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Cleaners have an elevated risk for the development or exacerbation of asthma and other respiratory conditions, possibly due to exposure to cleaning products containing volatile organic compounds (VOCs) leading to inflammation and oxidative stress. This pilot study aimed to quantify total personal exposure to VOCs and to assess biomarkers of inflammation and pulmonary oxidative stress in 15 predominantly Hispanic women working as domestic cleaners in San Antonio, Texas, between November 2019 and July 2020. In partnership with a community organization, Domesticas Unidas, recruited women were invited to attend a training session where they were provided 3M 3500 passive organic vapor monitors (badges) and began a 72-hour sampling period at which time they were instructed to wear one badge during the entire period ("AT", for All the Time), a second badge only while they were inside their home ("INS", for INSide), and a third badge only when they were outside their home ("OUT", for OUTside). At the end of the sampling period, women returned the badges and provided blood and exhaled breath condensate (EBC) samples. From the badges, 30 individual VOCs were measured and summed to inform total VOC (TVOC) concentrations, as well as concentrations of the following VOC groups: aromatic hydrocarbons, alkanes, halogenated hydrocarbons, and terpenes. From the blood and EBC samples, concentrations of serum C-reactive protein (CRP) and EBC 8-isoprostane (8-ISP) and pH were quantified. Data analyses included descriptive statistics. The 72-hour average of personal exposure to TVOC was 34.4 ppb and ranged from 9.2-219.5 ppb. The most prevalent class of VOC exposures for most women (66.7%) was terpenes, specifically d-limonene. Overall, most women also experienced higher TVOC concentrations while outside their home (86.7%) as compared to inside their home. Serum CRP concentrations ranged from 0.3-20.3 mg/dL; 8-ISP concentrations ranged from 9.5-44.1 pg/mL; and EBC pH ranged from 7.1-8.6. Overall, this pilot study demonstrated personal VOC exposure among Hispanic domestic cleaners, particularly to d-limonene, which may result from the use of scented cleaning products.

The sediment distribution of per- and polyfluoroalkyl substances (PFAS) along a river to ocean transect was investigated. Samples were collected between September 2017 and October 2019 with targeted quantification of six legacy and replacement PFAS by LC-MS/MS. Total PFAS concentrations ranged from below the LOQ to 7.47 ng per g dry weight with PFOA, PFOS, HFPO-DA and PFMOAA the most frequently detected. Significant correlations (

Background Remote monitoring (RM) can facilitate early detection of subclinical and symptomatic atrial fibrillation (AF), providing an opportunity to evaluate the need for stroke prevention therapies. We aimed to characterize the burden of RM AF alerts and its impact on anticoagulation of patients with device-detected AF. Methods Consecutive patients with a cardiac implantable electronic device, at least one AF episode, undergoing RM were included and assigned an estimated minimum CHA2DS2-VASc score based on age and device type. RM was provided via automated software system, providing rapid alert processing by device specialists and systematic, recurrent prompts for anticoagulation. Results From 7651 individual, 389,188 AF episodes were identified, 3120 (40.8%) permanent pacemakers, 2260 (29.5%) implantable loop recorders (ILRs), 987 (12.9%) implantable cardioverter defibrillators, 968 (12.7%) cardiac resynchronization therapy (CRT) defibrillators, and 316 (4.1%) CRT pacemakers. ILRs transmitted 48.8% of all AF episodes. At twelve-months, 3404 (44.5%) AF 2DS2-VASc score of 2 was assigned to 1704 (63.1%) of the patients with an AF episode of ≥ 6 h, 531 (31.2%) who were not anticoagulated at 12-months, and 1031 (61.6%) patients with an AF episode duration of ≥ 24 h, 290 (28.1%) were not anticoagulated. Conclusions Despite being intensively managed via RM software system incorporating cues for anticoagulation, a substantial proportion of patients with increased stroke risk remained unanticoagulated after a device-detected AF episode of significant duration. These data highlight the need for improved clinical response pathways and an integrated care approach to RM. Trial registration Australian New Zealand Clinical Trial Registry: ACTRN12620001232921. Graphical Abstract

Background Every year, many thousands of travellers return to the United Kingdom (UK) from visits to other countries and some will become unwell due to infections acquired abroad. Many imported infections have similar clinical presentations, such as fever and myalgia, so diagnostic testing is an important tool to improve patient management and outcomes. The aim of this study was to examine the demographics, travel history, presenting symptoms and diagnostic outcomes of referrals to the UK’s specialist diagnostic Rare & Imported Pathogens Laboratory (RIPL) for the period 2015–2020. Methods Anonymised clinical and laboratory data were extracted from RIPL’s Laboratory Information Management System and cleaned prior to descriptive analysis of the data. Travel history data were mapped to one of eight world regions, whereas symptom data were categorised into presenting syndromes. Diagnostic data were categorised as either positive, equivocal or negative. Results During the period 2015–2020, RIPL received 73 951 samples from 53 432 patients suspected of having infections that are rare in the UK. The most common age group for unwell returning travellers was 30–39 years and the most commonly reported travel destination was Southern and SE Asia. Dengue virus was the most diagnosed infection overall, followed by chikungunya, Zika, leptospirosis and spotted fever group Rickettsia. Dengue virus was among the top three most frequent diagnoses for all world regions except Europe and represented 62.5% of all confirmed/probable diagnoses. Conclusions None of the top five infections diagnosed by RIPL in travellers are vaccine-preventable, therefore understanding traveller demographics, destination-specific risk factors and encouraging preventative behaviours is the best available strategy to reduce the number of returning travellers who become infected. Prompt referral of acute samples with a detailed travel history, including purpose of travel and activities undertaken as well as dates and destinations can be a valuable tool in designing public health interventions and diagnostic algorithms.

Inhibiting PD-1:PD-L1 signaling has transformed therapeutic immune restoration. CD4+ T cells sustain immunity in chronic infections and cancer, yet little is known about how PD-1 signaling modulates CD4+ helper T (TH) cell responses or the ability to restore CD4+ TH-mediated immunity by checkpoint blockade. We demonstrate that PD-1:PD-L1 specifically suppressed CD4+ TH1 cell amplification, prevents CD4+ TH1 cytokine production and abolishes CD4+ cytotoxic killing capacity during chronic infection in mice. Inhibiting PD-L1 rapidly restored these functions, while simultaneously amplifying and activating TH1-like T regulatory cells, demonstrating a system-wide CD4–TH1 recalibration. This effect coincided with decreased T cell antigen receptor signaling, and re-directed type I interferon (IFN) signaling networks towards dominant IFN-γ-mediated responses. Mechanistically, PD-L1 blockade specifically targeted defined populations with pre-established, but actively suppressed proliferative potential, with limited impact on minimally cycling TCF-1+ follicular helper T cells, despite high PD-1 expression. Thus, CD4+ T cells require unique differentiation and functional states to be targets of PD-L1-directed suppression and therapeutic restoration. Snell et al. examine the heterogeneity of CD4+ T cells in chronic viral infection, showing that PD-L1 blockade enhances a cytotoxic gene program in antigen-specific TH1 cells and can restore antiviral CD4+ T cell killer function.

Circadian omics analyses present investigators with large amounts of data to consider and many choices for methods of analysis. Visualization is crucial as rhythmicity can take many forms and p-values offer an incomplete picture. Yet statically viewing the entirety of high-throughput datasets is impractical, and there is often limited ability to assess the impact of choices, such as significance threshold cutoffs. Nitecap provides an intuitive and unified web-based solution to these problems. Through highly responsive visualizations, Nitecap enables investigators to see dataset-wide behavior. It supports deep analyses, including comparisons of two conditions. Moreover, it focuses upon ease-of-use and enables collaboration through dataset sharing. As an application, we investigated cross talk between peripheral clocks in adipose and liver tissues and determined that adipocyte clock disruption does not substantially modulate the transcriptional rhythmicity of liver but does advance the phase of core clock gene Bmal1 (Arntl) expression in the liver. Nitecap is available at nitecap.org and is free-to-use.

Hybrid lead halide perovskites have reached comparable efficiencies to state-of-the-art silicon solar cell technologies. However, a remaining key challenge toward commercialization is the resolution of the perovskite device instability. In this work, we identify for the first time the mobile nature of bis(trifluoromethanesulfonyl)imide (TFSI-), a typical anion extensively employed in p-type dopants for 2,2'7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9'spirofluorene (spiro-OMeTAD). We demonstrate that TFSI- can migrate through the perovskite layer via the grain boundaries and accumulate at the perovskite/electron-transporting layer (ETL) interface. Our findings reveal that the migration of TFSI- enhances the device performance and stability, resulting in highly stable p-i-n cells that retain 90% of their initial performance after 1600 h of continuous testing. Our systematic study, which targeted the effect of the nature of the dopant and its concentration, also shows that TFSI- acts as a dynamic defect-healing agent, which self-passivates the perovskite crystal defects during the migration process and thereby decreases nonradiative recombination pathways.

A growing number of analyses presume that distinctive “partisan types” exist in the American public’s eyes in foreign policy, with implications for questions ranging from the ability of leaders to ...

How do concerns about fairness shape foreign policy preferences? In this article, we show that fairness has two faces—one concerning equity, the other concerning equality—and that taking both into account can shed light on the structure of important foreign policy debates. Fielding an original survey on a national sample of Americans, we show that different types of Americans think about fairness in different ways, and that these fairness concerns shape foreign policy preferences: individuals who emphasize equity are far more sensitive to concerns about burden sharing, are far less likely to support US involvement abroad when other countries aren’t paying their fair share, and often support systematically different foreign policies than individuals who emphasize equality. As long as IR scholars focus only on the equality dimension of fairness, we miss much about how fairness concerns matter in world politics.

Background The accurate interpretation of RNA-Seq data presents a moving target as scientists continue to introduce new experimental techniques and analysis algorithms. Simulated datasets are an invaluable tool to accurately assess the performance of RNA-Seq analysis methods. However, existing RNA-Seq simulators focus on modeling the technical biases and artifacts of sequencing, rather than on simulating the original RNA samples. A first step in simulating RNA-Seq is to simulate RNA. Results To fill this need, we developed the Configurable And Modular Program Allowing RNA Expression Emulation (CAMPAREE), a simulator using empirical data to simulate diploid RNA samples at the level of individual molecules. We demonstrated CAMPAREE’s use for generating idealized coverage plots from real data, and for adding the ability to generate allele-specific data to existing RNA-Seq simulators that do not natively support this feature. Conclusions Separating input sample modeling from library preparation/sequencing offers added flexibility for both users and developers to mix-and-match different sample and sequencing simulators to suit their specific needs. Furthermore, the ability to maintain sample and sequencing simulators independently provides greater agility to incorporate new biological findings about transcriptomics and new developments in sequencing technologies. Additionally, by simulating at the level of individual molecules, CAMPAREE has the potential to model molecules transcribed from the same genes as a heterogeneous population of transcripts with different states of degradation and processing (splicing, editing, etc.). CAMPAREE was developed in Python, is open source, and freely available at https://github.com/itmat/CAMPAREE.

Responsiveness to PD-1 blockade depends on a cell subset known as Tpex cells, but how these cells are sustained is less understood. In this issue of Immunity, Dähling et al. show how dendritic cells form a niche for Tpex preservation.

Background For dermatology to effectively address the ever-growing medical needs, longstanding communication barriers across investigators working in different research pillars and practicing clinicians must be improved. To address this problem, trainee-specific programs are now evolving to align their educational landscape across basic science, translational and clinical research programs. Objectives To establish a Skin Investigation Network of Canada (SkIN Canada) training roadmap for the career and skill development of future clinicians, clinican scientists and basic scientists in Canada. This Working Group aims to strengthen and harmonize collaborations and capacity across the skin research community. Methods The Working Group conducted a search of established international academic societies which offered trainee programs with mandates similar to SkIN Canada. Societies’ program items and meetings were evaluated by use of an interview survey and/or the collection of publicly available data. Program logistics, objectives and feedback were assessed for commonalities and factors reported or determined to improve trainee experience. Results Through the various factors explored, the Working Group discovered the need for increasing program accessibility, creating opportunities for soft skill development, emphasizing the importance of current challenges, collecting and responding to feedback, and improving knowledge sharing to bridge pillars of skin research. Conclusions Although improvements have been made to trainee education in recent years, a plurality of approaches exist and many of the underlying roadblocks remain unresolved. To establish fundamental clinician-basic scientist collaboration and training efforts, this Working Group highlights important factors to include and consider in building a trainee program and emphasizes the importance of trainee education.

Serial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited data exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations in BRCA2 are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations and B2M loss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity and resistance. We identified the upregulated expression of PLA2G2D, an immune-regulating phospholipase, as a potential biomarker of adaptive resistance to ICB. Together, these findings provide insights into the diversity of immunogenomic mechanisms that underpin pembrolizumab outcomes., Although circulating tumour DNA (ctDNA) can predict immune checkpoint blockade (ICB) responses, its association with tumour biomarkers remains unknown. Here, the authors use ctDNA to inform exome and transcriptome profiling of >100 patients with 30 cancer types on a single clinical ICB trial and identify tumour microenvironment features associated with response.

Objectives This study sought to evaluate the effect of weight loss on the atrial substrate for atrial fibrillation (AF). Background Whether weight loss can reverse the atrial substrate of ...

Wet deposition and dry deposition of legacy per- and polyfluoroalkyl substances (PFAS) and perfluoroalkyl ether carboxylic acids (PFECAs) were assessed on the southeastern coast of the United States, specifically, in Wilmington, NC, which is located 110 km from a fluorochemical manufacturer. Analytes were quantified by liquid chromatography coupled to electrospray ionization with triple-quadrupole mass spectrometry. Total concentrations of six PFAS compounds ranged from below the method quantification limit to 110 ng L–¹ by wet deposition, and total fluxes of 0.3–29 ng m–² day–¹ by dry deposition were found. The estimated annual flux of all six PFAS was 30 μg m–² by wet deposition and 1.4 μg m–² by dry deposition, indicating that PFAS are more effectively removed from the atmosphere by wet deposition. There was a significant rainout/washout effect observed in our data, but there was no impact of the origin of the air mass on concentration or flux, suggesting that the incorporation of PFAS into rainwater is a relatively local phenomenon. This study shows the first direct evidence of PFECAs in wet and dry deposition. The data suggest that the particle-bound and gas-phase PFAS that may have undergone long-range transport can be incorporated into raindrops and removed rapidly.

The COVID-19 pandemic has been a major cause of mortality worldwide While respiratory pathology seems to be the major mechanism of disease, cardiovascular pathology has increasingly been reported to play a role in adverse outcomes A variety of different cardiovascular histopathologies have been reported at postmortem examination including myocarditis Because of limited autopsy numbers and lack of standardized reporting of such cases, however, the prevalence of COVID-19 (2019 coronavirus disease)-associated myocarditis is unknown The current autopsy case report illustrates how COVID-19 pulmonary pathology can be accompanied by right ventricular myocarditis The discussion reviews the pathophysiology of myocarditis, as well as diagnostic strategies, adding to the growing body of literature describing myocarditis in association with COVID-19 disease

The sedimentary fate of hexafluoropropylene oxide dimer acid (HFPO-DA) was investigated over a 12 week time series in HFPO-DA-amended (600 ng of spike addition) freshwater and estuarine tidal sedim...

Introduction Understanding the effectiveness and durability of protection against SARS-CoV-2 infection conferred by previous infection and COVID-19 is essential to inform ongoing management of the pandemic. This study aims to determine whether prior SARS-CoV-2 infection or COVID-19 vaccination in healthcare workers protects against future infection. Methods and analysis This is a prospective cohort study design in staff members working in hospitals in the UK. At enrolment, participants are allocated into cohorts, positive or naïve, dependent on their prior SARS-CoV-2 infection status, as measured by standardised SARS-CoV-2 antibody testing on all baseline serum samples and previous SARS-CoV-2 test results. Participants undergo monthly antibody testing and fortnightly viral RNA testing during follow-up and based on these results may move between cohorts. Any results from testing undertaken for other reasons (eg, symptoms, contact tracing) or prior to study entry will also be captured. Individuals complete enrolment and fortnightly questionnaires on exposures, symptoms and vaccination. Follow-up is 12 months from study entry, with an option to extend follow-up to 24 months. The primary outcome of interest is infection with SARS-CoV-2 after previous SARS-CoV-2 infection or COVID-19 vaccination during the study period. Secondary outcomes include incidence and prevalence (both RNA and antibody) of SARS-CoV-2, viral genomics, viral culture, symptom history and antibody/neutralising antibody titres. Ethics and dissemination The study was approved by the Berkshire Research Ethics Committee, Health Research Authority (IRAS ID 284460, REC reference 20/SC/0230) on 22 May 2020; the vaccine amendment was approved on 12 January 2021. Participants gave informed consent before taking part in the study. Regular reports to national and international expert advisory groups and peer-reviewed publications ensure timely dissemination of findings to inform decision making. Trial registration number NCT11041050.

Intracellular RIG-I receptors represent key innate sensors of RNA virus infection, and RIG-I activation results in the induction of hundreds of host effector genes, including interferon-stimulated genes (ISGs). Synthetic RNA agonists targeting RIG-I have shown promise as antivirals against a broad spectrum of viruses, including influenza A virus (IAV), in both in vitro and mouse models of infection. Herein, we demonstrate that treatment of a ferret airway epithelial (FRL) cell line with a RIG-I agonist rapidly and potently induced expression of a broad range of ISGs and resulted in potent inhibition of growth of different IAV strains. In ferrets, a single intravenous injection of RIG-I agonist was associated with upregulated ISG expression in peripheral blood mononuclear cells and lung tissue, but not in nasal tissues. In a ferret model of viral contact transmission, a single treatment of recipient animals 24 h prior to cohousing with IAV-infected donors did not reduce virus transmission and shedding but did result in reduced lung virus titers 6 days after treatment. A single treatment of the IAV-infected donor animals also resulted in reduced virus titers in the lungs 2 days later. Thus, a single intravenous treatment with RIG-I agonist prior to infection or to ferrets with an established IAV infection can reduce virus growth in the lungs. These findings support further development of RIG-I agonists as effective antiviral treatments to limit the impact of IAV infections, particularly in reducing virus replication in the lower airways. IMPORTANCE RIG-I agonists have shown potential as broad-spectrum antivirals in vitro and in mouse models of infection. However, their antiviral potential has not been reported in outbred animals such as ferrets, which are widely regarded as the gold standard small animal model for human IAV infections. Herein, we demonstrate that RIG-I agonist treatment of a ferret airway cell line resulted in ISG induction and inhibition of a broad range of human influenza viruses. A single intravenous treatment of ferrets also resulted in systemic induction of ISGs, including in lung tissue, and when delivered to animals prior to IAV exposure or to animals with established IAV infection treatment resulted in reduced virus replication in the lungs. These data demonstrate the effectiveness of single RIG-I treatment against IAV in the ferret model and highlight the importance of future studies to optimize treatment regimens and delivery routes to maximize their ability to ameliorate IAV infections.