgE-dependent mast cell activation in the pathogenesis of osteoarthritis, suggesting that targeting mast cells could provide therapeutic benefit in human osteoarthritis., Editorial Note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter)., Competing Interests: QW, CL, HR, LR, MT, HW, Ev, NL, MB, NH, EE, FO, LP, NG, SG, CC, JS, YF, SG, WR No competing interests declared, LS Virginia Commonwealth University collects royalties for the tryptase assay licensed to Thermofisher and for tryptase antibodies licensed to Millipore and Santa Cruz, which are shared with Lawrence B Schwartz, who also is a paid consultant for Genentech., (© 2019, Wang et al.)

Background: Clostridioides difficile infection (CDI) is among the most common health care-associated infections in the United States and is increasingly affecting the elderly. Although carbapenem-resistant Enterobacteriaceae (CRE) infections are still relatively uncommon, there are reported increases in the rate of infection for certain strains, such as Klebsiella pneumoniae. This study examines the burden of mortality and morbidity for CDI and CRE infections in the United States and estimates the societal willingness to pay to avoid them., Methods: We use an analytic model to estimate the number of incident cases and associated health outcomes for CDI and CRE infections., Results: The number of CDI and CRE infection incident cases in the United States in 2016, is estimated at 468,567 and 9,620, respectively. These infections result in a total of 17,630 estimated deaths and 8,624 lost quality-adjusted life years among patients who survive per year., Conclusions: Given the significant mortality and morbidity from these infections, the estimated societal willingness to pay to avoid them is high at $176.7 billion per year, of which 93.9% ($166.0 billion) is for CDI. Our estimates far exceed the medical care costs for CDIs and CRE infections reported in the literature despite not capturing the additional costs borne by third-party payers. As incident cases increase or resistant strains develop, the societal willingness to pay is also expected to increase., (Copyright © 2018. Published by Elsevier Inc.)